Journal of Medical Genetics最新文献

{"title":"A comparative medical genomics approach may facilitate the interpretation of rare missense variation.","authors":"Bushra Haque, George Guirguis, Meredith Curtis, Hera Mohsin, Susan Walker, Michelle M Morrow, Gregory Costain","doi":"10.1136/jmg-2023-109760","DOIUrl":"10.1136/jmg-2023-109760","url":null,"abstract":"<p><strong>Purpose: </strong>To determine the degree to which likely causal missense variants of single-locus traits in domesticated species have features suggestive of pathogenicity in a human genomic context.</p><p><strong>Methods: </strong>We extracted missense variants from the Online Mendelian Inheritance in Animals database for nine animals (cat, cattle, chicken, dog, goat, horse, pig, rabbit and sheep), mapped coordinates to the human reference genome and annotated variants using genome analysis tools. We also searched a private commercial laboratory database of genetic testing results from >400 000 individuals with suspected rare disorders.</p><p><strong>Results: </strong>Of 339 variants that were mappable to the same residue and gene in the human genome, 56 had been previously classified with respect to pathogenicity: 31 (55.4%) pathogenic/likely pathogenic, 1 (1.8%) benign/likely benign and 24 (42.9%) uncertain/other. The odds ratio for a pathogenic/likely pathogenic classification in ClinVar was 7.0 (95% CI 4.1 to 12.0, p<0.0001), compared with all other germline missense variants in these same 220 genes. The remaining 283 variants disproportionately had allele frequencies and REVEL scores that supported pathogenicity.</p><p><strong>Conclusion: </strong>Cross-species comparisons could facilitate the interpretation of rare missense variation. These results provide further support for comparative medical genomics approaches that connect big data initiatives in human and veterinary genetics.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"817-821"},"PeriodicalIF":3.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140175023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive preimplantation genetic testing for balanced insertional translocation carriers.","authors":"Shuo Zhang, Zhenle Pei, Min Xiao, Jing Zhou, Bin Hu, Saijuan Zhu, Xiaoxi Sun, Junping Wu, Caixia Lei, Congjian Xu","doi":"10.1136/jmg-2024-109851","DOIUrl":"10.1136/jmg-2024-109851","url":null,"abstract":"<p><strong>Background: </strong>Balanced insertional translocations (BITs) can increase the risk of infertility, recurrent miscarriages or neonatal birth defects due to chromosomal imbalances in gametes. However, studies on preimplantation genetic testing (PGT) for patients carrying BITs are inadequate.</p><p><strong>Methods: </strong>A preimplantation genetic genotyping and haplotype analysis approach was developed and implemented in this study. Genome-wide SNP genotyping was performed, followed by core family-based haplotype analysis. The balanced insertion segments in euploid embryos were inferred from the haplotypes inherited from the carrier parent.</p><p><strong>Results: </strong>A total of 10 BIT carrier couples were enrolled in our study. 15 in vitro fertilisation cycles were conducted, resulting in 73 blastocysts biopsied and subjected to PGT analysis. Among these, 20 blastocysts displayed rearrangement-related imbalances, 13 exhibited de novo aneuploidies, 15 presented a complex anomaly involving both imbalances and additional aneuploidies, while 25 were euploid. Within the euploid embryos, 12 were balanced carrier embryos and 13 were non-carrier embryos. To date, eight non-carrier and one carrier embryos have been transferred, resulting in seven clinical pregnancies. All pregnancies were recommended to perform prenatal diagnosis, our date revealed complete concordance between fetal genetic testing results and PGT results. Presently, five infants have been born from these pregnancies, and two pregnancies are still ongoing.</p><p><strong>Conclusion: </strong>The proposed method facilitates comprehensive chromosome screening and the concurrent identification of balanced insertions or normal karyotypes in embryos. This study offers an effective and universally applicable strategy for BIT carriers to achieve a healthy pregnancy and prevent the transmission of BITs to their offspring.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"794-802"},"PeriodicalIF":3.