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.