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A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure

Bronwyn E. Grinton, Erandee Robertson, Liam G. Fearnley, Ingrid E. Scheffer, Anthony G. Marson, Terence J. O’Brien, Owen Pickrell Orcid Logo, Mark Rees, Sanjay M. Sisodiya, David J. Balding, Mark F. Bennett, Melanie Bahlo, Samuel F. Berkovic Orcid Logo, Karen L. Oliver

The American Journal of Human Genetics, Volume: 109, Issue: 11, Pages: 2080 - 2087

Swansea University Authors: Owen Pickrell Orcid Logo, Mark Rees

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DOI (Published version): 10.1016/j.ajhg.2022.10.004

Abstract

Genetic epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant familial epilepsy syndrome characterised by distinctive phenotypic heterogeneity within families. The SCN1B c.363C>G (p.Cys121Trp) variant has been identified in independent, multi-generational families with GEFS+. Despi...

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Published in: The American Journal of Human Genetics
ISSN: 0002-9297
Published: Elsevier BV 2022
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URI: https://cronfa.swan.ac.uk/Record/cronfa61445
Abstract: Genetic epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant familial epilepsy syndrome characterised by distinctive phenotypic heterogeneity within families. The SCN1B c.363C>G (p.Cys121Trp) variant has been identified in independent, multi-generational families with GEFS+. Despite the variant being 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 epilepsy. A common haplotype was observed in all families, with the age of the most recent common ancestor estimated to be approximately 800 years ago. Analysis of UK Biobank whole exome sequencing data identified 74 individuals with the same variant. All individuals carried haplotypes matching the epilepsy families, suggesting all instances of the variant derive from a single mutational event. This unusual finding of a variant causing an autosomal dominant, early-onset disease in an outbred population that has persisted over many generations can be attributed to the relatively mild phenotype in most carriers and incomplete penetrance. Founder events are well established in autosomal recessive and late-onset disorders, but are rarely observed in early-onset, autosomal dominant diseases. These findings suggest variants present in the population at low frequencies should be considered potentially pathogenic in mild phenotypes with incomplete penetrance and may be more important contributors to the genetic landscape than previously thought.
Keywords: epilepsy; founder event; haplotypes; genetics; autosomal dominant; childhood-onset disease
College: Faculty of Medicine, Health and Life Sciences
Funders: 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.
Issue: 11
Start Page: 2080
End Page: 2087

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