Journal of Medical Genetics最新文献

{"title":"Reclassification of candidate splicing variants refines clinically conflicting interpretations in <i>SLC26A4</i>-associated hearing loss.","authors":"Yue Liang, Shubin Fang, Xiaoqing Cen, Yueying Wang, Anhai Chen, Lusha Huang, Juan Wang, Wenbin Lei, Guanxia Xiong, Kaitian Chen","doi":"10.1136/jmg-2024-110425","DOIUrl":"10.1136/jmg-2024-110425","url":null,"abstract":"<p><strong>Purpose: </strong>Variants in the human <i>SLC26A4</i> gene are a major cause of hereditary hearing loss. Many splice site variants have been identified, but their pathogenicity is not well understood.</p><p><strong>Methods: </strong>In accordance with the guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, we analysed the spectrum of <i>SLC26A4</i> gene variants. We performed in silico analysis and in vitro splicing assays to evaluate novel or known variants of uncertain significance that may contribute to aberrant alternative splicing.</p><p><strong>Results: </strong>In a cohort of 178 patients carrying <i>SLC26A4</i> variants, selected from 202 hearing loss patients with or without inner ear malformations who underwent <i>SLC26A4</i> gene testing, we identified a total of 50 variants. Among these, 10 intronic variants potentially affecting splicing collectively accounted for 54.8% of the total allele frequency of all identified variant types and were prioritised for messenger RNA (mRNA) splicing analysis. Further investigation demonstrated that four variants led to distinct types of aberrant splicing outcomes. Overall, the clinical significance of seven splice site variants was reclassified, representing at least 4.34% (14/323) of the variants within our cohort.</p><p><strong>Conclusion: </strong>By using the standard classification of <i>SLC26A4</i> variants, our results were able to interpret novel or uncertain <i>SLC26A4</i> gene variants in a pathogenic or benign variant direction. This approach facilitates more refined genetic counselling for patients carrying <i>SLC26A4</i> gene variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"516-522"},"PeriodicalIF":3.5,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012014","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":"Canadian College of Medical Geneticists (CCMG) position statement on the storage of patient genetic and genomic information in electronic health records.","authors":"Anne-Marie Laberge, Nolan D'Souza, Lynette S Penney, Karim Jessa, Lauren Chad","doi":"10.1136/jmg-2025-110629","DOIUrl":"10.1136/jmg-2025-110629","url":null,"abstract":"<p><p>The aim of this document is to provide an updated statement from the Canadian College of Medical Geneticists (CCMG) regarding the current state and some future considerations on the collection, distribution, and storage of genomic information within electronic health records (EHRs), including which aspects of genomic data might warrant special attention. The original version of this document was written by the CCMG Ethics and Public Policy committee in 2010 based on data collected via an online survey of the CCMG membership at the time. It is updated here to reflect the current state of healthcare in 2024, where EHRs are almost ubiquitously used, and genomic medicine has expanded in its breadth and scope. The document was circulated to the general membership for review and feedback and has been approved by the CCMG Board of Directors.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"540-544"},"PeriodicalIF":3.5,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159480","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":"Genotype-phenotype correlations and phenotypic expansion in a case series of ReNU syndrome associated with <i>RNU4-2</i> variants.","authors":"Yukiko Kuroda, Koki Nagai, Yasuhiro Kawai, Takuya Naruto, Harutaka Saijou, Shotaro Morikawa, Tomohide Goto, Mutsumi Sato, Kenji Kurosawa","doi":"10.1136/jmg-2024-110604","DOIUrl":"10.1136/jmg-2024-110604","url":null,"abstract":"<p><p><i>RNU4-2</i> encodes U4 small nuclear RNA (snRNA), a non-coding RNA forming the spliceosome complex via the U4/U6 snRNA duplex. <i>RNU4-2</i> heterozygous variants cause ReNU syndrome, which is characterised by intellectual disability, developmental delay, epilepsy, short stature and distinctive dysmorphic features. ReNU syndrome accounts for 0.4-0.5% of all cases of developmental delay, and <i>RNU4-2</i> variants are located in the T-loop or stem III region of U4 snRNA, of which approximately 80% are the n.64_65insT variant in the T-loop. We