Journal of Medical Genetics最新文献

{"title":"Novel variants and genotype-phenotype correlation in a multicentre cohort of GNE myopathy in China.","authors":"Kexin Jiao, Jialong Zhang, Qiuxiang Li, Xiaoqing Lv, Yanyan Yu, Bochen Zhu, Huahua Zhong, Xu'en Yu, Jia Song, Qing Ke, Fangyuan Qian, Xinghua Luan, Xiaojie Zhang, Xueli Chang, Liang Wang, Meirong Liu, Jihong Dong, Zhangyu Zou, Bitao Bu, Haishan Jiang, LingChun Liu, Yue Li, Dongyue Yue, Xuechun Chang, Yongsheng Zheng, Ningning Wang, Mingshi Gao, Xingyu Xia, Nachuan Cheng, Tao Wang, Su-Shan Luo, Jianying Xi, Jie Lin, Jiahong Lu, Chongbo Zhao, Huan Yang, Pengfei Lin, Daojun Hong, Zhe Zhao, Zhiqiang Wang, Wenhua Zhu","doi":"10.1136/jmg-2024-110149","DOIUrl":"10.1136/jmg-2024-110149","url":null,"abstract":"<p><strong>Background: </strong>GlcNAc2-epimerase (GNE) myopathy is a rare autosomal recessive disorder caused by pathogenic variants in the <i>GNE</i> gene, which is essential for the sialic acid biosynthesis pathway.</p><p><strong>Objective: </strong>This multi-centre study aimed to delineate the clinical phenotype and <i>GNE</i> variant spectrum in Chinese patients, enhancing our understanding of the genetic diversity and clinical manifestation across different populations.</p><p><strong>Methods: </strong>We retrospectively analysed <i>GNE</i> variants from 113 patients, integrating these data with external <i>GNE</i> variants from online databases for a global perspective, examining their consequences, distribution, ethnicity and severity.</p><p><strong>Results: </strong>This study revealed 97 distinct <i>GNE</i> variants, including 35 (36.08%) novel variants. Two more patients with deep intronic variant c.862+870C>T were identified, while whole genome sequencing (WGS) uncovered another two novel intronic variants: c.52-8924G>T and c.1505-12G>A. Nanopore long reads sequencing (LRS) and further PCR analysis verified a 639 bp insertion at chr9:36249241. Missense variants predominantly located in the epimerase/kinase domain coding region, indicating the impairment of catalytic function as a key pathogenic consequence. Comparative studies with Japanese, Korean and Jewish, our cohorts showed later onset ages by 2 years. The high allele frequency of the non-catalytic <i>GNE</i> variant, c.620A>T, might underlie the milder phenotype of Chinese patients.</p><p><strong>Conclusions: </strong>Comprehensive techniques such as WGS and Nanopore LRS warrants the identifying of <i>GNE</i> variants. Patients with the non-catalytic <i>GNE</i> variant, c.620A>T, had a milder disease progression and later wheelchair use.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"1053-1061"},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348353","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":"Pathogenic <i>SATB2</i> missense variants affecting p.Gly392 have variable functional implications and result in diverse clinical phenotypes.","authors":"Joery den Hoed, Hirokazu Hashimoto, Mubeen Khan, Fleur Semmekrot, Katherine A Bosanko, Chihiro Abe-Hatano, Eiji Nakagawa, Hanka Venselaar, Nada Quercia, Lauren Chad, Hiroshi Kurosaka, Stephane Rondeau, Simon E Fisher, Shinya Yamamoto, Yuri A Zarate","doi":"10.1136/jmg-2024-110015","DOIUrl":"10.1136/jmg-2024-110015","url":null,"abstract":"<p><p><i>SATB2</i>-associated syndrome (SAS) is caused by pathogenic variants in <i>SATB2</i>, which encodes an evolutionarily conserved transcription factor. Despite the broad range of phenotypic manifestations and variable severity related to this syndrome, haploinsufficiency has been assumed to be the primary molecular explanation.In this study, we describe eight individuals with <i>SATB2</i> variants that affect p.Gly392 (four women, age range 2-16 years; p.Gly392Arg, p.Gly392Glu and p.Gly392Val). Of these, individuals with p.Gly392Arg substitutions were found to have more severe neurodevelopmental phenotypes based on an established rubric scoring system when compared with individuals with p.Gly392Glu, p.Gly392Val and other previously reported causative <i>SATB2</i> missense variants. Consistent with the observations at the phenotypic level, using human cell-based and model organism functional data, we documented that while all three described p.Gly392 variants affect the same residue and seem to all have a partial loss-of-function effect, some effects on SATB2 protein function appear to be variant-specific. Our results indicate that genotype-phenotype correlations in SAS are more complex than originally thought, and variant-specific genotype-phenotype correlations are needed.