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ECG pattern and an increased risk of sudden cardiac death. Central to the aetiology of BrS, the\n                  <jats:italic>SCN5A<\/jats:italic>\n                  region harbours both common non-coding risk variants and rare coding variants that are causative in approximately 20% of patients. However, rare non-coding genetic variation in this region remains largely unexplored. Here, we used whole-genome sequencing (WGS) of 752 European-ancestry BrS cases and 1,827 ancestry-matched controls to identify BrS-associated rare non-coding genetic variation at the\n                  <jats:italic>SCN5A<\/jats:italic>\n                  locus. Sliding-window and\n                  <jats:italic>cis<\/jats:italic>\n                  -regulatory element (CRE)-based rare-variant aggregate testing implicated three conserved CREs, including a dense aggregation of case singleton variants within a 178 bp enhancer in intron 17 of\n                  <jats:italic>SCN5A<\/jats:italic>\n                  which replicated in an independent BrS cohort. Prioritised BrS-associated rare and low-frequency non-coding variants within these elements were predicted to alter cardiac transcription factor motifs, and altered CRE activity in hiPSC-CM luciferase assays or were associated with BrS-relevant ECG endophenotypes in the UK Biobank. Single-variant analysis across the region identified a Bonferroni-significant five-fold case-enriched low-frequency variant within a known CRE in intron 1 of\n                  <jats:italic>SCN5A,<\/jats:italic>\n                  which replicated, was associated with slower cardiac conduction in the UK Biobank and accounted for part of the BrS GWAS signal at this locus. Structural variant analyses identified a 10.5 kb deletion upstream of\n                  <jats:italic>SCN5A<\/jats:italic>\n                  in a BrS case that encompassed a cardiac CRE and reduced sodium current density in a hiPSC-CM model, as well as a 6 kb BrS-enriched retrotransposon insertion in\n                  <jats:italic>SCN5A<\/jats:italic>\n                  that appeared to underlie part of the GWAS signal in this region. Together, these findings implicate rare and low-frequency non-coding variation at the\n                  <jats:italic>SCN5A<\/jats:italic>\n                  locus in BrS susceptibility and demonstrate the value of targeted WGS analysis of key disease loci.\n                <\/jats:p>","DOI":"10.64898\/2026.07.07.26356386","type":"posted-content","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T22:50:12Z","timestamp":1783723812000},"source":"Crossref","is-referenced-by-count":0,"title":["Whole-genome sequencing implicates rare, low-frequency and structural non-coding variation at the\n                  <i>SCN5A<\/i>\n                  locus in Brugada syndrome"],"prefix":"10.64898","author":[{"given":"Alex","family":"Lipov","sequence":"first","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Cardiomyopathy and Arrhythmia, Amsterdam, The Netherlands"},{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manon","family":"Baudic","sequence":"additional","affiliation":[{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"},{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019Institut du Thorax, Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Lindenbaum","sequence":"additional","affiliation":[{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"},{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019Institut du Thorax, Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Mengarelli","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Cardiomyopathy and Arrhythmia, Amsterdam, The Netherlands"},{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"O\u2019Neill","sequence":"additional","affiliation":[{"name":"Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernanda M.","family":"Bosada","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Cardiomyopathy and Arrhythmia, Amsterdam, The Netherlands"},{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanushi","family":"Wijeyeratne","sequence":"additional","affiliation":[{"name":"Cardiovascular and Genomics Research Institute, City St George\u2019s, University of London, London, UK"},{"name":"Cardiovascular Clinical Academic Group, St George\u2019s University Hospitals NHS Foundation Trust, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"de la Higuera Romero","sequence":"additional","affiliation":[{"name":"Health in Code S.L., A Coru\u00f1a, Spain"},{"name":"Spanish National Center for Cardiovascular Research (CNIC), Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maarten","family":"Kooyman","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Gaudin","sequence":"additional","affiliation":[{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"},{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019Institut du Thorax, Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graziella","family":"Aquilina","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Cardiomyopathy and Arrhythmia, Amsterdam, The Netherlands"},{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leander","family":"Beekman","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Cardiomyopathy and Arrhythmia, Amsterdam, The Netherlands"},{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estelle","family":"Baron","sequence":"additional","affiliation":[{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"},{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019Institut du Thorax, Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathilde","family":"Bertrand","sequence":"additional","affiliation":[{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"},{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019Institut du Thorax, Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoya","family":"Kingsbury","sequence":"additional","affiliation":[{"name":"Illumina Cambridge Ltd, Granta Park, Great Abington, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark T.","family":"Ross","sequence":"additional","affiliation":[{"name":"Illumina Cambridge Ltd, Granta Park, Great Abington, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marre","family":"Corver","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Cardiomyopathy and Arrhythmia, Amsterdam, The Netherlands"},{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Lombardi","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Cardiomyopathy and Arrhythmia, Amsterdam, The Netherlands"},{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Krapels","sequence":"additional","affiliation":[{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"},{"name":"Department of Clinical Genetics, Maastricht University Medical