A Rare Noncoding Enhancer Variant in SCN5A Contributes to the High Prevalence of Brugada Syndrome in Thailand
2
Issued Date
2024-01-01
Resource Type
ISSN
00097322
eISSN
15244539
Scopus ID
2-s2.0-85207699814
Pubmed ID
39391988
Journal Title
Circulation
Rights Holder(s)
SCOPUS
Bibliographic Citation
Circulation (2024)
Suggested Citation
Walsh R., Mauleekoonphairoj J., Mengarelli I., Bosada F.M., Verkerk A.O., Van Duijvenboden K., Poovorawan Y., Wongcharoen W., Sutjaporn B., Wandee P., Chimparlee N., Chokesuwattanaskul R., Vongpaisarnsin K., Dangkao P., Wu C.I., Tadros R., Amin A.S., Lieve K.V.V., Postema P.G., 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 M.T., Grace A., Lambiase P.D., Behr E.R., Schott J.J., Redon R., Barc J., Christoffels V.M., Wilde A.A.M., Nademanee K., Bezzina C.R., Khongphatthanayothin A. A Rare Noncoding Enhancer Variant in SCN5A Contributes to the High Prevalence of Brugada Syndrome in Thailand. Circulation (2024). doi:10.1161/CIRCULATIONAHA.124.069041 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/101923
Title
A Rare Noncoding Enhancer Variant in SCN5A Contributes to the High Prevalence of Brugada Syndrome in Thailand
Author(s)
Walsh R.
Mauleekoonphairoj J.
Mengarelli I.
Bosada F.M.
Verkerk A.O.
Van Duijvenboden K.
Poovorawan Y.
Wongcharoen W.
Sutjaporn B.
Wandee P.
Chimparlee N.
Chokesuwattanaskul R.
Vongpaisarnsin K.
Dangkao P.
Wu C.I.
Tadros R.
Amin A.S.
Lieve K.V.V.
Postema P.G.
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 M.T.
Grace A.
Lambiase P.D.
Behr E.R.
Schott J.J.
Redon R.
Barc J.
Christoffels V.M.
Wilde A.A.M.
Nademanee K.
Bezzina C.R.
Khongphatthanayothin A.
Mauleekoonphairoj J.
Mengarelli I.
Bosada F.M.
Verkerk A.O.
Van Duijvenboden K.
Poovorawan Y.
Wongcharoen W.
Sutjaporn B.
Wandee P.
Chimparlee N.
Chokesuwattanaskul R.
Vongpaisarnsin K.
Dangkao P.
Wu C.I.
Tadros R.
Amin A.S.
Lieve K.V.V.
Postema P.G.
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 M.T.
Grace A.
Lambiase P.D.
Behr E.R.
Schott J.J.
Redon R.
Barc J.
Christoffels V.M.
Wilde A.A.M.
Nademanee K.
Bezzina C.R.
Khongphatthanayothin A.
Author's Affiliation
Amsterdam Cardiovascular Sciences
Ramathibodi Hospital
Siriraj Hospital
L'institut du Thorax
St George's University Hospitals NHS Foundation Trust
University of Cambridge
St George’s, University of London
Faculty of Medicine, Khon Kaen University
King Chulalongkorn Memorial Hospital
University College London
Bumrungrad International Hospital
Taipei Veterans General Hospital
Institut de Cardiologie de Montreal
Maharaj Nakhon Ratchasima Hospital
St Bartholomew's Hospital
Faculty of Medicine, Chulalongkorn University
Amsterdam UMC - University of Amsterdam
Bangkok Heart Hospital
Central Chest Institute of Thailand
Illumina Cambridge Ltd
Piyavate Hospital
Ramathibodi Hospital
Siriraj Hospital
L'institut du Thorax
St George's University Hospitals NHS Foundation Trust
University of Cambridge
St George’s, University of London
Faculty of Medicine, Khon Kaen University
King Chulalongkorn Memorial Hospital
University College London
Bumrungrad International Hospital
Taipei Veterans General Hospital
Institut de Cardiologie de Montreal
Maharaj Nakhon Ratchasima Hospital
St Bartholomew's Hospital
Faculty of Medicine, Chulalongkorn University
Amsterdam UMC - University of Amsterdam
Bangkok Heart Hospital
Central Chest Institute of Thailand
Illumina Cambridge Ltd
Piyavate Hospital
Corresponding Author(s)
Other Contributor(s)
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.