Journal of Medical Genetics最新文献

{"title":"Six at Sixty. Commentary on osteogenesis imperfecta 1975-2025.","authors":"David Sillence","doi":"10.1136/jmg-2025-110807","DOIUrl":"https://doi.org/10.1136/jmg-2025-110807","url":null,"abstract":"<p><p>Between 1975 and 1977, my collaborators and I conducted a whole-of-population study in Victoria, Australia, examining the various presentations and clinical manifestations of osteogenesis imperfecta (OI) and familial forms of bone fragility. In 1975, the prevailing view was that all presentations of OI reflected variable expression of pathogenic genomic variants at a single gene locus-possibly involving the recently identified protein, type I collagen. We concluded that OI was in fact genetically heterogeneous, setting the scene for future biochemical and genomic discoveries. Currently, OI is recognised to result from pathological variants in >20 genes, with variants in many further loci resulting in related forms of familial osteoporosis or special syndromes characterised by bone fragility. A dyadic nosology has been adopted to help clinicians, researchers and affected individuals in accessing OI diagnosis, treatment and research with a focus on precision medicine.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":"62 6","pages":"422-426"},"PeriodicalIF":3.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159486","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":"https://doi.org/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":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-24","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":"RNU4-2 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":"https://doi.org/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":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Incidence of positive genetic testing among patients referred for cardiac positron emission tomography.","authors":"Kathleen Trinh, Annika Dries, Kristin Boulier, Jessica Wang","doi":"10.1136/jmg-2025-110626","DOIUrl":"https://doi.org/10.1136/jmg-2025-110626","url":null,"abstract":"<p><strong>Background: </strong>Positron emission tomography-CT (PET-CT) is widely used to diagnose cardiac sarcoidosis (CS). Emerging evidence suggests genetic arrhythmogenic cardiomyopathies (ACMs) may similarly present with episodes of myocardial inflammation resembling CS. We hypothesise a high rate of ACM diagnosis and associated pathogenic variants in patients with positive cardiac PET-CT scans referred for genetic testing. This study also seeks to delineate the role of PET-CT and anti-inflammatory therapy in ACM.</p><p><strong>Methods: </strong>Patients at the UCLA Cardiovascular Genetics Clinic who underwent a cardiomyopathy gene panel were included. Genotypes were classified as genotype-positive (pathogenic or likely pathogenic variants), uncertain (variant of uncertain significance) or negative. Genes were grouped into ACM or non-ACM. PET-CT positivity was defined by cardiac fludeoxyglucose uptake without extracardiac involvement.</p><p><strong>Results: </strong>Among 48 patients receiving PET-CT scans, 48% (23/48) were genotype-positive. Of 268 patients with pathogenic/likely pathogenic variants, 23 (8.6%) underwent PET-CT (11 ACM, 12 non-ACM). PET-CT positivity was observed in 27% (3/11) of ACM and 8% (1/12) of non-ACM cases. Two PET-CT-positive patients (<i>FLNC</i>, <i>MYH7</i>) received steroids with variable outcomes.</p><p><strong>Conclusion: </strong>Receiving a PET-CT scan yielded a high genetic diagnostic yield (48%) in our clinic. Randomised controlled trials of immunosuppressive responsiveness and novel therapeutics are needed to address treatment gaps for ACM.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127869","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":"Contemporary practice and resource availability for genetic testing in paediatric hypertrophic cardiomyopathy.","authors":"Christoph Sandmann, Sabine Klaassen, Juan Pablo Kaski, Gabrielle Norrish","doi":"10.1136/jmg-2025-110696","DOIUrl":"https://doi.org/10.1136/jmg-2025-110696","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086238","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":"https://doi.org/10.1136/jmg-2025-110897","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and genetic characteristics of <i>PLA2G6</i>-related parkinsonism in Southwest China and a comprehensive literature review.","authors":"Yangfan Cheng, Yang Zhang, Yi Xiao, Shichan Wang, Sihui Chen, Xiaoting Zheng, Tianmi Yang, Qirui Jiang, Jingxuan Huang, Junyu Lin, Ruwei Ou, Chunyu Li, Qianqian Wei, Xueping Chen, Huifang Shang","doi":"10.1136/jmg-2024-110479","DOIUrl":"https://doi.org/10.1136/jmg-2024-110479","url":null,"abstract":"<p><strong>Background: </strong>Biallelic <i>PLA2G6</i> mutations are associated with early onset autosomal recessive parkinsonism, exhibiting a broad spectrum of clinical heterogeneity.</p><p><strong>Objective: </strong>To comprehensively characterise the clinical, imaging and genetic features of <i>PLA2G6</i>-related parkinsonism.</p><p><strong>Methods: </strong>We report 14 new cases of <i>PLA2G6</i>-related parkinsonism in Southwest China and conduct a systematic literature review.</p><p><strong>Results: </strong>Among the 14 patients in our cohort, 16 <i>PLA2G6</i> variants were identified, including seven novel and nine previously reported variants. The mean age at symptom onset was 26.50±6.57 years. The most common initial presentation was parkinsonism (9/14, 64.3%), followed by gait disturbance (6/14, 42.9%) and psychiatric symptoms (1/14, 7.1%). A literature review identified 118 patients with <i>PLA2G6</i>-related parkinsonism, with a mean age at onset of 24.53±8.84 years. The most common initial clinical features included parkinsonism (61/117, 52.1%), cerebellar signs (46/85, 54.1%), cognitive impairment (65/92, 70.7%) and psychiatric symptoms (80/93, 86.0%). Subgroup analysis showed that the mean age at symptom onset was older in Chinese patients (26.65±7.08 years) compared with those of European ancestry (20.83±9.79 years) (p=0.016). Additionally, patients of European ancestry showed delayed parkinsonism 5.35±8.14 years after onset. Iron deposition was reported more frequently in patients of European ancestry (10/16, 62.5%) than that in Chinese patients (6/37, 16.2%) (p=0.0002).