A Rare Noncoding Enhancer Variant in <i>SCN5A</i> Contributes to the High Prevalence of Brugada Syndrome in Thailand
Abstract
BACKGROUND: Brugada syndrome (BrS) is a cardiac arrhythmia disorder that causes sudden death in young adults. Rare genetic variants in the SCN5A gene encoding the Na v 1.5 sodium channel and common noncoding variants at this locus are robustly associated with the condition. BrS is particularly prevalent in Southeast Asia but the underlying ancestry-specific factors remain largely unknown. METHODS: Genome sequencing of BrS probands and population-matched controls from Thailand was performed to identify rare noncoding variants at the SCN5A-SCN10A locus that were enriched in patients with BrS. A likely causal variant was prioritized by computational methods and introduced into human induced pluripotent stem cell (hiPSC) lines using CRISPR-Cas9. The effect of the variant on SCN5A expression and Na v 1.5 sodium channel current was then assessed in hiPSC-derived cardiomyocytes (hiPSC-CMs). RESULTS: A rare noncoding variant in an SCN5A intronic enhancer region was highly enriched in patients with BrS (detected in 3.9% of cases with a case-control odds ratio of 45.2). The variant affects a nucleotide conserved across all mammalian species and predicted to disrupt a Mef2 transcription factor binding site. Heterozygous introduction of the enhancer variant in hiPSC-CMs caused significantly reduced SCN5A expression from the variant-containing allele and a 30% reduction in Na v 1.5-mediated sodium current density compared with isogenic controls, confirming its pathogenicity. Patients with the variant had severe phenotypes, with 89% experiencing cardiac arrest. CONCLUSIONS: This is the first example of a functionally validated rare noncoding variant at the SCN5A locus and highlights how genome sequencing in understudied populations can identify novel disease mechanisms. The variant partly explains the increased prevalence of BrS in this region and enables the identification of at-risk variant carriers to reduce the burden of sudden cardiac death in Thailand.
Article Details
Authors (45)
Roddy Walsh
Cardiovascular and Genomics Research Institute, City St. George’s, University of London, London, UK (R.W.).
John Mauleekoonphairoj
Department of Medicine, Center of Excellence in Arrhythmia Research (J.M., W.W., B.S., P.W., N.C., R.C., S.P., K.N., A.K.), Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Isabella Mengarelli
Departments of Experimental Cardiology (R.W., I.M., F.M.B., A.O.V., M.K., L.B., C.R.B.), Amsterdam University Medical Centers, University of Amsterdam, the Netherlands.
Fernanda M. Bosada
Departments of Experimental Cardiology (R.W., I.M., F.M.B., A.O.V., M.K., L.B., C.R.B.), Amsterdam University Medical Centers, University of Amsterdam, the Netherlands.
Arie O. Verkerk
Karel van Duijvenboden
Yong Poovorawan
Wanwarang Wongcharoen
Boosamas Sutjaporn
Department of Medicine, Center of Excellence in Arrhythmia Research (J.M., W.W., B.S., P.W., N.C., R.C., S.P., K.N., A.K.), Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Pharawee Wandee
Department of Medicine, Center of Excellence in Arrhythmia Research (J.M., W.W., B.S., P.W., N.C., R.C., S.P., K.N., A.K.), Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Nitinan Chimparlee
Department of Medicine, Center of Excellence in Arrhythmia Research (J.M., W.W., B.S., P.W., N.C., R.C., S.P., K.N., A.K.), Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Ronpichai Chokesuwattanaskul
Department of Medicine, Center of Excellence in Arrhythmia Research (J.M., W.W., B.S., P.W., N.C., R.C., S.P., K.N., A.K.), Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Kornkiat Vongpaisarnsin
Piyawan Dangkao
Center of Excellence in Forensic Genetics, Ratchadapiseksompotch Fund (K.V., P.D.), Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Cheng-I Wu
Heart Rhythm Center, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taiwan (C.-I.W.).
Rafik Tadros
Research Center (S.S., P.J., S.G., I.H.-C., A.F., N.E.I., N.B., M.A., K.D., P.G.G., P.K., L.M., B.M., A.M.P., L.R., D.R., B.T., J.-C.T., J.C.-T., A.R.-P., R.T.), Montreal Heart Institute, QC, Canada.