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"1062-1067"},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348354","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":"Genetic findings in people with schwannomas who do not meet clinical diagnostic criteria for <i>NF2</i>-related schwannomatosis.","authors":"Miriam J Smith, Cristina Perez-Becerril, Mwee van der Meer, George J Burghel, Sarah J Waller, Megan Carney, Sancha Bunstone, Katherine Fryer, Naomi L Bowers, Claire L Hartley, Philip T Smith, Scott A Rutherford, Simon R Freeman, Simon K W Lloyd, Omar N Pathmanaban, Andrew Thomas King, Dorothy Halliday, Chris Duff, D Gareth Evans","doi":"10.1136/jmg-2024-110217","DOIUrl":"10.1136/jmg-2024-110217","url":null,"abstract":"<p><strong>Background: </strong>Most schwannomas are isolated tumours occurring in otherwise healthy people. However, bilateral vestibular schwannomas (BVS) or multiple non-vestibular schwannomas indicate an underlying genetic predisposition. This is most commonly <i>NF2</i>-related schwannomatosis (SWN), but when BVS are absent, this can also indicate <i>SMARCB1</i>-related or <i>LZTR1</i>-related SWN.</p><p><strong>Methods: </strong>We assessed the variant detection rates for the three major SWN genes (<i>NF2</i>, <i>LZTR1</i> and <i>SMARCB1</i>) in 154 people, from 150 families, who had at least one non-vestibular schwannoma, but who did not meet clinical criteria for <i>NF2</i>-related SWN at the time of genetic testing.</p><p><strong>Results: </strong>We found that 17 (11%) people from 13 families had a germline <i>SMARCB1</i> variant and 19 (12%) unrelated individuals had a germline <i>LZTR1</i> variant. 19 people had an <i>NF2</i> variant, but 18 of these were mosaic and 17 were only detected when 2 tumours were available for testing. The overall detection rate was 25% using blood alone, but increased to 36% when tumour analysis was included. Another 12 people had a germline variant of uncertain significance (VUS).</p><p><strong>Conclusions: </strong>There were similar proportions of <i>LZTR1</i>, <i>SMARCB1</i> or mosaic <i>NF2</i>. However, since an <i>NF2</i> variant was detected in tumours from 103 people, it is likely that further cases of mosaicism would be detected if more people had additional tumours available for analysis. In addition, if further evidence becomes available to show that the VUSs are pathogenic, this would significantly increase the proportion of people with a genetic diagnosis. Our results indicate the importance of comprehensive genetic testing and improved variant classification.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"1011-1015"},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108225","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":"Histone modifications in Duchenne muscular dystrophy: pathogenesis insights and therapeutic implications.","authors":"Yanning Wei, Yuanyuan Jiang, Yufei Lu, Qiping Hu","doi":"10.1136/jmg-2024-110045","DOIUrl":"10.1136/jmg-2024-110045","url":null,"abstract":"<p><p>Duchenne muscular dystrophy (DMD) is a commonly encountered genetic ailment marked by loss-of-function mutations in the <i>Dystrophin</i> gene, ultimately resulting in progressive debilitation of skeletal muscle. The investigation into the pathogenesis of DMD has increasingly converged on the role of histone modifications within the broader context of epigenetic regulation. These modifications, including histone acetylation, methylation and phosphorylation, are catalysed by specific enzymes and play a critical role in gene expression. This article provides an overview of the histone modifications occurring in DMD and analyses the research progress and potential of different types of histone modifications in DMD due to changes in cellular signalling for muscle regeneration, to provide new insights into diagnostic and therapeutic options for DMD.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"1003-1010"},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348351","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 germline <i>TP53</i> variant (p.