PO-629-03 IN-DEPTH ANALYSIS OF THE SCN5A LOCUS HIGHLIGHTS DISTINCT GENETIC ARCHITECTURES FOR BRUGADA SYNDROME IN DIFFERENT ANCESTRIES AND IDENTIFIES A NOVEL RARE ENHANCER VARIANT ASSOCIATED WITH DISEASE IN SOUTHEAST ASIAN PATIENTS

Abstract

Brugada syndrome (BrS) is a cardiac arrhythmia disorder that can cause sudden death in young adults. Genetic variation in the Nav1.5 cardiac sodium channel encoding SCN5A gene is robustly associated with BrS, across both rare coding and common non-coding variants. Despite a markedly higher prevalence of BrS, the diagnostic yield from SCN5A genetic testing in east and southeast Asia has been reported to be much lower than other regions. To compare the contribution of different classes of SCN5A variants (by variant type and rarity) to BrS between northwest European and Thai populations in order to investigate the apparent paradox between high disease prevalence and low diagnostic yield in southeast Asia. Genome sequencing data from European (412 cases, 769 controls) and Thai (202 cases, 410 controls) samples was analysed. SCN5A coding variants were binned by gnomAD exomes (v2.1) filtering allele frequency (FAF) and case-control odds ratios (OR) were calculated for each bin and ancestry. Rare non-coding variants in promoter and enhancer regions of SCN5A and SCN10A were assessed for enrichment or depletion in BrS cohorts. Ultra-rare (FAF<0.00001) SCN5A coding variants are more prevalent and enriched in European (22.6% of cases, OR=22.1, 11.4-43.0) compared to Thai (5.9% of cases, OR=4.3, 1.6-11.5) BrS patients. In contrast, low frequency variants (FAF 0.00005-0.001) that are expected to have intermediate effect sizes are uniquely enriched in Thai samples, occurring in 9.9% of patients. 3/6 of these variants (p.R965C, p.A1428S, p.V2016M) are known to affect Nav1.5 function. A rare non-coding variant in the SCN5A RE5 enhancer region (GRCh37:3-38621871-A-C), affecting a base conserved across species, was highly and uniquely enriched in Thai BrS cases (4.5% vs 0.2%, OR=19.1, p=3e-04). Distinct SCN5A genetic architectures are observed in European and southeast Asian BrS patients. The increased prevalence of BrS in southeast Asia is not due to an increased population burden of ultra-rare and highly deleterious SCN5A coding variants (which are relatively depleted in case cohorts). Our data suggest that other SCN5A variant classes, including coding variants of intermediate effect size and rare non-coding enhancer variants, are genetic risk factors in Thai BrS cases.