Journal of Medical Genetics最新文献

{"title":"Clinicogenetic characterisation of SLC29A3-related syndromes: a case series, tracing ancestral variants and molecular dynamics simulation.","authors":"Sajjad Biglari, Mohammad Shahrooei, Fatemeh Vahidnezhad, Leila Youssefian, Vahid Ziaee, Nima Rezaei, Atefeh Sohanforooshan Moghaddam, Sahar Sedighzadeh, Hossein Moravej, Parisa Safari Foroushani, Majid Keivanfar, Homa Ilkhanipoor, Amir Hozhabrpour, Hooria Seyedhosseini-Ghaheh, Iraj Mohammadzadeh, Majid Naderi, Elham Sheikhi Ghayur, Nader Mansour Samaei, Saeed Dorgaleleh, Emran Esmaeilzadeh, Roya Sherkat, Hamid Reza Khorram Khorshid, Mohammad Amin Tabatabaiefar, Hakon Hakonarson, Hassan Vahidnezhad","doi":"10.1136/jmg-2024-110606","DOIUrl":"10.1136/jmg-2024-110606","url":null,"abstract":"<p><strong>Background: </strong>SLC29A3-related syndromes (SLC29A3-RS) are characterised by severe and multiorgan involvement that has a severe impact on the quality of life of the affected persons and therefore merit further genetic and clinical research. We investigated the clinical and genetic aspects of patients with SLC29A3-RS.</p><p><strong>Methods: </strong>Six pathogenic variants of the <i>SLC29A3</i> gene were identified in eight families in the current study. RNA sequencing was used for evaluating <i>SLC29A3</i> variant gene expression and protein stability by molecular dynamics (MD) simulations. This study conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant systematic review of cases across five electronic databases.</p><p><strong>Results: </strong>Genetic analysis revealed six pathogenic variants of the <i>SLC29A3</i> gene in eight families; one variant was shared among three families, indicating a possible founder effect. The estimated most recent common ancestor for these patients lived approximately 8.5 generations ago. MD studies revealed structural instability in mutant proteins. RNA sequencing also demonstrated that the expression of SLC29A3 was downregulated while the expression of the immune markers CD68 and LYZ was upregulated. A systematic search of 197 patients of different ethnic backgrounds revealed that the following symptoms were frequent findings: hyperpigmentation, hypertrichosis, hearing loss, short stature and hepatomegaly. The age of onset of SLC29A3-RS was 5.53±5.24 years with an IQR of 1.4-8.25 years.</p><p><strong>Conclusions: </strong>The characterisation of the founder variants and the genotype-phenotype correlations helps delineate the phenotype spectrum of SLC29A3-RS, which will facilitate the genetic counselling and screening of the high-risk population. Findings on <i>SLC29A3</i> variants show the way to proceed in the process of developing the diagnostic and therapeutic methods in the management of SLC29A3-RS.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"369-380"},"PeriodicalIF":3.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657470","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":"De novo heterozygous missense variants in <i>ATP11A</i> are associated with refractory focal epilepsy.","authors":"Zi-Long Ye, Nan-Xiang Shen, Xiang-Yun Luo, Hai-Sheng Lin, Yu-Tao Guo, Dong-Jie Qiu, Shi-Zhan Yuan, Ming-Feng He, Cui-Xia Fan, Wen-Bin Li, Yi-Wu Shi, Li-Bin Zhang","doi":"10.1136/jmg-2024-110540","DOIUrl":"10.1136/jmg-2024-110540","url":null,"abstract":"<p><strong>Background: </strong><i>ATP11A</i> encodes an integral-membrane type IV P-type-adenosine triphosphatase that plays an important role in neural development by maintaining membrane lipid asymmetry. <i>ATP11A</i> de novo heterozygous missense variants have been reported to be associated with hypomyelinating leukodystrophy; however, the neurological symptoms of patients are often varying. In this study, we aimed to explore the relationship between <i>ATP11A</i> variants and epilepsy.</p><p><strong>Methods: </strong>Trio-based whole-exome sequencing was performed on patients with focal epilepsy. Multiple bioinformatics analyses were used to predict the pathogenicity of the variants. Previously reported literature was collected to analyse the relation between variants and phenotypes.</p><p><strong>Results: </strong>Two de novo heterozygous missense variants of <i>ATP11A</i> were identified in two unrelated patients with refractory focal epilepsy and were predicted to be pathogenic using multiple bioinformatics analyses. Then, six patients associated with missense variants were collected. Half of the patients (3/6) with variants located on/near the transmembrane regions (TMs) had more severe and multiple neurological symptoms, while the other half with non-TM variants had mild and single symptoms, indicating a correlation between variant location and phenotype. All patients showed progressively worsening conditions, potentially due to a gradually increased expression of <i>ATP11A</i> in the human brain over time.</p><p><strong>Conclusion: </strong>This study suggested that de novo heterozygous missense variants of <i>ATP11A</i> are associated with refractory focal epilepsy. Missense variant-associated phenotypes range from epileptic seizures to severe neurological symptoms. It should be noted that patients with <i>ATP11A</i> variants have a gradually worsening potential.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"396-404"},"PeriodicalIF":3.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788524","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":"Analysing tumours for genetic diagnosis in mosaic neurofibromatosis type 1.","authors":"Tabea Isabelle Hartung, Lan Kluwe, Said Chosro Farschtschi","doi":"10.1136/jmg-2024-110580","DOIUrl":"10.1136/jmg-2024-110580","url":null,"abstract":"<p><p>Neurofibromatosis type 1 (NF1) is an autosomal dominantly inherited disorder caused by pathogenic variants in the <i>NF1</i> gene, resulting in diverse clinical manifestations, especially multiple cutaneous neurofibromas. In approximately 50% of cases, variants occur de novo, and a portion of these cases involves genetic mosaicism, where variants are present in a subset of cells of an individual. Mosaic NF1 often presents with a milder phenotype and reduced transmission risk, complicating clinical diagnosis and genetic consulting. Conventional blood-based genetic testing may fail to detect the pathogenic variants in mosaic cases, necessitating additional analysis using tumour-derived DNA. We present five such cases and suggest a comprehensive diagnostic workflow focusing on tumour-based analysis for mosaic cases.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"405-408"},"PeriodicalIF":3.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729946","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":"Six at Sixty. Commentary on osteogenesis imperfecta 1975-2025.","authors":"David Sillence","doi":"10.1136/jmg-2025-110807","DOIUrl":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12171489/pdf/","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":"OA","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":"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}