(Phe109Ile)) confers high risk of cancer.","authors":"Anna Byrjalsen, Ulrik Kristoffer Stoltze, Charlotte Lautrup, Lise Lotte Christensen, Torben Mikkelsen, Lisa Hjalgrim, Jesper Sune Brok, Christine Dahl, Kjeld Schmiegelow, Lotte Borgwardt, Birgitte Rode Diness, Thomas Van Overeem Hansen, Karin A W Wadt","doi":"10.1136/jmg-2024-110255","DOIUrl":"10.1136/jmg-2024-110255","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"1023-1025"},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348352","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":"Biallelic variants in α-tubulin isotypes cause female infertility characterised as recurrent preimplantation embryo arrest.","authors":"Huiling Hu, Xian Wan, Honghui Zhang, Jiaqi Sun, Fei Meng, Shuoping Zhang, Yifan Gu, Fei Gong, Han Zhao, Ge Lin, Wei Zheng","doi":"10.1136/jmg-2024-110163","DOIUrl":"10.1136/jmg-2024-110163","url":null,"abstract":"<p><strong>Background: </strong>Recurrent preimplantation embryo developmental arrest (RPEA) is the most common phenotype in assisted reproductive technology treatment failure associated with identified genetic abnormalities. Currently known maternal genetic variants explain only a limited number of cases. Variants of the β-tubulin subunit gene, <i>TUBB8</i>, cause oocyte meiotic arrest and RPEA through a broad spectrum of spindle defects. In contrast, α-tubulin subunit genes are poorly studied in the context of preimplantation embryonic development.</p><p><strong>Methods: </strong>Whole exome sequencing was performed on the PREA cohort. Functional characterisations of the identified candidate disease-causing variants were validated using Sanger sequencing, bioinformatics, in vitro functional analyses and single-cell RNA-sequencing of arrested embryos.</p><p><strong>Results: </strong>Four homozygous variants were identified in the PREA cohort: two of <i>TUBA1C</i> (p.Gln358Ter and p.Asp444Metfs*42) and two of <i>TUBA4A</i> (p.Arg339Cys and p.Tyr440Ter). These variants cause varying degrees of spindle assembly defects. Additionally, we characterised changes in the human arrested embryo transcriptome carrying <i>TUBA4A</i> variants, with a particular focus on spindle organisation, chromosome segregation and mRNA decay.</p><p><strong>Conclusion: </strong>Our findings identified <i>TUBA1C</i> as a novel genetic marker and expanded the genetic and phenotypic spectrum of <i>TUBA4A</i> in female infertility and RPEA, which altogether highlighted the importance of α-tubulin isotypes in preimplantation embryonic development.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"1045-1052"},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108224","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":"Male-female phenotype correlation and dissociation related to mutations in the <i>ARX</i> gene.","authors":"Chumei Li Li","doi":"10.1136/jmg-2024-109979","DOIUrl":"10.1136/jmg-2024-109979","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"1068-1069"},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307944","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":"Splice site variants in the canonical donor site of <i>MED13L</i> exon 7 lead to intron retention in patients with <i>MED13L</i> syndrome.","authors":"Jade Fauqueux, Simon Boussion, Caroline Thuillier, Evine Meurisse, Didier Lacombe, Marjolaine Willems, Amélie Piton, Emilie Ait-Yahya, Jamal Ghoumid, Thomas Smol","doi":"10.1136/jmg-2024-110154","DOIUrl":"10.1136/jmg-2024-110154","url":null,"abstract":"<p><p>Pathogenic variants in the <i>MED13L</i> gene are associated with the autosomal dominant <i>MED13L</i> syndrome, which is characterised by global developmental delay and cardiac malformations. We investigated two heterozygous <i>MED13L</i> variants located at the canonical donor splice site motif of exon 7: c.1009+1G>C and c.1009+5G>C. We report that in silico predictions suggested two possible outcomes: exon 7 skipping, resulting in loss of the phosphodegron motif essential for <i>MED13L</i> regulation, or activation of a cryptic donor site in intron 7, leading to intron retention. RNA analysis confirmed that both variants affected the exon 7 splice donor site, resulting in the retention of 73 bp of intron 7. This retention caused a frameshift and premature translation termination, consistent with haploinsufficiency. Our results highlight the importance of combining predictive and experimental approaches to understand the functional impact of splice site variants. These insights into the molecular consequences of <i>MED13L</i> variants provide a deeper understanding of the genetic basis of <i>MED13L</i> syndrome.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"1040-1044"},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055811","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":"Protein-truncating and rare missense variants in <i>ATM</i> and <i>CHEK2</i> and associations with cancer in UK Biobank whole-exome sequence data.","authors":"Toqir K Mukhtar, Naomi Wilcox, Joe Dennis, Xin Yang, Marc Naven, Nasim Mavaddat, John R B Perry, Eugene Gardner, Douglas F Easton","doi":"10.1136/jmg-2024-110127","DOIUrl":"10.1136/jmg-2024-110127","url":null,"abstract":"<p><strong>Background: </strong>Deleterious germline variants in <i>ATM</i> and <i>CHEK2</i> have been associated with a moderately increased risk of breast cancer. Risks for other cancers remain unclear.