Key result
A rare noncoding variant in an SCN5A intronic enhancer region was highly enriched in patients with Brugada syndrome, detected in 3.9% of cases with an odds ratio of 45.2.
Why the study?
Brugada syndrome is particularly prevalent in Southeast Asia, but the underlying ancestry-specific factors remain largely unknown.
Does a rare noncoding enhancer variant in SCN5A reduce sodium channel current and contribute to Brugada syndrome?
Case-Control
Does a rare noncoding enhancer variant in SCN5A reduce sodium channel current and contribute to Brugada syndrome?
Odds Ratio: 45.2
A rare noncoding enhancer variant in SCN5A reduces sodium channel current and is highly enriched in Thai patients with Brugada syndrome, explaining part of the regional prevalence.
Supports targeted SCN5A enhancer screening in Thai populations to reduce sudden death; extends evidence for rare noncoding variants in BrS.
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.
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Walsh et al. (2024) conducted a case-control in Brugada syndrome. Rare noncoding variant in an SCN5A intronic enhancer region vs. Absence of the variant (population-matched controls) was evaluated on Brugada syndrome (OR 45.2). A rare noncoding variant in an SCN5A intronic enhancer region was highly enriched in patients with Brugada syndrome, detected in 3.9% of cases with an odds ratio of 45.2.
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