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141158143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Guidelines for NGS procedures applied to prenatal diagnosis by the Spanish Society of Gynecology and Obstetrics and the Spanish Association of Prenatal Diagnosis.","authors":"Anna Abulí, Eugenia Antolín, Antoni Borrell, Maria Garcia-Hoyos, Fe García Santiago, Irene Gómez Manjón, Nerea Maíz, Cristina González González, Laia Rodríguez-Revenga, Irene Valenzuena Palafoll, Javier Suela","doi":"10.1136/jmg-2024-109878","DOIUrl":"10.1136/jmg-2024-109878","url":null,"abstract":"<p><strong>Objective: </strong>This document addresses the clinical application of next-generation sequencing (NGS) technologies for prenatal genetic diagnosis and aims to establish clinical practice recommendations in Spain to ensure uniformity in implementing these technologies into prenatal care.</p><p><strong>Methods: </strong>A joint committee of expert obstetricians and geneticists was created to review the existing literature on fetal NGS for genetic diagnosis and to make recommendations for Spanish healthcare professionals.</p><p><strong>Results: </strong>This guideline summarises technical aspects of NGS technologies, clinical indications in prenatal setting, considerations regarding findings to be reported, genetic counselling considerations as well as data storage and protection policies.</p><p><strong>Conclusions: </strong>This document provides updated recommendations for the use of NGS diagnostic tests in prenatal diagnosis. These recommendations should be periodically reviewed as our knowledge of the clinical utility of NGS technologies, applied during pregnancy, may advance.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"727-733"},"PeriodicalIF":3.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141247235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterozygous deletion of <i>HOXC10-HOXC9</i> causes lower limb abnormalities in congenital vertical talus.","authors":"Liheng Chen, Shuoyang Zhao, Wenxia Song, Lihong Wang, Zerong Yao, Jianfei Gao, Xiaoze Li","doi":"10.1136/jmg-2023-109656","DOIUrl":"10.1136/jmg-2023-109656","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"777-779"},"PeriodicalIF":3.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139650910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Validation of the BOADICEA model in a prospective cohort of <i>BRCA1/2</i> pathogenic variant carriers.","authors":"Xin Yang, Thea M Mooij, Goska Leslie, Lorenzo Ficorella, Nadine Andrieu, Karin Kast, Christian F Singer, Anna Jakubowska, Carla H van Gils, Yen Y Tan, Christoph Engel, Muriel A Adank, Christi J van Asperen, Margreet G E M Ausems, Pascaline Berthet, Margriet J Collee, Jackie A Cook, Jacqueline Eason, Karin Y van Spaendonck-Zwarts, D Gareth Evans, Encarna B Gómez García, Helen Hanson, Louise Izatt, Zoe Kemp, Fiona Lalloo, Christine Lasset, Fabienne Lesueur, Hannah Musgrave, Sophie Nambot, Catherine Noguès, Jan C Oosterwijk, Dominique Stoppa-Lyonnet, Marc Tischkowitz, Vishakha Tripathi, Marijke R Wevers, Emily Zhao, Flora E van Leeuwen, Marjanka K Schmidt, Douglas F Easton, Matti A Rookus, Antonis C Antoniou","doi":"10.1136/jmg-2024-109943","DOIUrl":"10.1136/jmg-2024-109943","url":null,"abstract":"<p><strong>Background: </strong>No validation has been conducted for the BOADICEA multifactorial breast cancer risk prediction model specifically in <i>BRCA1/2</i> pathogenic variant (PV) carriers to date. Here, we evaluated the performance of BOADICEA in predicting 5-year breast cancer risks in a prospective cohort of <i>BRCA1/2</i> PV carriers ascertained through clinical genetic centres.</p><p><strong>Methods: </strong>We evaluated the model calibration and discriminatory ability in the prospective TRANsIBCCS cohort study comprising 1614 <i>BRCA1</i> and 1365 <i>BRCA2</i> PV carriers (209 incident cases). Study participants had lifestyle, reproductive, hormonal, anthropometric risk factor information, a polygenic risk score based on 313 SNPs and family history information.</p><p><strong>Results: </strong>The full multifactorial model considering family history together with all other risk factors was well calibrated overall (E/O=1.07, 95% CI: 0.92 to 1.24) and in quintiles of predicted risk. Discrimination was maximised when all risk factors were considered (Harrell's C-index=0.70, 95% CI: 0.67 to 0.74; area under the curve=0.79, 95% CI: 0.76 to 0.82). The model performance was similar when evaluated separately in <i>BRCA1</i> or <i>BRCA2</i> PV carriers. The full model identified 5.8%, 12.9% and 24.0% of <i>BRCA1/2</i> PV carriers with 5-year breast cancer risks of <1.65%, <3% and <5%, respectively, risk thresholds commonly used for different management and risk-reduction options.