</p><p><strong>Methods: </strong>Cancer associations for coding variants in <i>ATM</i> and <i>CHEK2</i> were evaluated using whole-exome sequence data from UK Biobank linked to cancer registration data (348 488 participants), and analysed both as a retrospective case-control and a prospective cohort study. Odds ratios, hazard ratios, and combined relative risks (RRs) were estimated by cancer type and gene. Separate analyses were performed for protein-truncating variants (PTVs) and rare missense variants (rMSVs; allele frequency <0.1%).</p><p><strong>Results: </strong>PTVs in <i>ATM</i> were associated with increased risks of nine cancers at p<0.001 (pancreas, oesophagus, lung, melanoma, breast, ovary, prostate, bladder, lymphoid leukaemia (LL)), and three at p<0.05 (colon, diffuse non-Hodgkin's lymphoma (DNHL), rectosigmoid junction). Carriers of rMSVs had increased risks of four cancers (p<0.05: stomach, pancreas, prostate, Hodgkin's disease (HD)). RRs were highest for breast, prostate, and any cancer where rMSVs lay in the FAT or PIK domains, and had a Combined Annotation Dependent Depletion score in the highest quintile.PTVs in <i>CHEK2</i> were associated with three cancers at p<0.001 (breast, prostate, HD) and six at p<0.05 (oesophagus, melanoma, ovary, kidney, DNHL, myeloid leukaemia). Carriers of rMSVs had increased risks of five cancers (p<0.001: breast, prostate, LL; p<0.05: melanoma, multiple myeloma).</p><p><strong>Conclusion: </strong>PTVs in <i>ATM</i> and <i>CHEK2</i> are associated with a wide range of cancers, with the highest RR for pancreatic cancer in <i>ATM</i> PTV carriers. These findings can inform genetic counselling of carriers.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"1016-1022"},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11503094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108128","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":"Lynch syndrome diagnostic testing pathways in endometrial cancers: a nationwide English registry-based study.","authors":"Lucy Loong, Catherine Huntley, Joanna Pethick, Fiona McRonald, Francesco Santaniello, Brian Shand, Oliver Tulloch, Shilpi Goel, Margreet Lüchtenborg, Sophie Allen, Bethany Torr, Katie Snape, Angela George, Fiona Lalloo, Gail Norbury, Diana M Eccles, Marc Tischkowitz, Antonis C Antoniou, Paul Pharoah, Adam Shaw, Eva Morris, John Burn, Kevin Monahan, Steven Hardy, Clare Turnbull","doi":"10.1136/jmg-2024-110231","DOIUrl":"https://doi.org/10.1136/jmg-2024-110231","url":null,"abstract":"<p><strong>Background: </strong>For female patients with Lynch syndrome (LS), endometrial cancer (EC) is often their first cancer diagnosis. A testing pathway of somatic tumour testing triage followed by germline mismatch repair (MMR) gene testing is an effective way of identifying the estimated 3% of EC caused by LS.</p><p><strong>Methods: </strong>A retrospective national population-based observational study was conducted using comprehensive national data collections of functional, somatic and germline MMR tests available via the English National Cancer Registration Dataset. For all EC diagnosed in 2019, the proportion tested, median time to test, yield of abnormal results and factors influencing testing pathway initiation were examined.</p><p><strong>Results: </strong>There was an immunohistochemistry (IHC) or microsatellite instability (MSI) test recorded for 17.8% (1408/7928) of patients diagnosed with EC in 2019. Proportions tested varied by Cancer Alliance and age. There was an <i>MLH1</i> promoter hypermethylation test recorded for 43.1% (149/346) of patients with MLH1 protein IHC loss or MSI. Of patients with EC eligible from tumour-testing, 25% (26/104) had a germline MMR test recorded. Median time from cancer diagnosis to germline MMR test was 315 days (IQR 222-486).</p><p><strong>Conclusion: </strong>This analysis highlights the regional variation in recorded testing, patient attrition, delays and missed opportunities to diagnose LS, providing an informative baseline for measuring the impact of the national guidance from the National Institute for Health and Care Excellence on universal reflex LS testing in EC, implemented in 2020.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467715","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}