A Rare Noncoding Enhancer Variant in SCN5A Contributes to the High Prevalence of Brugada Syndrome in Thailand

Brugada syndrome (BrS) is a rare cardiac rhythm disorder with a high risk of sudden cardiac death. The disease is more frequently seen in Asian populations compared to Europeans and also more lethal arrhythmic events are seen in Asians. This is particular true for countries in South East Asia, including Thailand. Prior studies have shown that genetic variants or changes in the sodium channel gene (SCN5A), the only gene with pathogenic variants or changes causing Brugada syndrome, are relatively rare in the Thai population so this study aimed to investigated “the missing heritability” in the Thai population.

In 231 unrelated Thai Brugada syndrome patients the exact genetic sequence (DNA makeup) was determined of the region in the genome where the sodium channel gene resides (part of chromosome 3). Thai patients without Brugada syndrome served as controls. A total of 5.6% cases had an ultrarare variant in the part of the gene that directly translates into the SCN5A protein (the so-called ‘coding region’), compared to 1% in controls. In European population one would except this number to be in the range of 20%. In addition, in 6.5% of the Thai patients a specific variant or change was identified that only recently was found to be specific for the Thai Brugada syndrome population (reference: Makarawate et al. 2020). In addition, in 3.9% of Brugada cases a variant in the part of the genome that is not directly translated in the protein structure (i.e. the ‘non-coding’ part of the genome) was found. This latter finding is particularly new, as this is the first time that a variant, in the non-coding part of the genome, related to disease is identified.

Further, it was found that this latter variant did impact on the amplitude or measurement of the sodium channel current or flow (in Brugada syndrome a reduction in the sodium channel current, secondary to the variants in SCN5A directly impacting on sodium channel function, is expected). Indeed, the variant causes a ±30% reduction in the sodium current amplitude.

 

Translated by Arthur Wilde and Lorraine McGlinchey

Walsh R, Mauleekoonphairoj J, Mengarelli I, Bosada FM, Verkerk AO, van Duijvenboden K, Poovorawan Y, Wongcharoen W, Sutjaporn B, Wandee P, Chimparlee N, Chokesuwattanaskul R, Vongpaisarnsin K, Dangkao P, Wu CI, Tadros R, Amin AS, Lieve KVV, Postema PG, Kooyman M, Beekman L, Sahasatas D, Amnueypol M, Krittayaphong R, Prechawat S, Anannab A, Makarawate P, Ngarmukos T, Phusanti K, Veerakul G, Kingsbury Z, Newington T, Maheswari U, Ross MT, Grace A, Lambiase PD, Behr ER, Schott JJ, Redon R, Barc J, Christoffels VM, Wilde AAM, Nademanee K, Bezzina CR, Khongphatthanayothin A. A Rare Noncoding Enhancer Variant in SCN5A Contributes to the High Prevalence of Brugada Syndrome in Thailand. Circulation 151, 31-44, 2025. PMID: 39391988. doi: 10.1161/CIRCULATIONAHA.124.069041.

Extra reference:

Makarawate P, Glinge C, Khongphatthanayothin A, Walsh R, Mauleekoonphairoj J, Amnueypol M, Prechawat S, Wongcharoen W, Krittayaphong R, Anannab A, et al. Common and rare susceptibility genetic variants predisposing to Brugada syndrome in Thailand. Heart Rhythm.2020;17:2145–2153. doi: 10.1016/j.hrthm.2020.06.027