Journal of Medical Genetics最新文献

{"title":"National survey on the prevalence of single-gene aetiologies for genetic developmental and epileptic encephalopathies in Italy.","authors":"Davide Mei, Simona Balestrini, Elena Parrini, Antonio Gambardella, Grazia Annesi, Valentina De Giorgis, Simone Gana, Maria Teresa Bassi, Claudio Zucca, Maurizio Elia, Luigi Vetri, Barbara Castellotti, Francesca Ragona, Mario Mastrangelo, Francesco Pisani, Giuseppe d'Orsi, Massimo Carella, Dario Pruna, Sabrina Giglio, Carla Marini, Elisabetta Cesaroni, Antonella Riva, Marcello Scala, Laura Licchetta, Raffaella Minardi, Ilaria Contaldo, Maria Luigia Gambardella, Alberto Cossu, Jacopo Proietti, Gaetano Cantalupo, Marina Trivisano, Angela De Dominicis, Nicola Specchio, Laura Tassi, Renzo Guerrini","doi":"10.1136/jmg-2024-110328","DOIUrl":"10.1136/jmg-2024-110328","url":null,"abstract":"<p><strong>Background: </strong>We aimed to estimate real-world evidence of the prevalence rate of genetic developmental and epileptic encephalopathies (DEEs) in the Italian population over a 11-year period.</p><p><strong>Methods: </strong>Fifteen paediatric and adult tertiary Italian epilepsy centres participated in a survey related to 98 genes included in the molecular diagnostic workflows of most centres. We included patients with a clinical diagnosis of DEE, caused by a pathogenic or likely pathogenic variant in one of the selected genes, with a molecular diagnosis established between 2012 and 2022. These data were used as a proxy to estimate the prevalence rate of DEEs.</p><p><strong>Results: </strong>We included 1568 unique patients and found a mean incidence proportion of 2.6 patients for 100.000 inhabitants (SD=1.13) with consistent values across most Italian regions. The number of molecular diagnoses showed a continuing positive trend, resulting in more than a 10-fold increase between 2012 and 2022. The mean age at molecular diagnosis was 11.2 years (range 0-75). Pathogenic or likely pathogenic variants in genes with an autosomal dominant inheritance pattern occurred in 77% (n=1207) patients; 17% (n=271) in X-linked genes and 6% (n=90) in genes with autosomal recessive inheritance. The most frequently reported genes in the survey were <i>SCN1A</i> (16%), followed by <i>KCNQ2</i> (5.6%) and <i>SCN2A</i> (5%).</p><p><strong>Conclusion: </strong>Our study provides a large dataset of patients with monogenic DEE, from a European country. This is essential for informing decision-makers in drug development on the appropriateness of initiatives aimed at developing precision medicine therapies and is instrumental in implementing disease-specific registries and natural history studies.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"25-31"},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755205","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":"Heterozygous de novo variants in <i>HSPD1</i> cause hypomyelinating leukodystrophy through impaired HSP60 oligomerisation.","authors":"Marina Eskin-Schwartz, Shaikah Seraidy, Eyal Paz, Maism Molhem, Emmanuelle Ranza, Stylianos E Antonarakis, Xavier Blanc, Kristin Herman, William S Benko, Stephanie Libzon, Liat Ben Sira, Aviva Fattal-Valevski, Vadim Dolgin, Ohad S Birk, Amit Kessel, Peter Bross, Celeste Weiss, Abdussalam Azem, Ayelet Zerem","doi":"10.1136/jmg-2024-109862","DOIUrl":"10.1136/jmg-2024-109862","url":null,"abstract":"<p><strong>Introduction: </strong>Hypomyelinating leukodystrophies are a group of genetic disorders, characterised by severe permanent myelin deficiency. Their clinical features include developmental delay with or without neuroregression, nystagmus, central hypotonia, progressing to spasticity and ataxia. <i>HSPD1</i> encodes the HSP60 chaperonin protein, mediating ATP-dependent folding of imported proteins in the mitochondrial matrix. Pathogenic variants in <i>HSPD1</i> have been related to a number of neurological phenotypes, including the dominantly inherited pure hereditary spastic paraplegia (MIM 605280) and the recessively inherited hypomyelinating leukodystrophy 4 (MIM 612233). Subsequently, an additional phenotype of hypomyelinating leukodystrophy has been reported due to de novo heterozygous <i>HSPD1</i> variants.In the current work, we expand the clinical and genetic spectrum of this hypomyelinating disorder by describing a cohort of three patients, being heterozygous for <i>HSPD1</i> variants involving residue Ala536 of HSP60 (the novel p.Ala536Pro variant and the previously reported p.Ala536Val).</p><p><strong>Methods: </strong>Clinical and radiological evaluation; whole exome sequencing, in vitro reconstitution assay and patient fibroblast cell lysate analysis.