identified four Japanese patients (4.3%) with novel and recurrent <i>RNU4-2</i> variants from 93 individuals of developmental delay with negative results from exome sequencing. Genotype-phenotype correlations were observed in the present case series and a literature review. T-loop variants manifested severe developmental delay with more than 70% of cases being non-verbal. Stem III region variants resulted in milder developmental delay with fluent speech and nearly normal gross motor development milestones. In addition, we report a patient demonstrating intractable epilepsy with neurological regression harbouring a novel de novo heterozygous <i>RNU4-2</i> variant (n.66A>G). This report expands the phenotypic spectrum of ReNU syndrome and suggests the presence of phenotypic variability related to variant location.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"531-535"},"PeriodicalIF":3.5,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142737","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 biallelic <i>NUP107</i> variants affect the nuclear pore complex and expand the clinical spectrum to include brain malformations.","authors":"Loisa Dana Bonde, Laura Hecher, Malik Alawi, Kirsten P Forbes, Joseph D Symonds, Mark J Hamilton, Kerstin Kutsche","doi":"10.1136/jmg-2025-110671","DOIUrl":"10.1136/jmg-2025-110671","url":null,"abstract":"<p><p>Biallelic variants in <i>NUP107</i> cause isolated or syndromic steroid-resistant nephrotic syndrome (SRNS), characterised by proteinuria, hypoalbuminaemia and focal segmental glomerulosclerosis that progresses to end-stage renal disease. Patients with syndromic SRNS have microcephaly, developmental delay or intellectual disability and short stature. Simplified gyration is observed in some individuals. We report on a 2-year-old girl with novel biallelic <i>NUP107</i> variants, c.2606G>T; p.(Gly869Val) and c.1576+1G>A, proteinuria and a severe neurodevelopmental disorder with microcephaly, developmental delay, early-onset seizures, sensorineural hearing loss and brain structural anomalies, including simplified gyral pattern and hypoplasia of the corpus callosum, pons, brainstem and cerebellum. NUP107 is part of the NUP107-160 complex, which, together with other proteins termed nucleoporins, forms the nuclear pore complex (NPC). The NPC regulates nucleocytoplasmic transport and other cellular processes. In patient-derived fibroblasts, we identified aberrantly spliced <i>NUP107</i> mRNAs with a frameshift and premature stop codon leading to non-sense-mediated mRNA decay, reduced levels of <i>NUP107</i> transcripts, reduced NUP107 and NUP133 proteins, and a reduced NPC number. In addition, an abnormal nucleolar morphology was found in patient-derived cells. Our functional data support the conclusion that the <i>NUP107</i> variants underlie the patient's phenotype, thereby broadening the clinical spectrum associated with <i>NUP107</i> variants to include abnormal brain development.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"497-501"},"PeriodicalIF":3.5,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143996441","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":"Correction: Expanding the phenotype of Kleefstra syndrome: speech, language and cognition in 103 individuals.","authors":"","doi":"10.1136/jmg-2023-109702.corr1","DOIUrl":"10.1136/jmg-2023-109702.corr1","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"545"},"PeriodicalIF":3.5,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144317081","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":"Ending nuclear weapons, before they end us.","authors":"Chris Zielinski","doi":"10.1136/jmg-2025-110897","DOIUrl":"10.1136/jmg-2025-110897","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"495-496"},"PeriodicalIF":3.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12322440/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078500","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":"<i>RNU4-2</i> monoallelic variants as a leading cause of syndromic neurodevelopmental disorder, including in patients with parental consanguinity.","authors":"Aida M Bertoli-Avella, Christian A Ganoza, Mariana Ferreira, Maryam Najafi, Daniel L Polla, Krishna Kandaswamy, Kornelia Tripolszki, Peter Bauer, Jorge Pinto Basto","doi":"10.1136/jmg-2024-110556","DOIUrl":"10.1136/jmg-2024-110556","url":null,"abstract":"<p><p>We analysed rare variants in the non-coding <i>RNU4-2</i> gene as a potential cause of neurodevelopmental disorder (NDD) and intellectual disability (ID) in a large