A rare non-coding enhancer variant in SCN5A contributes to the high prevalence of Brugada syndrome in Thailand

Brugada syndrome (BrS) is a cardiac arrhythmia disorder that causes sudden death in young adults. Rare genetic variants in the SCN5A gene, 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 an SCN5A intronic 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 reduced SCN5A expression 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 the SCN5A locus and partly explains the increased prevalence of BrS in this geographic region. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement J.M. received support by the Second Century Fund (C2F), Chulalongkorn University. Y.P., K.N. and A.K. received support from the National Research Council of Thailand. C.W. received support from the Yin Shu-Tien Foundation, Taipei Veterans General Hospital-National Yang-Ming University Excellent Physician Scientists Cultivation Program (No.108-V-A-013). E.R.B. received support from the Robert Lancaster Memorial Fund and UKRI. V.M.C received support from EIC Pathfinder Challenges (Nav1.5-CARED) and the Netherlands Organization for Scientific Research (OCENW.GROOT.2019.029). C.R.B. received support from the Dutch Heart Foundation (CVON PREDICT2), the Netherlands Organization for Scientific Research (VICI fellowship, 016.150.610), Fondation Leducq (17CVD02) and EIC Pathfinder Challenges (Nav1.5-CARED). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand (IRB No. 431/58). Informed consent was obtained from all participants. All methods were performed in accordance with relevant guidelines/regulations. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript.