Journal of Medical Genetics最新文献

{"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":"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":"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":"Loss-of-function variants in <i>JPH1</i> cause congenital myopathy with prominent facial and ocular involvement.","authors":"Mridul Johari, Ana Topf, Chiara Folland, Jennifer Duff, Lein Dofash, Pilar Marti, Thomas Robertson, Juan Vilchez, Anita Cairns, Elizabeth Harris, Chiara Marini-Bettolo, Khalid Hundallah, Amal M Alhashem, Mohammed Al-Owain, Reza Maroofian, Gianina Ravenscroft, Volker Straub","doi":"10.1136/jmg-2024-109970","DOIUrl":"10.1136/jmg-2024-109970","url":null,"abstract":"<p><strong>Background: </strong>Weakness of facial, ocular and axial muscles is a common clinical presentation in congenital myopathies caused by pathogenic variants in genes encoding triad proteins. Abnormalities in triad structure and function resulting in disturbed excitation-contraction coupling and Ca²⁺ homeostasis can contribute to disease pathology.</p><p><strong>Methods: </strong>We analysed exome and genome sequencing data from four unrelated individuals with congenital myopathy characterised by facial, ocular and bulbar involvement. We collected deep phenotypic data from the affected individuals. We analysed the RNA-sequencing (RNA-seq) data of F3-II.1 and performed gene expression outlier analysis in 129 samples.</p><p><strong>Results: </strong>The four probands had a remarkably similar clinical presentation with prominent facial, ocular and bulbar features. Disease onset was in the neonatal period with hypotonia, poor feeding, cleft palate and talipes. Muscle weakness was generalised but prominent in the lower limbs with facial weakness also present. All patients had myopathic facies, bilateral ptosis, ophthalmoplegia and fatigability. Muscle biopsy on light microscopy showed type 1 myofiber predominance and ultrastructural analysis revealed slightly reduced triads, and structurally abnormal sarcoplasmic reticulum.DNA sequencing identified four unique homozygous loss-of-function variants in <i>JPH1</i>, encoding junctophilin-1 in the four families; one stop-gain (c.354C>A;p.Tyr118*) and three frameshift (c.373delG;p.Asp125Thrfs*30, c.1738delC;p.Leu580Trpfs*16 and c.1510delG;p. Glu504Serfs*3) variants. Muscle RNA-seq showed strong downregulation of <i>JPH1</i> in the F3 proband.</p><p><strong>Conclusions: </strong>Junctophilin-1 is critical for the formation of skeletal muscle triad junctions by connecting the sarcoplasmic reticulum and T-tubules. Our findings suggest that loss of <i>JPH1</i> results in a congenital myopathy with prominent facial, bulbar and ocular involvement.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"992-998"},"PeriodicalIF":3.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11503096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108227","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":"Novel truncating germline variant reinforces <i>TINF2</i> as a susceptibility gene for familial non-medullary thyroid cancer.","authors":"Josep Oriola, Orland Díez, Mireia Mora, Irene Halperin, Sandra Martínez, Miriam Masas, Anna Tenes, Anna Bernal, Rafael Duran, Aida Orois","doi":"10.1136/jmg-2024-110185","DOIUrl":"10.1136/jmg-2024-110185","url":null,"abstract":"<p><strong>Background: </strong>It has long been observed that there are families in which non-medullary thyroid cancer (NMTC) occurs, but few syndromes and genes have been described to date. Proteins in the shelterin complex have been implied in cancer. Here, we have studied shelterin genes in families affected by NMTC (FNMTC).</p><p><strong>Methods: </strong>We performed whole-exome sequencing (WES) in 10 affected individuals from four families with at least three affected members. Polymerase chain reaction (PCR) and Sanger sequencing were performed to search for variants in the <i>TINF2</i> gene in 40 FNMTC families. TINF2 transcripts and loss of heterozygosity (LOH) were studied in several affected patients of one family.</p><p><strong>Results: </strong>We found the c.507G>T variant in heterozygosis in the <i>TINF2</i> gene in one family, co-segregating in all five affected members. This variant affects the normal splicing. LOH was not observed.</p><p><strong>Conclusions: </strong>Our results reinforce the <i>TINF2</i> gene as a susceptibility cause of FNMTC suggesting the importance of location of frameshift variants in <i>TINF2</i>. According to our data and previous literature, <i>TINF2</i> pathogenic variants appear to be a significant risk factor for the development of NMTC and/or melanoma.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"939-942"},"PeriodicalIF":3.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893590","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":"Genetics of prostate cancer: a review of latest evidence.","authors":"Rose Hall, Elizabeth Bancroft, Nora Pashayan, Zsofia Kote-Jarai, Rosalind A Eeles","doi":"10.1136/jmg-2024-109845","DOIUrl":"10.1136/jmg-2024-109845","url":null,"abstract":"<p><p>Prostate cancer (PrCa) is a largely heritable and polygenic disease. It is the most common cancer in people with prostates (PwPs) in Europe and the USA, including in PwPs of African descent. In the UK in 2020, 52% of all cancers were diagnosed at stage I or II. The National Health Service (NHS) long-term plan is to increase this to 75% by 2028, to reduce absolute incidence of late-stage disease. In the absence of a UK PrCa screening programme, we should explore how to identify those at increased risk of clinically significant PrCa.Incorporating genomics into the PrCa screening, diagnostic and treatment pathway has huge potential for transforming patient care. Genomics can increase efficiency of PrCa screening by focusing on those with genetic predisposition to cancer-which when combined with risk factors such as age and ethnicity, can be used for risk stratification in risk-based screening (RBS) programmes. The goal of RBS is to facilitate early diagnosis of clinically significant PrCa and reduce overdiagnosis/overtreatment in those unlikely to experience PrCa-related symptoms in their lifetime. Genetic testing can guide PrCa management, by identifying those at risk of lethal PrCa and enabling access to novel targeted therapies.PrCa is curable if diagnosed below stage III when most people do not experience symptoms. RBS using genetic profiling could be key here if we could show better survival outcomes (or reduction in cancer-specific mortality accounting for lead-time bias), in addition to more cost efficiency than age-based screening alone. Furthermore, PrCa outcomes in underserved communities could be optimised if genetic testing was accessible, minimising health disparities.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"915-926"},"PeriodicalIF":3.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975878","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}