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

Grinton, Bronwyn E; Robertson, Erandee; Fearnley, Liam G; Scheffer, Ingrid E; Marson, Anthony G; O'Brien, Terence J; Pickrell, W Owen; ... Oliver, Karen L; + view all (2022) A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure. American Journal of Human Genetics , 109 (11) pp. 2080-2087. 10.1016/j.ajhg.2022.10.004. Green open access

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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 epilepsy. A common haplotype was observed in all families, and the age of the most recent common ancestor was 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-affected 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.

Type: Article
Title: A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ajhg.2022.10.004
Publisher version: https://doi.org/10.1016/j.ajhg.2022.10.004
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: autosomal dominant, childhood-onset disease, epilepsy, founder event, genetics, haplotypes
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
URI: https://discovery.ucl.ac.uk/id/eprint/10158802
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