Center+, Maastricht, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul G.","family":"Volders","sequence":"additional","affiliation":[{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"},{"name":"Department of Cardiology, CARIM, Maastricht University Medical Center, Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafik","family":"Tadros","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cardiovascular Genetics Center, Montreal Heart Institute, Universit\u00e9 de Montr\u00e9al, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fenna","family":"Tuijnenburg","sequence":"additional","affiliation":[{"name":"Department of Clinical Cardiology, Heart Centre, Amsterdam University Medical Centre, location AMC, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karel","family":"van Duijvenboden","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ammar","family":"Al-Chalabi","sequence":"additional","affiliation":[{"name":"Department of Neurology, King\u2019s College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan H.","family":"Veldink","sequence":"additional","affiliation":[{"name":"Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean J.","family":"Jurgens","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Cardiomyopathy and Arrhythmia, Amsterdam, The Netherlands"},{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"},{"name":"The Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aur\u00e9lie","family":"Thollet","sequence":"additional","affiliation":[{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"},{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019Institut du Thorax, Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Charpentier","sequence":"additional","affiliation":[{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"},{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019Institut du Thorax, Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille","family":"Maiano","sequence":"additional","affiliation":[{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"},{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019Institut du Thorax, Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Mabo","sequence":"additional","affiliation":[{"name":"Service de Cardiologie, CHU de Rennes, Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoine","family":"Leenhardt","sequence":"additional","affiliation":[{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"},{"name":"CNMR Maladies Cardiaques H\u00e9r\u00e9ditaires Rares, H\u00f4pital Bichat, Universit\u00e9 de Paris, Paris, France"},{"name":"AP-HP, Service de Cardiologie, H\u00f4pital Bichat, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederic","family":"Sacher","sequence":"additional","affiliation":[{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"},{"name":"Cardiac Arrhythmia Department, IHU Liryc, Univ. Bordeaux, INSERM 1045, CHU de Bordeaux, F-Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjan C.","family":"Houweling","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Amsterdam UMC, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanno L.","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent M.","family":"Christoffels","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W.","family":"Tanck","sequence":"additional","affiliation":[{"name":"Epidemiology and Data Science, Amsterdam Public Health, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Grace","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Cambridge, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koonlawee","family":"Nademanee","sequence":"additional","affiliation":[{"name":"Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Apichai","family":"Khongphatthanayothin","sequence":"additional","affiliation":[{"name":"Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew M.","family":"Glazer","sequence":"additional","affiliation":[{"name":"Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART), Division of Genetic Medicine and Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean Fran\u00e7ois","family":"Deleuze","sequence":"additional","affiliation":[{"name":"Centre National de Recherche en G\u00e9nomique Humaine (CNRGH), Institut de Biologie Fran\u00e7ois Jacob, CEA, Universit\u00e9 Paris-Saclay, Evry, France"},{"name":"Laboratory of Excellence GENMED (Medical Genomics), Paris, France"},{"name":"Centre d\u2019Etude du Polymorphisme Humain, Fondation Jean Dausset, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"FranceGenRef consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Pablo","family":"Ochoa","sequence":"additional","affiliation":[{"name":"Health in Code S.L., A Coru\u00f1a, Spain"},{"name":"Spanish National Center for Cardiovascular Research (CNIC), Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9r\u00f4me","family":"Montnach","sequence":"additional","affiliation":[{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"},{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019Institut du Thorax, Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"De Waard","sequence":"additional","affiliation":[{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"},{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019Institut du Thorax, Nantes, France"},{"name":"LabEx \u2018Ion Channels Science & Therapeutics\u2019, Valbonne, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter G.","family":"Postema","sequence":"additional","affiliation":[{"name":"Amsterdam Cardiovascular Sciences, Cardiomyopathy and Arrhythmia, Amsterdam, The Netherlands"},{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"},{"name":"Department of Clinical Cardiology, Heart Centre, Amsterdam University Medical Centre, location AMC, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad S.","family":"Amin","sequence":"additional","affiliation":[{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"},{"name":"Department of Clinical Cardiology, Heart Centre, Amsterdam University Medical Centre, location AMC, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Baptiste","family":"Gourraud","sequence":"additional","affiliation":[{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"},{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019Institut du Thorax, Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascale","family":"Guicheney","sequence":"additional","affiliation":[{"name":"INSERM, Sorbonne University, UMRS 1166, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan M.","family":"Roden","sequence":"additional","affiliation":[{"name":"Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Jacques","family":"Schott","sequence":"additional","affiliation":[{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart"},{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019Institut du Thorax, Nantes, 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