A Rare Noncoding Enhancer Variant in <i>SCN5A</i> Contributes to the High Prevalence of Brugada Syndrome in Thailand.

Abstract

Brugada syndrome (BrS) is a cardiac arrhythmia disorder that causes sudden death in young adults. Rare genetic variants in the <i>SCN5A</i> gene encoding the Na_v1.5 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. Genome sequencing of BrS probands and population-matched controls from Thailand was performed to identify rare noncoding variants at the <i>SCN5A-SCN10A</i> 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 <i>SCN5A</i> expression and Na_v1.5 sodium channel current was then assessed in hiPSC-derived cardiomyocytes (hiPSC-CMs). A rare noncoding variant in an <i>SCN5A</i> 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 <i>SCN5A</i> expression from the variant-containing allele and a 30% reduction in Na_v1.5-mediated sodium current density compared with isogenic controls, confirming its pathogenicity. Patients with the variant had severe phenotypes, with 89% experiencing cardiac arrest. This is the first example of a functionally validated rare noncoding variant at the <i>SCN5A</i> 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.