Author:
Walsh Roddy,Mauleekoonphairoj John,Mengarelli Isabella,Verkerk Arie O.,Bosada Fernanda M.,van Duijvenboden Karel,Poovorawan Yong,Wongcharoen Wanwarang,Sutjaporn Boosamas,Wandee Pharawee,Chimparlee Nitinan,Chokesuwattanaskul Ronpichai,Vongpaisarnsin Kornkiat,Dangkao Piyawan,Wu Cheng-I,Tadros Rafik,Amin Ahmad S.,Lieve Krystien V.V.,Postema Pieter G.,Kooyman Maarten,Beekman Leander,Sahasatas Dujdao,Amnueypol Montawatt,Krittayaphong Rungroj,Prechawat Somchai,Anannab Alisara,Makarawate Pattarapong,Ngarmukos Tachapong,Phusanti Keerapa,Veerakul Gumpanart,Kingsbury Zoya,Newington Taksina,Maheswari Uma,Ross Mark T.,Grace Andrew,Lambiase Pier D.,Behr Elijah R.,Schott Jean-Jacques,Redon Richard,Barc Julien,Christoffels Vincent M.,Wilde Arthur A.M.,Nademanee Koonlawee,Bezzina Connie R.,Khongphatthanayothin Apichai
Abstract
AbstractBrugada syndrome (BrS) is a cardiac arrhythmia disorder that causes sudden death in young adults. Rare genetic variants in theSCN5Agene, encoding the Nav1.5 sodium channel, and common non-coding 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. Here, we performed genome sequencing of BrS probands from Thailand and population-matched controls and identified a rare non-coding variant in anSCN5Aintronic enhancer that is highly enriched in BrS cases (3.9% in cases, odds ratio 20.2-45.2) and predicted to disrupt a Mef2 transcription factor binding site. Heterozygous introduction of the enhancer variant in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) caused significantly reducedSCN5Aexpression from the variant-containing allele and a 30% reduction in Nav1.5-mediated sodium-current density compared to isogenic controls. This is the first example of a validated rare non-coding variant at theSCN5Alocus and partly explains the increased prevalence of BrS in this geographic region.
Publisher
Cold Spring Harbor Laboratory