Systematic re-annotation of 191 genes associated with early-onset epilepsy unmasks de novo variants linked to Dravet syndrome in novel SCN1A exons
Systematic re-annotation of 191 genes associated with early-onset epilepsy unmasks de novo variants linked to Dravet syndrome in novel SCN1A exons
Abstract The early infantile epileptic encephalopathies (EIEE) are a group of rare, severe neurodevelopmental disorders, where even the most thorough sequencing studies leave 60-65% of patients without a molecular diagnosis. Here, we explore the incompleteness of transcript models used for exome and genome analysis as one potential explanation for lack of current diagnoses. Therefore, we have updated the GENCODE gene annotation for 191 epilepsy-associated genes, using human brain-derived transcriptomic libraries and other data to build 3,550 novel putative transcript models. The extended transcriptional footprint of these genes allowed for 294 intronic or intergenic variants, found in human mutation databases, to be reclassified as exonic, while a further 70 intronic variants were reclassified as splice-site proximal. Using SCN1A as a case study due to its close phenotype/genotype correlation with Dravet syndrome, we screened 122 people with Dravet syndrome, or a similar phenotype, with a panel of novel exon sequences representing eight established genes and identified two de novo SCN1A variants that now, through improved gene annotation can be ascribed to residing among novel exons. These two (from 122 screened patients, 1.6%) new molecular diagnoses carry significant clinical implications. Furthermore, we identified a previously-classified SCN1A intronic Dravet-associated variant that now lies within a deeply conserved novel exon. Our findings illustrate the potential gains of thorough gene annotation in improving diagnostic yields for genetic disorders. We would expect to find new molecular diagnoses in our 191 genes that were originally suspected by clinicians for patients, with a negative diagnosis.
Steward Charles A.、Roovers Jolien、Frankish Adam、Weckhuysen Sarah、Viola Margarida、Hamdan Fadi F.、Ceulemans Berten、Leroy Patricia、Lepine Anne、Tapanari Electra、Keiller Don、Grozeva Detelina、Rogers Anthony S.、Wright James、Diekhans Mark、Minassian Berge A.、Fitzgerald Stephen、Suner Marie-Marthe、De Jonghe Peter、Mudge Jonathan M.、Vitsios Dimitrios、Pervouchine Dmitri、Sanchis-Juan Alba、Choudhary Jyoti、Guig¨? Roderic、Uszczynska-Ratajczak Barbara、Harrow Jennifer、Sisodiya Sanjay M.、Nava Caroline、Stamberger Hannah、Petryszak Robert、Flicek Paul、Abbs Stephen、Lench Nicholas J.、Cavalleri Gianpiero、Raymond F. Lucy、Gonzalez Jose M.、Petrovski Slav¨|
Congenica Ltd, Wellcome Genome Campus||Wellcome Trust Sanger Institute, Wellcome Genome CampusNeurogenetics Group, Center for Molecular Neurology, University of Antwerp||Laboratory of Neurogenetics, Institute Born-Bunge, University of AntwerpWellcome Trust Sanger Institute, Wellcome Genome Campus||European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Genome CampusNeurogenetics Group, Center for Molecular Neurology, University of Antwerp||Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp||Department of Neurology, University Hospital AntwerpNeurogenetics Group, Center for Molecular Neurology, University of Antwerp||Laboratory of Neurogenetics, Institute Born-Bunge, University of AntwerpMolecular Diagnostic Laboratory and Division of Medical Genetics, Department of Pediatrics, CHU Sainte-JustineDepartment of Pediatric Neurology, University Hospital AntwerpDepartment of Neuropediatrics, CHR Citadelle, CHU Sart-TilmanPediatric Neurology Department, Timone Hospital, APHMWellcome Trust Sanger Institute, Wellcome Genome Campus||European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Genome CampusAnglia Ruskin UniversityDepartment of Medical Genetics, Cambridge Institute for Medical Research, University of CambridgeCongenica Ltd, Wellcome Genome CampusFunctional Proteomics, Department of Cancer Biology, The Institute of Cancer ResearchCenter for Biomolecular Science and Engineering, University of CaliforniaThe Hospital for Sick Children||Department of Pediatrics (Neurology), University of Texas SouthwesternWellcome Trust Sanger Institute, Wellcome Genome CampusWellcome Trust Sanger Institute, Wellcome Genome Campus||European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Genome CampusNeurogenetics Group, Center for Molecular Neurology, University of Antwerp||Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp||Department of Neurology, University Hospital AntwerpWellcome Trust Sanger Institute, Wellcome Genome Campus||European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Genome CampusCentre for Genomics Research, Discovery Sciences, R&D BioPharmaceuticals, AstraZenecaSkolkovo Institute for Science and Technology 3 Nobel St., Skolkovo Innovation CentreDepartment of Haematology, University of Cambridge, NHS Blood and Transplant CentreFunctional Proteomics, Department of Cancer Biology, The Institute of Cancer ResearchCentre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology||Universitat Pompeu Fabra (UPF)Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology||Universitat Pompeu Fabra (UPF)||Centre of New Technologies, University of WarsawWellcome Trust Sanger Institute, Wellcome Genome Campus||European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Genome Campus||Illumina Inc, Great ChesterfordDepartment of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology||Chalfont Centre for EpilepsyDepartment of Genetics, La Piti¨|-Salp¨otri¨¨re Hospital||Sorbonne UniversitiesNeurogenetics Group, Center for Molecular Neurology, University of Antwerp||Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp||Department of Neurology, University Hospital AntwerpEuropean Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Genome CampusEuropean Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Genome CampusDepartment of Clinical Genetics, Cambridge University Hospitals NHS Foundation TrustCongenica Ltd, Wellcome Genome Campus||North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation TrustThe FutureNeuro Research Centre, Royal College of Surgeons in IrelandDepartment of Medical Genetics, Cambridge Institute for Medical Research, University of CambridgeWellcome Trust Sanger Institute, Wellcome Genome Campus||European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Genome CampusCentre for Genomics Research, Discovery Sciences, R&D BioPharmaceuticals, AstraZeneca
神经病学、精神病学基础医学分子生物学
Steward Charles A.,Roovers Jolien,Frankish Adam,Weckhuysen Sarah,Viola Margarida,Hamdan Fadi F.,Ceulemans Berten,Leroy Patricia,Lepine Anne,Tapanari Electra,Keiller Don,Grozeva Detelina,Rogers Anthony S.,Wright James,Diekhans Mark,Minassian Berge A.,Fitzgerald Stephen,Suner Marie-Marthe,De Jonghe Peter,Mudge Jonathan M.,Vitsios Dimitrios,Pervouchine Dmitri,Sanchis-Juan Alba,Choudhary Jyoti,Guig¨? Roderic,Uszczynska-Ratajczak Barbara,Harrow Jennifer,Sisodiya Sanjay M.,Nava Caroline,Stamberger Hannah,Petryszak Robert,Flicek Paul,Abbs Stephen,Lench Nicholas J.,Cavalleri Gianpiero,Raymond F. Lucy,Gonzalez Jose M.,Petrovski Slav¨|.Systematic re-annotation of 191 genes associated with early-onset epilepsy unmasks de novo variants linked to Dravet syndrome in novel SCN1A exons[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/648576.点此复制
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