</p><p><strong>Conclusion: </strong>BOADICEA may be used to aid personalised cancer risk management and decision-making for <i>BRCA1</i> and <i>BRCA2</i> PV carriers. It is implemented in the free-access CanRisk tool (https://www.canrisk.org/).</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"803-809"},"PeriodicalIF":3.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141247237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variant classification changes over time in the clinical molecular diagnostic laboratory setting.","authors":"Elan Hahn, Chloe Mighton, Yael Fisher, Andrew Wong, Vanessa Di Gioacchino, Nicholas Watkins, Justin Mayers, Yvonne Bombard, George S Charames, Jordan Lerner-Ellis","doi":"10.1136/jmg-2023-109772","DOIUrl":"10.1136/jmg-2023-109772","url":null,"abstract":"<p><strong>Background: </strong>Variant classification in the setting of germline genetic testing is necessary for patients and their families to receive proper care. Variants are classified as pathogenic (P), likely pathogenic (LP), uncertain significance (VUS), likely benign (LB) and benign (B) using the standards and guidelines recommended by the American College of Medical Genetics and the Association for Molecular Pathology, with modifications for specific genes. As the literature continues to rapidly expand, and evidence continues to accumulate, prior classifications can be updated accordingly. In this study, we aim to characterise variant reclassifications in Ontario.</p><p><strong>Methods: </strong>DNA samples from patients seen at hereditary cancer clinics in Ontario from January 2012 to April 2022 were submitted for testing. Patients met provincial eligibility criteria for testing for hereditary cancer syndromes or polycystic kidney disease. Reclassification events were determined to be within their broader category of significance (B to LB or vice versa, or P to LP or vice versa) or outside of their broader category as significance (ie, significant reclassifications from B/LB or VUS or P/LP, from P/LP to VUS or B/LB, or from VUS to any other category).</p><p><strong>Results: </strong>Of the 8075 unique variants included in this study, 23.7% (1912) of variants were reassessed, and 7.2% (578) of variants were reclassified. Of these, 351 (60.7%) variants were reclassified outside of their broader category of significance. Overall, the final classification was significantly different for 336 (58.1%) variants. Importantly, most reclassified variants were downgraded to a more benign classification (n=245; 72.9%). Of note, most reclassified VUS was downgraded to B/LB (n=233; 84.7%).</p><p><strong>Conclusions: </strong>The likelihood for reclassification of variants on reassessment is high. Most reclassified variants were downgraded to a more benign classification. Our findings highlight the importance of periodic variant reassessment to ensure timely and appropriate care for patients and their families.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"788-793"},"PeriodicalIF":3.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141160573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ZFYVE19 deficiency: a ciliopathy involving failure of cell division, with cell death.","authors":"Jing Yang, Ya-Nan Zhang, Ren-Xue Wang, Chen-Zhi Hao, Yiling Qiu, Hao Chi, Wei-Sha Luan, HongYi Tang, Xiu-Juan Zhang, XuXu Sun, Jonathan A Sheps, Victor Ling, Muqing Cao, Jian-She Wang","doi":"10.1136/jmg-2023-109779","DOIUrl":"10.1136/jmg-2023-109779","url":null,"abstract":"<p><strong>Background and aims: </strong>Variants in <i>ZFYVE19</i> underlie a disorder characterised by progressive portal fibrosis, portal hypertension and eventual liver decompensation. We aim to create an animal model to elucidate the pathogenic mechanism.</p><p><strong>Methods: </strong><i>Zfyve19</i> knockout (<i>Zfyve19^-/-</i> ) mice were generated and exposed to different liver toxins. Their livers were characterised at the tissue, cellular and molecular levels. Findings were compared with those in wild-type mice and in ZFYVE19-deficient patients. <i>ZFYVE19</i> knockout and knockdown retinal pigment epithelial-1 cells and mouse embryonic fibroblasts were generated to study cell division and cell death.