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, Owen; Rees, Mark; Sisodiya, Sanjay M.; Balding, David J.; Bennett, Mark F.; Bahlo, Melanie; Berkovic, Samuel F.; Oliver, Karen L.

doi:10.1016/j.ajhg.2022.10.004

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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

, Mark Rees, Sanjay M. Sisodiya, David J. Balding, Mark F. Bennett, Melanie Bahlo, Samuel F. Berkovic

, Karen L. Oliver

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

Swansea University Authors: Owen Pickrell , 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
Online Access:	Check full text
URI:	https://cronfa.swan.ac.uk/Record/cronfa61445
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first_indexed	2022-10-06T08:32:18Z
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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.</abstract><type>Journal Article</type><journal>The American Journal of Human Genetics</journal><volume>109</volume><journalNumber>11</journalNumber><paginationStart>2080</paginationStart><paginationEnd>2087</paginationEnd><publisher>Elsevier BV</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>0002-9297</issnPrint><issnElectronic/><keywords>epilepsy; founder event; haplotypes; genetics; autosomal dominant; childhood-onset disease</keywords><publishedDay>25</publishedDay><publishedMonth>10</publishedMonth><publishedYear>2022</publishedYear><publishedDate>2022-10-25</publishedDate><doi>10.1016/j.ajhg.2022.10.004</doi><url/><notes/><college>COLLEGE NANME</college><department>Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDS</DepartmentCode><institution>Swansea University</institution><apcterm/><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). 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spelling	v2 61445 2022-10-06 A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure 1c3044b5ff7a6552ff5e8c9e3901c807 0000-0003-4396-5657 Owen Pickrell Owen Pickrell true false 10f39a4e9c2ee00d453cd84c10667ac8 Mark Rees Mark Rees true false 2022-10-06 MEDS 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. Journal Article The American Journal of Human Genetics 109 11 2080 2087 Elsevier BV 0002-9297 epilepsy; founder event; haplotypes; genetics; autosomal dominant; childhood-onset disease 25 10 2022 2022-10-25 10.1016/j.ajhg.2022.10.004 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University 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. 2024-07-09T11:03:07.5490008 2022-10-06T09:20:31.0657210 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Bronwyn E. Grinton 1 Erandee Robertson 2 Liam G. Fearnley 3 Ingrid E. Scheffer 4 Anthony G. Marson 5 Terence J. O’Brien 6 Owen Pickrell 0000-0003-4396-5657 7 Mark Rees 8 Sanjay M. Sisodiya 9 David J. Balding 10 Mark F. Bennett 11 Melanie Bahlo 12 Samuel F. Berkovic 0000-0003-4580-841x 13 Karen L. Oliver 14 61445__30857__3579e27c9e2a480dabe99694bd76fa94.pdf Grinton et al SCN1B founder.61445.AAM.pdf 2024-07-09T10:58:54.4650530 Output 1408300 application/pdf Accepted Manuscript true true eng
title	A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure
spellingShingle	A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure Owen Pickrell Mark Rees
title_short	A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure
title_full	A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure
title_fullStr	A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure
title_full_unstemmed	A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure
title_sort	A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure
author_id_str_mv	1c3044b5ff7a6552ff5e8c9e3901c807 10f39a4e9c2ee00d453cd84c10667ac8
author_id_fullname_str_mv	1c3044b5ff7a6552ff5e8c9e3901c807_*_Owen Pickrell 10f39a4e9c2ee00d453cd84c10667ac8_*_Mark Rees
author	Owen Pickrell Mark Rees
author2	Bronwyn E. Grinton Erandee Robertson Liam G. Fearnley Ingrid E. Scheffer Anthony G. Marson Terence J. O’Brien Owen Pickrell Mark Rees Sanjay M. Sisodiya David J. Balding Mark F. Bennett Melanie Bahlo Samuel F. Berkovic Karen L. Oliver
format	Journal article
container_title	The American Journal of Human Genetics
container_volume	109
container_issue	11
container_start_page	2080
publishDate	2022
institution	Swansea University
issn	0002-9297
doi_str_mv	10.1016/j.ajhg.2022.10.004
publisher	Elsevier BV
college_str	Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id	facultyofmedicinehealthandlifesciences
hierarchy_top_title	Faculty of Medicine, Health and Life Sciences
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hierarchy_parent_title	Faculty of Medicine, Health and Life Sciences
department_str	Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str	1
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description	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.
published_date	2022-10-25T11:03:07Z
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A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure

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