Targeted gene sequencing in 6994 individuals with neurodevelopmental disorder with epilepsy
Targeted gene sequencing in 6994 individuals with neurodevelopmental disorder with epilepsy
Abstract PurposeWe aimed to gain insight into frequencies of genetic variants in genes implicated in neurodevelopmental disorder with epilepsy (NDD+E) by investigating large cohorts of patients in a diagnostic setting. MethodsWe analyzed variants in NDD+E using epilepsy gene panel sequencing performed between 2013 and 2017 by two large diagnostic companies. We compared variant frequencies in 6,994 panels to other 8,588 recently published panels as well as exome-wide de novo variants in 1,942 individuals with NDD+E and 10,937 controls. ResultsGenes with highest frequencies of ultra-rare variants in NDD+E comprised SCN1A, KCNQ2, SCN2A, CDKL5, SCN8A and STXBP1, concordant with the two other epilepsy cohorts we investigated. Only 46% of the analysed 262 dominant and X-linked panel genes contained ultra-rare variants in patients. Among genes with contradictory evidence of association with epilepsy CACNB4, CLCN2, EFHC1, GABRD, MAGI2 and SRPX2 showed equal frequencies in cases and controls. ConclusionWe show that improvement of panel design increased diagnostic yield over time, but panels still display genes with low or no diagnostic yield. With our data, we hope to improve current diagnostic NDD+E panel design and provide a resource of ultra-rare variants in individuals with NDD+E to the community.
Bianchini Claudia、Liebmann Nora、Tadigotla Vasisht、Lerche Holger、Helbig Ingo、Lemke Johannes R.、Stanley Christine M.、Rehm Heidi、Daly Mark J.、Biskup Saskia、Lal Dennis、Smith Douglas R.、Weber Yvonne G.、Heyne Henrike O.、Battke Florian、Artomov Mykyta
Pediatric Neurology, Neurogenetics and Neurobiology, Unit and Laboratories, Neuroscience Department, A Meyer Children?ˉs Hospital, University of FlorenceInstitute of Human Genetics, University of Leipzig Medical CenterCourtagen Life Sciences Inc.Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, and Department of Neurosurgery, University of T¨1bingenDivision of Neurology Children?ˉs Hospital of PhiladelphiaInstitute of Human Genetics, University of Leipzig Medical CenterCourtagen Life Sciences Inc.Department of Medicine, Massachusetts General HospitalAnalytic and Translational Genetics Unit, Massachusetts General Hospital||Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT||Medical and Population Genetics Program, Broad Institute of Harvard and MITPraxis f¨1r Humangenetik and CeGaT GmbHAnalytic and Translational Genetics Unit, Massachusetts General Hospital||Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT||Medical and Population Genetics Program, Broad Institute of Harvard and MIT||Cleveland Clinic Genomic Medicine Institute and Neurological InstituteCourtagen Life Sciences Inc.Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, and Department of Neurosurgery, University of T¨1bingenAnalytic and Translational Genetics Unit, Massachusetts General Hospital||Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT||Medical and Population Genetics Program, Broad Institute of Harvard and MIT||Institute of Human Genetics, University of Leipzig Medical CenterPraxis f¨1r Humangenetik and CeGaT GmbHAnalytic and Translational Genetics Unit, Massachusetts General Hospital||Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT||Medical and Population Genetics Program, Broad Institute of Harvard and MIT
神经病学、精神病学医学研究方法遗传学
epilepsygene panel designMendelian geneticsclinical geneticsneurodevelopmental disorder
Bianchini Claudia,Liebmann Nora,Tadigotla Vasisht,Lerche Holger,Helbig Ingo,Lemke Johannes R.,Stanley Christine M.,Rehm Heidi,Daly Mark J.,Biskup Saskia,Lal Dennis,Smith Douglas R.,Weber Yvonne G.,Heyne Henrike O.,Battke Florian,Artomov Mykyta.Targeted gene sequencing in 6994 individuals with neurodevelopmental disorder with epilepsy[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/602524.点此复制
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