</p><p><strong>Results: </strong>Clinical manifestation was of early-onset nystagmus, tremor and hypotonia evolving into spasticity and ataxia and childhood-onset neuroregression in one case. Brain MRI studies revealed diffuse hypomyelination.The 3D protein structure showed these variants to lie in spatial proximity to the previously reported Leu47Val variant, associated with a similar clinical phenotype. In vitro reconstitution assay and patient fibroblast cell lysate analysis demonstrated that these mutants display aberrant chaperonin protein complex assembly.</p><p><strong>Discussion: </strong>We provide evidence that impaired oligomerisation of the chaperonin complex might underlie this HSPD1-related phenotype, possibly through exerting a dominant negative effect.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"15-24"},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582367","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":"Classification of <i>PTEN</i> germline non-truncating variants: a new approach to interpretation.","authors":"Henri Margot, Natalie Jones, Thibaut Matis, Dominique Bonneau, Tiffany Busa, Françoise Bonnet, Solene Conrad, Louise Crivelli, Pauline Monin, Sandra Fert-Ferrer, Isabelle Mortemousque, Sabine Raad, Didier Lacombe, Frédéric Caux, Nicolas Sevenet, Virginie Bubien, Michel Longy","doi":"10.1136/jmg-2024-109982","DOIUrl":"10.1136/jmg-2024-109982","url":null,"abstract":"<p><strong>Background: </strong>PTEN hamartoma tumour syndrome (PHTS) encompasses distinct syndromes, including Cowden syndrome resulting from <i>PTEN</i> pathogenic variants. Missense variants account for 30% of PHTS cases, but their classification remains challenging. To address these difficulties, guidelines were published by the Clinical Genome Resource PTEN Variant Curation Expert Panel.</p><p><strong>Methods: </strong>Between 2010 and 2020, the Bergonie Institute reference laboratory identified 76 different non-truncating <i>PTEN</i> variants in 166 patients, 17 of which have not previously been reported. Variants were initially classified following the current guidelines. Subsequently, a new classification method was developed based on four main criteria: functional exploration, phenotypic features and familial segregation, in silico modelling, and allelic frequency.</p><p><strong>Results: </strong>This new method of classification is more discriminative and reclassifies 25 variants, including 8 variants of unknown significance.</p><p><strong>Conclusion: </strong>This report proposes a revision of the current <i>PTEN</i> variant classification criteria which at present rely on functional tests evaluating only the phosphatase activity of PTEN and apply a particularly stringent clinical PHTS score.The classification of non-truncating variants of <i>PTEN</i> is facilitated by taking into consideration protein stability for variants with intact phosphatase activity, clinical and segregation criteria adapted to the phenotypic variability of PHTS and by specifying the allelic frequency of variants in the general population. This novel method of classification remains to be validated in a prospective cohort.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"1071-1079"},"PeriodicalIF":3.5,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365530","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>UBTF</i> haploinsufficiency associated with <i>UBTF</i>-related global developmental delay and distinctive facial features without neuroregression.","authors":"Xueqian Wang, Bingyu Yang, Shengnan Wu, Qisang Fan, Qing Wang, Dandan Zhang, Hongying Wang, Tao Feng, Haitao Lv, Ting Chen","doi":"10.1136/jmg-2024-110061","DOIUrl":"10.1136/jmg-2024-110061","url":null,"abstract":"<p><strong>Background: </strong>The Upstream Binding Transcription Factor (<i>UBTF</i>) gene encodes two nucleolar proteins, UBTF1 and UBTF2. UBTF1 regulates rRNA transcription by RNA polymerase I, while UBTF2 regulates mRNA transcription by RNA polymerase II. A recurrent de novo dominant mutation c.628G>A (p.Glu210Lys) has been identified as a gain-of-function mutation associated with childhood onset neurodegeneration with brain atrophy (CONDBA). Evidence from large-scale population databases and <i>Ubtf^+/-</i> mouse models indicates that <i>UBTF</i> haploinsufficiency is not tolerated.</p><p><strong>Methods: </strong>Three unrelated patients with global developmental delay and distinctive facial features were recruited for the study. Whole exome sequencing (WES) was performed to identify potential genetic abnormalities. Additionally, copy number variation analysis was conducted based on the WES data.