</p><p><strong>Conclusion: </strong>Our study provides new insights on the diverse clinical spectrum of <i>PLA2G6</i>-related parkinsonism, encompassing parkinsonian features, psychiatric symptoms, cognitive impairment and early levodopa-induced motor complications.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975706","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":"Identification of <i>MACF1</i> as a causative gene of generalised epilepsy.","authors":"Xiao-Yun Lei, Meng-Wen Zhang, Hui Sun, Wang Song, Xiao-Yu Liang, Cui-Shan Wang, Sheng Luo, Bing-Mei Li, Xiao-Rong Liu, Yao Wang, Yang Tian, Qian Peng, Jie Wang, Heng Meng, Na He, Wei-Ping Liao","doi":"10.1136/jmg-2025-110699","DOIUrl":"https://doi.org/10.1136/jmg-2025-110699","url":null,"abstract":"<p><strong>Background: </strong>The microtubule actin crosslinking factor 1 (<i>MACF1)</i> gene encodes microtubule-microfilament cross-linking factor 1 that plays an essential role in the embryonic brain development. <i>MACF1</i> variants were associated with lissencephaly-9 (LIS9). However, the <i>MACF1</i>-epilepsy relationship was unknown.</p><p><strong>Methods: </strong>Trios-based whole-exome sequencing was performed on a cohort with generalised epilepsy from the China Epilepsy Gene 1.0 project. The spatial-temporal expression, single-cell sequencing and genotype-phenotype correlation were analysed to explore the role of <i>MACF1</i> in epilepsy and neurodevelopment.</p><p><strong>Results: </strong>Two de novo heterozygous and eight biallelic <i>MACF1</i> variants were identified in 10 unrelated patients. The variants presented significantly high excess by multiple statistical analyses. All patients were diagnosed with generalised epilepsy, among whom three patients presented with neurodevelopmental delay. <i>MACF1</i> was expressed throughout the lifespan, with three major peaks in the fetal, early childhood and adulthood stages, consistent with seizure onset ages of the patients. The highest expression in adulthood was in the thalamus nucleus, potentially associated with the pathogenesis of generalised epilepsy. The single-cell sequencing in organoids showed <i>MACF1</i> is widely expressed in the developing brain, especially in the early stage, suggesting a vital role in neurodevelopment. Genotype-phenotype association analysis revealed that LIS9-associated variants were featured by de novo monoallelic variants clustered within the C-terminal; the autism spectrum disorder-associated variants were mainly de novo monoallelic variants located at the spectrin-repeat rod domains. In contrast, the epilepsy-associated variants were biallelic missense variants, and those in the plakin domain were potentially associated with neurodevelopment delay.</p><p><strong>Significance: </strong><i>MACF1</i> is potentially a novel causative gene of generalised epilepsy.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144021446","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":"Electronic health record-based registry for identification of individuals at risk for hereditary cancer syndromes.","authors":"Vinit Singh, Thomas E Rafter, Mohamad Sharbatji, Jing Liu, Quiana Brown, Karina Brierley, Claire Healy, Rosa M Xicola, Nitu M Kashyap, Xavier Llor","doi":"10.1136/jmg-2025-110718","DOIUrl":"https://doi.org/10.1136/jmg-2025-110718","url":null,"abstract":"<p><strong>Background: </strong>Despite well-established criteria for genetic testing to rule out hereditary cancer syndromes (HCSs), most pathogenic variant (PV) carriers are not being tested. Thus, mechanisms that allow for better identification and a streamlined process for testing need to be implemented. The main purpose was to develop a self-updating, guideline-driven tool integrated with the electronic health record (EHR) to prospectively identify at-risk individuals and facilitate outreach and diagnosis.</p><p><strong>Methods: </strong>National Comprehensive Cancer Network/American College of Medical Genetics criteria for genetic testing were translated into three distinct rule-based conditional logic statements in the EHR from 218 rules that serially evaluate each aspect of individual criteria, which together roll up into a logic statement of 'at-risk'. The rules evaluate personal or family history, determine age at onset and categorise family relationships. This tool is applied to a system-wide registry of active patients.</p><p><strong>Results: </strong>Out of 1 325 545 individuals, 59 377 (4.48%) were identified as at-risk and thus constitute the At-Risk Cancer Genetic Syndrome Identification (ARCAGEN-ID) registry. Of those, only 12 377 (20.9%) had previously been evaluated, and 2506 had a PV. ARCAGEN-ID appropriately included 96.2% of cases. ARCAGEN-ID individuals not previously evaluated were more often included based on family history criteria (79.8% vs 49.3%), and less often because of both personal and family history of cancer (13% vs 41%) (p<0.001).</p><p><strong>Conclusions: </strong>This study is the first to use an EHR-based registry for the automatic and prospective identification of individuals eligible for genetic testing based on current criteria for all major HCS. By streamlining the identification process, this approach has the potential to dramatically increase diagnostic rates and improve cancer-related survival.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143996437","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":"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":"https://doi.org/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":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-11","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}