Roddy Walsh, John Mauleekoonphairoj, Isabella Mengarelli, Fernanda M Bosada, Arie O Verkerk, Karel van Duijvenboden, Yong Poovorawan, Wanwarang Wongcharoen, Boosamas Sutjaporn, Pharawee Wandee, Nitinan Chimparlee, Ronpichai Chokesuwattanaskul, Kornkiat Vongpaisarnsin, Piyawan Dangkao, Cheng-I Wu, Rafik Tadros, Ahmad S Amin, Krystien V V Lieve, Pieter G Postema, Maarten Kooyman, Leander Beekman, Dujdao Sahasatas, Montawatt Amnueypol, Rungroj Krittayaphong, Somchai Prechawat, Alisara Anannab, Pattarapong Makarawate, Tachapong Ngarmukos, Keerapa Phusanti, Gumpanart Veerakul, Zoya Kingsbury, Taksina Newington, Uma Maheswari, Mark T Ross, Andrew Grace, Pier D Lambiase, Elijah R Behr, Jean-Jacques Schott, Richard Redon, Julien Barc, Vincent M Christoffels, Arthur A M Wilde, Koonlawee Nademanee, Connie R Bezzina, Apichai Khongphatthanayothin
{"title":"A Rare Noncoding Enhancer Variant in <i>SCN5A</i> Contributes to the High Prevalence of Brugada Syndrome in Thailand.","authors":"Roddy Walsh, John Mauleekoonphairoj, Isabella Mengarelli, Fernanda M Bosada, Arie O Verkerk, Karel van Duijvenboden, Yong Poovorawan, Wanwarang Wongcharoen, Boosamas Sutjaporn, Pharawee Wandee, Nitinan Chimparlee, Ronpichai Chokesuwattanaskul, Kornkiat Vongpaisarnsin, Piyawan Dangkao, Cheng-I Wu, Rafik Tadros, Ahmad S Amin, Krystien V V Lieve, Pieter G Postema, Maarten Kooyman, Leander Beekman, Dujdao Sahasatas, Montawatt Amnueypol, Rungroj Krittayaphong, Somchai Prechawat, Alisara Anannab, Pattarapong Makarawate, Tachapong Ngarmukos, Keerapa Phusanti, Gumpanart Veerakul, Zoya Kingsbury, Taksina Newington, Uma Maheswari, Mark T Ross, Andrew Grace, Pier D Lambiase, Elijah R Behr, Jean-Jacques Schott, Richard Redon, Julien Barc, Vincent M Christoffels, Arthur A M Wilde, Koonlawee Nademanee, Connie R Bezzina, Apichai Khongphatthanayothin","doi":"10.1161/CIRCULATIONAHA.124.069041","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Brugada syndrome (BrS) is a cardiac arrhythmia disorder that causes sudden death in young adults. Rare genetic variants in the <i>SCN5A</i> gene encoding the Na<sub>v</sub>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.</p><p><strong>Methods: </strong>Genome sequencing of BrS probands and population-matched controls from Thailand was performed to identify rare noncoding variants at the <i>SCN5A-SCN10A</i> 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 <i>SCN5A</i> expression and Na<sub>v</sub>1.5 sodium channel current was then assessed in hiPSC-derived cardiomyocytes (hiPSC-CMs).</p><p><strong>Results: </strong>A rare noncoding variant in an <i>SCN5A</i> 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 <i>SCN5A</i> expression from the variant-containing allele and a 30% reduction in Na<sub>v</sub>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.</p><p><strong>Conclusions: </strong>This is the first example of a functionally validated rare noncoding variant at the <i>SCN5A</i> 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.</p>","PeriodicalId":35,"journal":{"name":"Energy & Fuels","volume":null,"pages":null},"PeriodicalIF":5.2000,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Energy & Fuels","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/CIRCULATIONAHA.124.069041","RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ENERGY & FUELS","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍：
Energy & Fuels publishes reports of research in the technical area defined by the intersection of the disciplines of chemistry and chemical engineering and the application domain of non-nuclear energy and fuels. This includes research directed at the formation of, exploration for, and production of fossil fuels and biomass; the properties and structure or molecular composition of both raw fuels and refined products; the chemistry involved in the processing and utilization of fuels; fuel cells and their applications; and the analytical and instrumental techniques used in investigations of the foregoing areas.
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