cohort of individuals enriched for parental consanguinity.Genome sequencing (GS) data from 22 928 individuals in our Biodatabank were queried for rare, monoallelic variants in <i>RNU4-2</i> From these, 4918 patients presented with NDD/ID. Human Phenotype Ontology (HPO)-encoded clinical information was extracted and analysed using the ontologyX R package.Nearly 50% of the 4918 patients with NDD/ID reported parental consanguinity. Eight relevant heterozygous <i>RNU4-2</i> variants were identified in 28 patients. n.64_65insT was the most frequently detected variant (20 patients, 71%), while the remaining variants were found in 1 or 2 patients each (n.65A>G, n.66A>G, n.67A>G, n.70T>C, n.76C>T, n.95C>G and n.135A>C). Four variants are novel or ultra-rare, and two of them are in the 3' stem loops. HPO-based analysis revealed a consistent syndromic phenotype characterised by NDD, abnormal brain morphology, hypotonia, global developmental delay, microcephaly, seizures, atypical behaviour and facial dysmorphism. <i>RNU4-2</i> variants accounted for approximately 0.55% of NDD/ID cases in our full cohort, and 0.25% in the subset of consanguineous patients (all genetic causes included).This study underscores the significance of <i>RNU4-2</i> as a major genetic cause of NDD/ID, extending its relevance to consanguineous patients, where recessive disorders are often suspected. We advocate for the re-evaluation of existing GS data to uncover potential diagnoses and emphasise the importance of GS as a first-tier diagnostic test.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"536-539"},"PeriodicalIF":3.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12322396/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142685","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":"Economic evaluation of personalised versus conventional risk assessment for women who have undergone testing for hereditary breast and ovarian cancer genes: a modelling study.","authors":"Qin Xi, Nichola Fennell, Stephanie Archer, Marc Tischkowitz, Antonis C Antoniou, Stephen Morris","doi":"10.1136/jmg-2024-109948","DOIUrl":"10.1136/jmg-2024-109948","url":null,"abstract":"<p><strong>Background: </strong>The management of women with germline pathogenic variants (GPVs) in breast (BC) and ovarian cancer (OC) susceptibility genes is focused on surveillance and risk-reducing surgery/medication. Most women are assigned an average range of risk and treated accordingly, but it is possible to personalise this. Here, we explore the economic impact of risk personalisation.</p><p><strong>Method: </strong>We compared two strategies for risk stratification for female participants: conventional risk assessment (CRA), which only involves information from genetic testing and personalised risk assessment (PRA), using genetic and non-genetic risk modifiers. Three different versions of PRA were compared, which were combinations of polygenic risk score and questionnaire-based factors. A patient-level Markov model was designed to estimate the overall National Health Service cost and quality-adjusted life years (QALYs) after risk assessment. Results were given for 20 different groups of women based on their GPV status and family history.</p><p><strong>Results: </strong>Across the 20 scenarios, the results showed that PRA was cost-effective compared with CRA using a £20 000 per QALY threshold in women with a GPV in <i>PALB2</i> who have OC or BC+OC family history, and women with a GPV in <i>ATM</i>, <i>CHEK2</i>, <i>RAD51C</i> or <i>RAD51D</i>. For women with a GPV in <i>BRCA1</i> or <i>BRCA2</i>, women with no pathogenic variant and women with a GPV in <i>PALB2</i> who have unknown family history or BC family history, CRA was more cost-effective. PRA was cost-effective compared with CRA in specific situations predominantly associated with moderate-risk BC GPVs (<i>RAD51C</i>/<i>RAD51D</i>/<i>CHEK2</i>/<i>ATM</i>), while CRA was cost-effective compared with PRA predominantly with high-risk BC GPVs (<i>BRCA1</i>/<i>BRCA2</i>/<i>PALB2</i>).</p><p><strong>Conclusion: </strong>PRA was cost-effective in specific situations compared with CRA in the UK for assessment of women with or without GPVs in BC and OC susceptibility genes.