</p><p><strong>Results: </strong>The <i>Zfyve19^-/-</i> mice were normal overall, particularly with respect to hepatobiliary features. However, when challenged with α-naphthyl isothiocyanate, <i>Zfyve19^-/-</i> mice developed changes resembling those in ZFYVE19-deficient patients, including elevated serum liver injury markers, increased numbers of bile duct profiles with abnormal cholangiocyte polarity and biliary fibrosis. Failure of cell division, centriole and cilia abnormalities, and increased cell death were observed in knockdown/knockout cells. Increased cell death and altered mRNA expression of cell death-related signalling pathways was demonstrated in livers from <i>Zfyve19^-/-</i> mice and patients. Transforming growth factor-β (TGF-β) and Janus kinase-Signal Transducer and Activator of Transcription 3 (JAK-STAT3) signalling pathways were upregulated in vivo, as were chemokines such as C-X-C motif ligands 1, 10 and 12.</p><p><strong>Conclusions: </strong>Our findings demonstrated that ZFYVE19 deficiency is a ciliopathy with novel histological features. Failure of cell division with ciliary abnormalities and cell death activates macrophages and may thus lead to biliary fibrosis via TGF-β pathway in the disease.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"750-758"},"PeriodicalIF":3.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141179442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparing the frequency of variants of uncertain significance (VUS) between ancestry groups in a paediatric epilepsy cohort.","authors":"Bree E Martin, Tristan Sands, Louise Bier, Amanda Bergner, Amelia K Boehme, Natalie Lippa","doi":"10.1136/jmg-2023-109450","DOIUrl":"10.1136/jmg-2023-109450","url":null,"abstract":"<p><strong>Background: </strong>Studies indicate that variants of uncertain significance are more common in non-European populations due to lack of a diversity in population databases. This difference has not been explored in epilepsy, which is increasingly found to be genetic in paediatric populations, and has precision medicine applications. This study examines the differences in the frequency of uncertain next-generation sequencing (NGS) results among a paediatric epilepsy cohort between ancestral groups historically under-represented in biomedical research (UBR) and represented in biomedical research (RBR).</p><p><strong>Methods: </strong>A retrospective chart review of patients with epilepsy seen at Columbia University Irving Medical Center (CUIMC). One hundred seventy-eight cases met the following criteria: (1) visited any provider within the Pediatric Neurology Clinic at CUIMC, (2) had an ICD code indicating a diagnosis of epilepsy, (3) underwent NGS testing after March 2015 and (4) had self-reported ancestry that fit into a single dichotomous category of either historically represented or under-represented in biomedical research.</p><p><strong>Results: </strong>UBR cases had significantly higher rates of uncertain results when compared with RBR cases (79.2% UBR, 20.8% RBR; p value=0.002). This finding remained true after controlling for potential confounding factors, including sex, intellectual disability or developmental delay, epilepsy type, age of onset, number of genes tested and year of testing.</p><p><strong>Conclusion: </strong>Our results add to the literature that individuals who are of ancestries historically under-represented in genetics research are more likely to receive uncertain genetic results than those of represented majority ancestral groups and establishes this finding in an epilepsy cohort.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"645-651"},"PeriodicalIF":3.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140059629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variant characterisation and clinical profile in a large cohort of patients with Ellis-van Creveld syndrome and a family with Weyers acrofacial dysostosis.","authors":"Umut Altunoglu, Adrian Palencia-Campos, Nilay Güneş, Gozde Tutku Turgut, Julian Nevado, Pablo Lapunzina, Maria Valencia, Asier Iturrate, Ghada Otaify, Rasha Elhossini, Adel Ashour, Asmaa K Amin, Rania F Elnahas, Elisa Fernandez-Nuñez, Carmen-Lisset Flores, Pedro Arias, Jair Tenorio, Carlos Israel Chamorro Fernández, Yeliz Güven, Elif Özsu, Beray Selver Eklioğlu, Marisol Ibarra-Ramirez, Birgitte Rode Diness, Birute Burnyte, Houda Ajmi, Zafer Yüksel, Ruken Yıldırım, Edip Ünal, Ebtesam Abdalla, Mona Aglan, Hulya Kayserili, Beyhan Tuysuz, Victor Ruiz-Pérez","doi":"10.1136/jmg-2023-109546","DOIUrl":"10.1136/jmg-2023-109546","url":null,"abstract":"<p><strong>Background: </strong>Ellis-van Creveld syndrome (EvC) is a recessive disorder characterised by acromesomelic limb shortening, postaxial polydactyly, nail-teeth dysplasia and congenital cardiac defects, primarily caused by pathogenic variants in <i>EVC</i> or <i>EVC2</i>. Weyers acrofacial dysostosis (WAD) is an ultra-rare dominant condition allelic to EvC. The present work aimed to enhance current knowledge on the clinical manifestations of EvC and WAD and broaden their mutational spectrum.