Ahmad S. Amin
Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam University Medical Centers, University of Amsterdam, The Netherlands (A.S.A., E.P., C.R.B.).
Krystien V.V. Lieve
Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, the Netherlands (R.W., I.M., F.M.B., A.O.V., A.S.A., K.V.V.L., P.G.P., M.K., L.B., V.M.C., A.A.M.W., C.R.B.).
Pieter G. Postema
Department of Cardiology, Amsterdam UMC, Amsterdam, The Netherlands (L.H.G.A.H., M.J.W.G., M.F.K., M.J.S., P.G.P., S.A.J.C., C.P.A., M.J.B.K.).
Maarten Kooyman
Departments of Experimental Cardiology (R.W., I.M., F.M.B., A.O.V., M.K., L.B., C.R.B.), Amsterdam University Medical Centers, University of Amsterdam, the Netherlands.
Leander Beekman
Departments of Experimental Cardiology (R.W., I.M., F.M.B., A.O.V., M.K., L.B., C.R.B.), Amsterdam University Medical Centers, University of Amsterdam, the Netherlands.
Dujdao Sahasatas
Department of Medicine, Faculty of Medicine, Khon Kaen University, Thailand (D.S., P.M.).
Montawatt Amnueypol
Departments of Medicine, Faculty of Medicine at Ramathibodi Hospital (M.A., T. Ngarmukos), Mahidol University, Bangkok, Thailand.
Rungroj Krittayaphong
Somchai Prechawat
Department of Medicine, Center of Excellence in Arrhythmia Research (J.M., W.W., B.S., P.W., N.C., R.C., S.P., K.N., A.K.), Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Alisara Anannab
Department of Cardiovascular and Intervention, Central Chest Institute of Thailand, Nonthaburi, Thailand (A.A.).
Pattarapong Makarawate
Department of Medicine, Faculty of Medicine, Khon Kaen University, Thailand (D.S., P.M.).
Tachapong Ngarmukos
Departments of Medicine, Faculty of Medicine at Ramathibodi Hospital (M.A., T. Ngarmukos), Mahidol University, Bangkok, Thailand.
Keerapa Phusanti
Department of Medicine, Maharat Nakhon Ratchasima Hospital, Nakorn Ratchasima, Thailand (K.P.).
Gumpanart Veerakul
Bangkok Heart Hospital, Bangkok General Hospital, Thailand (G.V., A.K.).
Zoya Kingsbury
Taksina Newington
Illumina Cambridge Ltd, Granta Park, Great Abington, Cambridge, UK (Z.K., T. Newington, U.M., M.T.R.).
Uma Maheswari
Illumina Cambridge Ltd, Granta Park, Great Abington, Cambridge, UK (Z.K., T. Newington, U.M., M.T.R.).
Mark T. Ross
Andrew Grace
Department of Biochemistry, University of Cambridge, UK (A.G.).
Pier D. Lambiase
Elijah R. Behr
Jean-Jacques Schott
Nantes Université, CHU Nantes, Centre national de la recherche scientifique, Institut national de la santé et de la recherche médicale, L’Institut du Thorax, France (A.S.B., F.L., S.L.S., F.S., C.D., T.L.T., J.-J.S.).
Richard Redon
Nantes Université, Centre Hospitalier Universitaire (CHU) Nantes, Centre National de la Recherche Scientifique (CNRS), INSERM, l’Institut du Thorax, Nantes, France
Julien Barc
Nantes Universite, Nantes, France
Vincent M. Christoffels
Arthur A.M. Wilde
Heart Center, Department of Cardiology, Amsterdam Cardiovascular Sciences Heart Failure & Arrhythmias, Amsterdam UMC location University of Amsterdam, Amsterdam, the Netherlands (R.E.K., L.A.D., A.-F.B.E.Q., T.F.B., A.d.W., N.R.B., W.v.d.S., J.A.d.V., K.M.K., S.P., A.A.M.W., L.R.A.O.N., L.S., L.V.A.B.).
Koonlawee Nademanee
Department of Medicine, Center of Excellence in Arrhythmia Research (J.M., W.W., B.S., P.W., N.C., R.C., S.P., K.N., A.K.), Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Connie R. Bezzina
Apichai Khongphatthanayothin
Department of Medicine, Center of Excellence in Arrhythmia Research (J.M., W.W., B.S., P.W., N.C., R.C., S.P., K.N., A.K.), Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.