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"450-456"},"PeriodicalIF":3.7,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12322399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144006961","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":"Effects of higher-than-expected control population allele frequency on classification of loss-of-function variants in cancer susceptibility genes.","authors":"Miriam J Smith, George J Burghel, D Gareth Evans","doi":"10.1136/jmg-2025-110703","DOIUrl":"10.1136/jmg-2025-110703","url":null,"abstract":"<p><p>A query was sent to the cancer predisposition gene variant database Cancer Variant Interpretation Group UK, on the nonsense variant in NM_032043.3(<i>BRIP1</i>):c.2392C>T,p.(Arg798Ter). The submitter classified this as a variant of uncertain significance, providing very strong variant effect evidence with the intention of adding supporting pedigree information, according to the guidelines used for classification. However, the relatively high population frequency in the UKB cohort of 367/439 920 (0.083%) was a concern as it is higher than expected for the disease frequency, which would reduce the predicted pathogenicity score. This situation highlights the increasing concerns over the use of population data in pathogenicity classification of truncating/loss-of-function (LoF) variants in known cancer predisposition genes, particularly since the addition of UKB control data. Here, we have conducted a series of case-control comparisons for common truncating variants in known breast/ovarian cancer-associated genes, as well as <i>LZTR1</i>-related schwannomatosis, to address this issue using our Manchester cancer screening population compared with controls in UKB data.Our data show strong ORs for these common truncating variants. We propose that for truncating variants in cancer susceptibility genes with a significant case-control OR, apparently conflicting population frequency evidence criteria should be avoided.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"464-466"},"PeriodicalIF":3.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144029917","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":"<i>LSM1</i> c.231+4A>C hotspot variant is associated with a novel neurodevelopmental syndrome: first patient cohort.","authors":"Sivan Reytan Miron, Alina Kurolap, Bassam Abu-Libdeh, Abdel Salam Abu-Libdeh, Clara Velmans, Florian Erger, Vera Riehmer, Tzung-Chien Hsieh, Hellen Lesmann, Adi Reches, Chofit Chai Gadot, Adi Mory, Motee Al-Ashhab, Christian Netzer, Nadirah Damseh, Hagit Baris Feldman","doi":"10.1136/jmg-2024-110574","DOIUrl":"10.1136/jmg-2024-110574","url":null,"abstract":"<p><strong>Background: </strong>The <i>LSM1</i> gene encodes a subunit of the conserved LSM1-7 protein complex involved in messenger RNA (mRNA) metabolism. Variants in the <i>LSM1</i> gene have been described in two separate case reports. The first published report identified the homozygous splice-site variant c.231+4A>C, while the second reported a homozygous missense variant. Nevertheless, variation in <i>LSM1</i> has yet to be established as disease-causing in humans.</p><p><strong>Methods: </strong>Through exome sequencing and detailed phenotyping, we report six syndromic paediatric patients with the homozygous c.231+4A>C variant in the <i>LSM1</i> gene, collected via GeneMatcher. GestaltMatcher was used to analyse facial feature similarity, and real-time quantitative PCR (RT-qPCR) confirmed the splice defect caused by the variant. Haplotype analysis assessed whether this variant resulted from independent occurrences or a common ancestral haplotype.</p><p><strong>Results: </strong>Patients presented with dysmorphic facial features, developmental delay and multisystemic involvement, including urological, cardiac and skeletal manifestations, showcasing the phenotypic spectrum of this syndrome. RT-qPCR confirmed that the c.231+4A>C variant causes exon 3 skipping, producing negligible <i>wild-type LSM1</i> mRNA expression. Elevated mutant isoform expression confirmed pathogenicity according to the American College of Medical Genetics and Genomics (ACMG) guidelines. We identified this variant in the Muslim Arab and Ashkenazi Jewish populations and determined that it represents a hotspot variant through haplotype analysis.</p><p><strong>Conclusion: </strong>Our findings establish <i>LSM1</i>, and specifically the c.231+4A>C homozygous variant, as causative for a novel autosomal recessive syndromic neurodevelopmental disorder. These results expand the understanding of <i>LSM1</i>-related diseases and provide a foundation for further investigation of its molecular mechanisms.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"441-449"},"PeriodicalIF":3.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015469","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}