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Background: Brugada syndrome (BrS) is a cardiac arrhythmia disorder that causes sudden death in young adults. Rare genetic variants in the SCN5A gene encoding the Na v 1.5 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., Methods: Genome sequencing of BrS probands and population-matched controls from Thailand was performed to identify rare noncoding variants at the SCN5A-SCN10A 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 SCN5A expression and Na v 1.5 sodium channel current was then assessed in hiPSC-derived cardiomyocytes (hiPSC-CMs)., Results: A rare noncoding variant in an SCN5A 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 SCN5A expression from the variant-containing allele and a 30% reduction in Na v 1.5-mediated sodium current density compared with isogenic controls, confirming its pathogenicity. Patients with the variant had severe phenotypes, with 89% experiencing cardiac arrest., Conclusions: This is the first example of a functionally validated rare noncoding variant at the SCN5A 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., Competing Interests: None.

Background: Mutations in SCN5A are rarely found in Thai patients with Brugada syndrome (BrS). Recent evidence suggested that common genetic variations may underlie BrS in a complex inheritance model., Objective: The purpose of this study was to find common and rare/low-frequency genetic variants predisposing to BrS in persons in Thailand., Methods: We conducted a genome-wide association study (GWAS) to explore the association of common variants in 154 Thai BrS cases and 432 controls. We sequenced SCN5A in 131 cases and 205 controls. Variants were classified according to current guidelines, and case-control association testing was performed for rare and low-frequency variants., Results: Two loci were significantly associated with BrS. The first was near SCN5A/SCN10A (lead marker rs10428132; odds ratio [OR] 2.4; P = 3 × 10 -10 ). Conditional analysis identified a novel independent signal in the same locus (rs6767797; OR 2.3; P = 2.7 × 10 -10 ). The second locus was near HEY2 (lead marker rs3734634; OR 2.5; P = 7 × 10 -9 ). Rare (minor allele frequency [MAF] <0.0001) coding variants in SCN5A were found in 8 of the 131 cases (6.1% in cases vs 2.0% in controls; P = .046; OR 3.3; 95% confident interval [CI] 1.0-11.1), but an enrichment of low-frequency (MAF<0.001 and >0.0001) variants also was observed in cases, with 1 variant (SCN5A: p.Arg965Cys) detected in 4.6% of Thai BrS patients vs 0.5% in controls (P = 0.015; OR 9.8; 95% CI 1.2-82.3)., Conclusion: The genetic basis of BrS in Thailand includes a wide spectrum of variant frequencies and effect sizes. As previously shown in European and Japanese populations, common variants near SCN5A and HEY2 are associated with BrS in the Thai population, confirming the transethnic transferability of these 2 major BrS loci., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)