Journal article
A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure
BE Grinton, E Robertson, LG Fearnley, IE Scheffer, AG Marson, TJ O'Brien, WO Pickrell, MI Rees, SM Sisodiya, DJ Balding, MF Bennett, M Bahlo, SF Berkovic, KL Oliver
American Journal of Human Genetics | CELL PRESS | Published : 2022
Abstract
Genetic epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant familial epilepsy syndrome characterized by distinctive phenotypic heterogeneity within families. The SCN1B c.363C>G (p.Cys121Trp) variant has been identified in independent, multi-generational families with GEFS+. Although the variant is present in population databases (at very low frequency), there is strong clinical, genetic, and functional evidence to support pathogenicity. Recurrent variants may be due to a founder event in which the variant has been inherited from a common ancestor. Here, we report evidence of a single founder event giving rise to the SCN1B c.363C>G variant in 14 independent families with epil..
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Awarded by CURE Childhood Cancer
Funding Acknowledgements
We thank the families for participating in this study. We are grateful for research support from Dr. Alica M. Goldman and Dr. Slave ' Petrovski. Funding support was provided by the Epilepsy Society Tasmania and the Estate of Kathleen Beulah Grace; National Health and Medical Research Council (NHMRC) program grant 1091593 (S.F.B., I.E.S.); NHMRC investigator grants 1195236 (M.B.), 1196637 (S.F.B.), and 1172897 (I.E.S.); Australian Government Research Training Program Scholarship APP533086 provided by the Australian Commonwealth Government and the University of Melbourne (K.L.O.); DHB Foundation Centenary Postdoctoral Fellowship in Neurogenetic Systems Biology (L.G.F.); Taking Flight Award from CURE Epilepsy (M.F.B.); Epilepsy Society, UK (S.M.S.). Funding for the UK-Wales samples was provided by the Health and Care Research Wales funding for the Wales Epilepsy Research Network (WOP/MIR). This work was also supported by the Victorian Government's Operational Infrastructure Support Program and the NHMRC Independent Research Institute Infrastructure Support Scheme and partly supported by the Brain Repair and Intracranial Neurotherapeutics Unit. Part of this work was undertaken at University College London Hospitals NHS Foundation Trust, which received a proportion of funding from the UK NIHR Biomedical Research Centre's funding scheme. We thank the Epi25 principal investigators, local staff from individual cohorts, and the individuals with epilepsy who participated in Epi25 for making possible this global collaboration and resource to advance epilepsy genetics research. This research was conducted with data from UK Biobank (www.ukbiobank.ac.uk), a major biomedical database, under data use agreement 36610 (PI Bahlo). Additional acknowledgments are included in supplemental information.