</p><p><strong>Methods: </strong>We conducted molecular studies in 46 individuals from 43 unrelated families with a preliminary clinical diagnosis of EvC and 3 affected individuals from a family with WAD and retrospectively analysed clinical data. The deleterious effect of selected variants of uncertain significance was evaluated by cellular assays.</p><p><strong>Main results: </strong>We identified pathogenic variants in <i>EVC/EVC2</i> in affected individuals from 41 of the 43 families with EvC. Patients from each of the two remaining families were found with a homozygous splicing variant in <i>WDR35</i> and a de novo heterozygous frameshift variant in <i>GLI3</i>, respectively. The phenotype of these patients showed a remarkable overlap with EvC. A novel <i>EVC2</i> C-terminal truncating variant was identified in the family with WAD. Deep phenotyping of the cohort recapitulated 'classical EvC findings' in the literature and highlighted findings previously undescribed or rarely described as part of EvC.</p><p><strong>Conclusions: </strong>This study presents the largest cohort of living patients with EvC to date, contributing to better understanding of the full clinical spectrum of EvC. We also provide comprehensive information on the <i>EVC</i>/<i>EVC2</i> mutational landscape and add <i>GLI3</i> to the list of genes associated with EvC-like phenotypes.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"633-644"},"PeriodicalIF":3.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140293764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel <i>TUBA4A</i> variant causes congenital myopathy with focal myofibrillar disorganisation.","authors":"Yalan Wan, Chao Zhou, Xingzhi Chang, Liwen Wu, Yilei Zheng, Jiaxi Yu, Li Bai, Mingyue Luan, Meng Yu, Qi Wang, Wei Zhang, Yun Yuan, Jianwen Deng, Zhaoxia Wang","doi":"10.1136/jmg-2023-109786","DOIUrl":"10.1136/jmg-2023-109786","url":null,"abstract":"<p><strong>Background: </strong>Congenital myopathies are a clinical, histopathological and genetic heterogeneous group of inherited muscle disorders that are defined on peculiar architectural abnormalities in the muscle fibres. Although there have been at least 33 different genetic causes of the disease, a significant percentage of congenital myopathies remain genetically unresolved. The present study aimed to report a novel <i>TUBA4A</i> variant in two unrelated Chinese patients with sporadic congenital myopathy.</p><p><strong>Methods: </strong>A comprehensive strategy combining laser capture microdissection, proteomics and whole-exome sequencing was performed to identify the candidate genes. In addition, the available clinical data, myopathological changes, the findings of electrophysiological examinations and thigh muscle MRIs were also reviewed. A cellular model was established to assess the pathogenicity of the <i>TUBA4A</i> variant.</p><p><strong>Results: </strong>We identified a recurrent novel heterozygous de novo c.679C>T (p.L227F) variant in the <i>TUBA4A</i> (NM_006000), encoding tubulin alpha-4A, in two unrelated patients with clinicopathologically diagnosed sporadic congenital myopathy. The prominent myopathological changes in both patients were muscle fibres with focal myofibrillar disorganisation and rimmed vacuoles. Immunofluorescence showed ubiquitin-positive TUBA4A protein aggregates in the muscle fibres with rimmed vacuoles. Overexpression of the L227F mutant TUBA4A resulted in cytoplasmic aggregates which colocalised with ubiquitin in cellular model.</p><p><strong>Conclusion: </strong>Our findings expanded the phenotypic and genetic manifestations of <i>TUBA4A</i> as well as tubulinopathies, and added a new type of congenital myopathy to be taken into consideration in the differential diagnosis.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"626-632"},"PeriodicalIF":3.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139983116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}