</p><p><strong>Results: </strong>All three patients exhibited intellectual disabilities, social challenges and developmental delays in language and gross motor skills. Distinctive facial features included a wide forehead, sparse eyebrows, hypertelorism, narrow palpebral fissures, single-fold eyelids, a flat nasal bridge, anteverted nares, a long philtrum and a thin upper lip. Additionally, patient C presented with more severe language delay, recurrent hepatic dysfunction and an atrial septal defect. Patient A was found to have a nonsense variant, c.1327C>T (p.R443Ter), in the exon 13 of <i>UBTF</i>. Patients B and C both carried a heterozygous deletion encompassing the <i>UBTF</i> gene.</p><p><strong>Conclusion: </strong>In this study, we analysed the detailed phenotypes associated with <i>UBTF</i> haploinsufficiency, which, to our knowledge, have not been previously reported. We propose that <i>UBTF</i> haploinsufficiency-related global developmental delay and distinctive facial features, without neuroregression, constitute a new syndrome distinct from CONDBA.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"1089-1095"},"PeriodicalIF":3.5,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375569","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":"Rare disease genomic testing in the UK and Ireland: promoting timely and equitable access.","authors":"Sian Ellard, Sian Morgan, Sarah L Wynn, Susan Walker, Andrew Parrish, Rachael Mein, Ana Juett, Joo Wook Ahn, Ian Berry, Emma-Jane Cassidy, Miranda Durkie, Louise Fish, Richard Hall, Emma Howard, Julia Rankin, Caroline F Wright, Zandra C Deans, Richard H Scott, Sue L Hill, Emma L Baple, Robert W Taylor","doi":"10.1136/jmg-2024-110228","DOIUrl":"10.1136/jmg-2024-110228","url":null,"abstract":"<p><strong>Purpose and scope: </strong>The aim of this position statement is to provide recommendations regarding the delivery of genomic testing to patients with rare disease in the UK and Ireland. The statement has been developed to facilitate timely and equitable access to genomic testing with reporting of results within commissioned turnaround times.</p><p><strong>Methods of statement development: </strong>A 1-day workshop was convened by the UK Association for Clinical Genomic Science and attended by key stakeholders within the NHS Genomic Medicine Service, including clinical scientists, clinical geneticists and patient support group representatives. The aim was to identify best practice and innovations for streamlined, geographically consistent services delivering timely results. Attendees and senior responsible officers for genomic testing services in the UK nations and Ireland were invited to contribute.</p><p><strong>Results and conclusions: </strong>We identified eight fundamental requirements and describe these together with key enablers in the form of specific recommendations. These relate to laboratory practice (proportionate variant analysis, bioinformatics pipelines, multidisciplinary team working model and test request monitoring), compliance with national guidance (variant classification, incidental findings, reporting and reanalysis), service development and improvement (multimodal testing and innovation through research, informed by patient experience), service demand, capacity management, workforce (recruitment, retention and development), and education and training for service users. This position statement was developed to provide best practice guidance for the specialist genomics workforce within the UK and Ireland but is relevant to any publicly funded healthcare system seeking to deliver timely rare disease genomic testing in the context of high demand and limited resources.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"1103-1112"},"PeriodicalIF":3.5,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348355","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":"Cardiac rhabdomyoma: a rare feature of Birt-Hogg-Dubé syndrome.","authors":"Florence Petit, Louise Devisme, Dimitri Tchernitchko, Olivia Domanski, Cecilia Gonzalez-Corcia, Lidwine Wemeau-Stervinou, Sophie Lejeune","doi":"10.1136/jmg-2024-110349","DOIUrl":"10.1136/jmg-2024-110349","url":null,"abstract":"<p><p>Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal disorder, primarily characterised in adults by cutaneous features, pulmonary cysts that predispose to spontaneous pneumothorax and renal tumours. The syndrome is caused by pathogenic variants in the <i>FLCN</i> tumour suppressor gene, which plays a role in the mammalian target of rapamycin (mTOR) signalling pathway. We present the case of a newborn infant diagnosed with BHDS, who died of sudden cardiac death due to complications from cardiac rhabdomyoma. This is only the second reported case of such an association. Both cases were initially misdiagnosed with tuberous sclerosis complex, highlighting the diagnostic challenges. We discuss this differential diagnosis and suggest that cardiac rhabdomyomas, although rare, may be associated with BHDS and potentially life threatening. Therefore, we recommend cardiac screening in newborns at risk.