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

Journal article

Roddy Walsh, J. Mauleekoonphairoj, I. Mengarelli, F. Bosada, A. Verkerk, K. van Duijvenboden, Y. Poovorawan, W. Wongcharoen, B. Sutjaporn, P. Wandee, Nitinan Chimparlee, Ronpichai Chokesuwattanaskul, Kornkiat Vongpaisarnsin, Piyawan Dangkao, Cheng-I Wu, R. Tadros, A. Amin, K. Lieve, P. Postema, M. Kooyman, L. Beekman, Dujdao Sahasatas, Montawatt Amnueypol, R. Krittayaphong, S. Prechawat, Alisara Anannab, P. Makarawate, T. Ngarmukos, Keerapa Phusanti, G. Veerakul, Z. Kingsbury, T. Newington, U. Maheswari, Mark Ross, Andrew Grace, P. Lambiase, Elijah R. Behr, J. Schott, R. Redon, J. Barc, Vincent M. Christoffels, A. Wilde, K. Nademanee, C. Bezzina, A. Khongphatthanayothin
Circulation, vol. 7(151), 2025, pp. 31-44

DOI: 10.1161/CIRCULATIONAHA.124.069041

Semantic Scholar DOI PubMedCentral PubMed

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APA Click to copy
Walsh, R., Mauleekoonphairoj, J., Mengarelli, I., Bosada, F., Verkerk, A., van Duijvenboden, K., … Khongphatthanayothin, A. (2025). A Rare Noncoding Enhancer Variant in SCN5A Contributes to the High Prevalence of Brugada Syndrome in Thailand. Circulation, 7(151), 31–44. https://doi.org/10.1161/CIRCULATIONAHA.124.069041

Chicago/Turabian Click to copy
Walsh, Roddy, J. Mauleekoonphairoj, I. Mengarelli, F. Bosada, A. Verkerk, K. van Duijvenboden, Y. Poovorawan, et al. “A Rare Noncoding Enhancer Variant in SCN5A Contributes to the High Prevalence of Brugada Syndrome in Thailand.” Circulation 7, no. 151 (2025): 31–44.

MLA Click to copy
Walsh, Roddy, et al. “A Rare Noncoding Enhancer Variant in SCN5A Contributes to the High Prevalence of Brugada Syndrome in Thailand.” Circulation, vol. 7, no. 151, 2025, pp. 31–44, doi:10.1161/CIRCULATIONAHA.124.069041.

BibTeX Click to copy

@article{roddy2025a,
  title = {A Rare Noncoding Enhancer Variant in SCN5A Contributes to the High Prevalence of Brugada Syndrome in Thailand},
  year = {2025},
  issue = {151},
  journal = {Circulation},
  pages = {31-44},
  volume = {7},
  doi = {10.1161/CIRCULATIONAHA.124.069041},
  author = {Walsh, Roddy and Mauleekoonphairoj, J. and Mengarelli, I. and Bosada, F. and Verkerk, A. and van Duijvenboden, K. and Poovorawan, Y. and Wongcharoen, W. and Sutjaporn, B. and Wandee, P. and Chimparlee, Nitinan and Chokesuwattanaskul, Ronpichai and Vongpaisarnsin, Kornkiat and Dangkao, Piyawan and Wu, Cheng-I and Tadros, R. and Amin, A. and Lieve, K. and Postema, P. and Kooyman, M. and Beekman, L. and Sahasatas, Dujdao and Amnueypol, Montawatt and Krittayaphong, R. and Prechawat, S. and Anannab, Alisara and Makarawate, P. and Ngarmukos, T. and Phusanti, Keerapa and Veerakul, G. and Kingsbury, Z. and Newington, T. and Maheswari, U. and Ross, Mark and Grace, Andrew and Lambiase, P. and Behr, Elijah R. and Schott, J. and Redon, R. and Barc, J. and Christoffels, Vincent M. and Wilde, A. and Nademanee, K. and Bezzina, C. and Khongphatthanayothin, A.}
}

Abstract

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 Nav1.5 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 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.