A rare non-coding enhancer variant in SCN5A contributes to the high prevalence of Brugada syndrome in Thailand
Walsh, R.; Mauleekoonphairoj, J.; Mengarelli, I.; Verkerk, A. O.; Bosada, F. M.; van Duijvenboden, K.; Poovorawan, Y.; Wongcharoen, W.; Sutjaporn, B.; Wandee, P.; Chimparlee, N.; Chokesuwattanaskul, R.; Vongpaisarnsin, K.; Dangkao, P.; Wu, C.-I.; Tadros, R.; Amin, A. S.; Lieve, K. V. V.; Postema, P. G.; Kooyman, M.; Beekman, L.; Phusanti, K.; Sahasatas, D.; Amnueypol, M.; Krittayaphong, R.; Prechawat, S.; Anannab, A.; Makarawate, P.; Ngarmukos, T.; Veerakul, G.; Kingsbury, Z.; Newington, T.; Maheswari, U.; Ross, M. T.; Grace, A.; Lambiase, P. D.; Behr, E. R.; Schott, J.-J.; Redon, R.; Barc, J.
Show abstract
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.
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