Whole-genome sequencing implicates rare, low-frequency and structural non-coding variation at the SCN5A locus in Brugada syndrome

Journal article

Alex Lipov, M. Baudic, P. Lindenbaum, I. Mengarelli, Matthew J Oneill, F. Bosada, Y. Wijeyeratne, L. de la Higuera Romero, M. Kooyman, Marion Gaudin, Graziella Aquilina, L. Beekman, E. Baron, Mathilde Bertrand, Z. Kingsbury, Mark Ross, M. Corver, Paola Lombardi, I. Krapels, P. Volders, R. Tadros, F. Tuijnenburg, K. van Duijvenboden, A. Al-Chalabi, J. Veldink, S. Jurgens, A. Thollet, Eric Charpentier, Camille Maiano, P. Mabo, A. Leenhardt, F. Sacher, A. Houweling, H. Tan, Vincent M. Christoffels, M. Tanck, Andrew Grace, K. Nademanee, A. Khongphatthanayothin, A. Glazer, J. Deleuze, Juan Pablo Ochoa, J. Montnach, M. De Waard, P. Postema, A. Amin, J. Gourraud, Pascale Guicheney, Dan M. Roden, Jean-Jacques Schott, Christian Dina, Vincent Probst, P. Lambiase, Elijah R. Behr, A. Wilde, R. Redon, Roddy Walsh, J. Barc, C. Bezzina
medRxiv, 2026

Semantic Scholar DOI PubMedCentral PubMed

Cite

APA Click to copy
Lipov, A., Baudic, M., Lindenbaum, P., Mengarelli, I., Oneill, M. J., Bosada, F., … Bezzina, C. (2026). Whole-genome sequencing implicates rare, low-frequency and structural non-coding variation at the SCN5A locus in Brugada syndrome. MedRxiv.

Chicago/Turabian Click to copy
Lipov, Alex, M. Baudic, P. Lindenbaum, I. Mengarelli, Matthew J Oneill, F. Bosada, Y. Wijeyeratne, et al. “Whole-Genome Sequencing Implicates Rare, Low-Frequency and Structural Non-Coding Variation at the SCN5A Locus in Brugada Syndrome.” medRxiv (2026).

MLA Click to copy
Lipov, Alex, et al. “Whole-Genome Sequencing Implicates Rare, Low-Frequency and Structural Non-Coding Variation at the SCN5A Locus in Brugada Syndrome.” MedRxiv, 2026.

BibTeX Click to copy

@article{alex2026a,
  title = {Whole-genome sequencing implicates rare, low-frequency and structural non-coding variation at the SCN5A locus in Brugada syndrome},
  year = {2026},
  journal = {medRxiv},
  author = {Lipov, Alex and Baudic, M. and Lindenbaum, P. and Mengarelli, I. and Oneill, Matthew J and Bosada, F. and Wijeyeratne, Y. and de la Higuera Romero, L. and Kooyman, M. and Gaudin, Marion and Aquilina, Graziella and Beekman, L. and Baron, E. and Bertrand, Mathilde and Kingsbury, Z. and Ross, Mark and Corver, M. and Lombardi, Paola and Krapels, I. and Volders, P. and Tadros, R. and Tuijnenburg, F. and van Duijvenboden, K. and Al-Chalabi, A. and Veldink, J. and Jurgens, S. and Thollet, A. and Charpentier, Eric and Maiano, Camille and Mabo, P. and Leenhardt, A. and Sacher, F. and Houweling, A. and Tan, H. and Christoffels, Vincent M. and Tanck, M. and Grace, Andrew and Nademanee, K. and Khongphatthanayothin, A. and Glazer, A. and Deleuze, J. and Ochoa, Juan Pablo and Montnach, J. and Waard, M. De and Postema, P. and Amin, A. and Gourraud, J. and Guicheney, Pascale and Roden, Dan M. and Schott, Jean-Jacques and Dina, Christian and Probst, Vincent and Lambiase, P. and Behr, Elijah R. and Wilde, A. and Redon, R. and Walsh, Roddy and Barc, J. and Bezzina, C.}
}

Abstract

Brugada syndrome (BrS) is an inherited cardiac condition characterized by a hallmark ECG pattern and an increased risk of sudden cardiac death. Central to the aetiology of BrS, the SCN5A 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 SCN5A locus. Sliding-window and cis-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 SCN5A 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 SCN5A, 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 SCN5A 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 SCN5A 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 SCN5A locus in BrS susceptibility and demonstrate the value of targeted WGS analysis of key disease loci.