A Rare Noncoding Enhancer Variant in SCN5A Contributes to the High Prevalence of Brugada Syndrome in Thailand.
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Walsh Roddy, Mauleekoonphairoj John, Mengarelli Isabella, Bosada Fernanda M, Verkerk Arie O, van Duijvenboden Karel, Poovorawan Yong, Wongcharoen Wanwarang, Sutjaporn Boosamas, Wandee Pharawee, Chimparlee Nitinan, Chokesuwattanaskul Ronpichai, Vongpaisarnsin Kornkiat, Dangkao Piyawan, Wu Cheng-I, Tadros Rafik, Amin Ahmad S, Lieve Krystien V V, Postema Pieter G, Kooyman Maarten, Beekman Leander, Sahasatas Dujdao, Amnueypol Montawatt, Krittayaphong Rungroj, Prechawat Somchai, Anannab Alisara, Makarawate Pattarapong, Ngarmukos Tachapong, Phusanti Keerapa, Veerakul Gumpanart, Kingsbury Zoya, Newington Taksina, Maheswari Uma, Ross Mark T, Grace Andrew, Lambiase Pier D, Behr Elijah R, Schott Jean-Jacques, Redon Richard, Barc Julien, Christoffels Vincent M, Wilde Arthur A M, Nademanee Koonlawee, Bezzina Connie R, Khongphatthanayothin Apichai
Аннотация
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 Nav1.5 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 Nav1.5-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.