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"1116-1118"},"PeriodicalIF":3.5,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502132","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":"K acetyltransferase 2B (<i>KAT2B</i>) variants can be responsible for early onset steroid-resistant nephrotic syndrome.","authors":"Olivier Niel, Ancuta Caliment, Charlotte Hougardy, Olivier Monestier, Karin Dahan","doi":"10.1136/jmg-2024-110142","DOIUrl":"10.1136/jmg-2024-110142","url":null,"abstract":"<p><p>In children, 15% of nephrotic syndromes are steroid-resistant (SRNS); approximately 30% of early onset SRNS have a genetic origin, with more than 100 causal genes described so far. SRNS can be syndromic, if associated with signs and symptoms affecting other organs or systems, such as the central nervous system, the heart or the eyes. Patients with SRNS are at high risk of chronic kidney disease and progressive renal failure, and as such need multidisciplinary care, centred on renal protection. Recently, K acetyltransferase 2B (<i>KAT2B</i>) loss of function was identified as a risk factor for morphological and functional defects in Drosophila nephrocytes; in vitro knockdown of <i>KAT2B</i> also impaired the adhesion and migration ability of human podocytes.Here we provide the first clinical description of a family affected by a loss of function mutation of <i>KAT2B</i> Clinically, both siblings presented with early onset SRNS and bilateral cataract, without neurological or heart defects. Renal function was maintained in the teenage years; nephrotic-range proteinuria was insensitive to immunosuppressive therapies. Therefore, mutations of <i>KAT2B</i> should be sought in patients with unexplained syndromic SRNS affecting the eye.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"1113-1115"},"PeriodicalIF":3.5,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375570","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. Malignant peripheral nerve sheath tumours in NF1: 20-year review of a highly cited paper.","authors":"D Gareth Evans, Emma Burkitt-Wright, John Ealing, Grace Vassello, Judith Eelloo, Alexander Lee","doi":"10.1136/jmg-2024-110396","DOIUrl":"10.1136/jmg-2024-110396","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"1132-1134"},"PeriodicalIF":3.5,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576424","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":"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":"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":"1080-1088"},"PeriodicalIF":3.5,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671912/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accurate prenatal diagnosis of facioscapulohumeral muscular dystrophy 1 using nanopore sequencing.","authors":"Yanan Wang, Zhenhua Zhao, Fei Meng, Xiangdong Kong","doi":"10.1136/jmg-2023-109832","DOIUrl":"10.1136/jmg-2023-109832","url":null,"abstract":"<p><strong>Background: </strong>Facioscapulohumeral muscular dystrophy 1 (FSHD1) is an autosomal dominant muscular disorder mainly caused by the contraction and hypomethylation of the D4Z4 repeat array in chromosome 4q35. Prenatal diagnosis of FSHD1 is challenging due to the highly repetitive and long genomic structure. In this study, a pregnant woman diagnosed with FSHD1 using optical genome mapping sought assistance for a healthy offspring.</p><p><strong>Methods: </strong>At the 17th week of gestation, she underwent amniocentesis, and genomic DNA (gDNA) was extracted from amniocytes. Whole-genome sequencing of the gDNA was performed using the nanopore MinION platform.</p><p><strong>Results: </strong>Despite a sequencing depth of only 7.3×, bioinformatic analyses revealed that the fetus inherited four D4Z4 repeat units with the permissive 4qA from the mother and the eight D4Z4 repeat units with the non-permissive 4qB from the father. To validate the results, SNP-based linkage analyses were conducted with gDNA from the proband, the proband's father and proband's amniocytes. Results indicated that the fetus inherited the maternal pathogenic haplotype based on 144 informative SNPs. Linkage analysis was consistent with the nanopore sequencing.</p><p><strong>Conclusion: </strong>Nanopore sequencing proves to be an accurate and direct method for genetic testing of monogenic diseases at the single-nucleotide level. This study represents the first application of nanopore sequencing in the prenatal diagnosis of FSHD1, providing a significant advantage for patients with de novo mutations.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"1096-1102"},"PeriodicalIF":3.5,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502131","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}