medRxiv : the preprint server for health sciences · 2026
Whole-genome sequencing implicates rare, low-frequency and structural non-coding variation at the SCN5A locus in Brugada syndrome.
СтатьяПрепринтНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Lipov Alex, Baudic Manon, Lindenbaum Pierre, Mengarelli Isabella, O'Neill Matthew J, Bosada Fernanda M, Wijeyeratne Yanushi, de la Higuera Romero Luis, Kooyman Maarten, Gaudin Marion, Aquilina Graziella, Beekman Leander, Baron Estelle, Bertrand Mathilde, Kingsbury Zoya, Ross Mark T, Corver Marre, Lombardi Paola, Krapels Ingrid, Volders Paul G, Tadros Rafik, Tuijnenburg Fenna, van Duijvenboden Karel, Al-Chalabi Ammar, Veldink Jan H, Jurgens Sean J, Thollet Aurélie, Charpentier Eric, Maiano Camille, Mabo Philippe, Leenhardt Antoine, Sacher Frederic, Houweling Arjan C, Tan Hanno L, Christoffels Vincent M, Tanck Michael W, Grace Andrew, Nademanee Koonlawee, Khongphatthanayothin Apichai, Glazer Andrew M, Deleuze Jean François, FranceGenRef consortium, Ochoa Juan Pablo, Montnach Jérôme, Waard Michel De, Postema Pieter G, Amin Ahmad S, Gourraud Jean-Baptiste, Guicheney Pascale, Roden Dan M, Schott Jean-Jacques, Dina Christian, Probst Vincent, Lambiase Pier D, Behr Elijah R, Wilde Arthur A M, Redon Richard, Walsh Roddy, Barc Julien, Bezzina Connie R
Аннотация
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.