{
  "abstract": "Background Dysfunction of the KCND3 -encoded K v 4.3 channel, which carries the transient outward potassium current ( I to ), has long been suspected to contribute to the pathophysiology of Brugada Syndrome (BrS). Although recent genome-wide association studies (GWAS) have implicated KCND3 , the role of rare variation in this gene remains uncertain and clinically unactionable. Methods Genome sequencing was performed in 983 BrS probands from Europe and Thailand. Putative gain-of-function (GoF) rare variants in KCND3 identified in patients were functionally characterized by patch-clamp analysis of K v 4.3 current properties using a HEK293 cell heterozygous model. Biobank datasets were utilized to evaluate rare-common variant interaction at the KCND3 locus. Results Eight BrS cases carried six different rare KCND3 variants which clustered at the K v 4.3 C-terminus, with terminal exon rare variants significantly enriched in cases versus study (p=0.004) and population (p=2.0e −6 ) controls. Four of the five KCND3 case variants studied demonstrated significant GoF effects versus wild-type and putative benign variants, including increased I to amplitude (p.Leu586Val, p.Ala634Thr) and slower inactivation (p.Gly600Arg, p.Ala654Thr, p.Ala634Thr). Analysis of p.Gly600Arg carriers in the UK Biobank and All of Us revealed a significant enrichment of the protective KCND3 expression-reducing allele of the GWAS lead single-nucleotide polymorphism rs12090194, suggesting a possible epistatic common-rare variant interaction modifies penetrance in carriers. Conclusions GoF rare variants at the C-terminus of KCND3 are associated with BrS in a small proportion of cases. Determination of the rare and common variant status in BrS patients and their relatives may provide information about disease risk.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 50,
  "authors": [
    {
      "name": "Henan Liu"
    },
    {
      "name": "Arie O Verkerk"
    },
    {
      "name": "Pierre Lindenbaum"
    },
    {
      "name": "Isabella Mengarelli"
    },
    {
      "name": "Fenna Tuijnenburg"
    },
    {
      "name": "Rezbieara P Rahman"
    },
    {
      "name": "John Mauleekoonphairoj"
    },
    {
      "name": "Maarten Kooyman"
    },
    {
      "name": "Dominic Zimmerman"
    },
    {
      "name": "Estelle Baron"
    },
    {
      "name": "Ingrid Krapels"
    },
    {
      "name": "Paul G Volders"
    },
    {
      "name": "Leander Beekman"
    },
    {
      "name": "Laura Cazón Varela"
    },
    {
      "name": "Amalio Ruiz Salas"
    },
    {
      "name": "Rafik Tadros"
    },
    {
      "name": "Ammar Al-Chalabi"
    },
    {
      "name": "Jan H Veldink"
    },
    {
      "name": "Aurélie Thollet"
    },
    {
      "name": "Eric Charpentier"
    },
    {
      "name": "Philippe Mabo"
    },
    {
      "name": "Pascale Guicheney"
    },
    {
      "name": "Antoine Leenhardt"
    },
    {
      "name": "Arjan C Houweling"
    },
    {
      "name": "Hanno L Tan"
    },
    {
      "name": "Jean François Deleuze"
    },
    {
      "name": "Juan Pablo Ochoa"
    },
    {
      "name": "Ruben Coronel"
    },
    {
      "name": "Ronald Wilders"
    },
    {
      "name": "Yanushi D Wijeyeratne"
    },
    {
      "name": "Wanwarang Wongcharoen"
    },
    {
      "name": "Pakorn Chandanamattha"
    },
    {
      "name": "Pieter G Postema"
    },
    {
      "name": "Jean-Baptiste Gourraud"
    },
    {
      "name": "Jean-Jacques Schott"
    },
    {
      "name": "Christian Dina"
    },
    {
      "name": "Gumpanart Veerakul"
    },
    {
      "name": "Frederic Sacher"
    },
    {
      "name": "Jacques Mansourati"
    },
    {
      "name": "Ahmad S Amin"
    },
    {
      "name": "Vincent Probst"
    },
    {
      "name": "Arthur A Wilde"
    },
    {
      "name": "Richard Redon"
    },
    {
      "name": "Pier D Lambiase"
    },
    {
      "name": "Elijah R Behr"
    },
    {
      "name": "Apichai Khongphatthanayothin"
    },
    {
      "name": "Koonlawee Nademanee"
    },
    {
      "name": "Julien Barc"
    },
    {
      "name": "Roddy Walsh"
    },
    {
      "name": "Connie R Bezzina"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4m5dnc0445565.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.30.26364181",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.09.30.26364181v1.full",
  "id": "4m5dnc0445565",
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  "landing_url": "https://hal.science/hal-05840486v1",
  "language": "en",
  "licence": "CC-BY-NC-4.0",
  "licence_label": "CC BY-NC 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "hal",
      "0.sdv"
    ],
    [
      "medrxiv",
      "cardiovascular medicine"
    ],
    [
      "openalex",
      "2705|Cardiac electrophysiology and arrhythmias"
    ]
  ],
  "openalex": "W7220391661",
  "pdf_url": "https://hal.science/hal-05840486/document",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-30",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/4m5dnc0445565.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:02Z",
      "native_id": "hal-05840486",
      "source": "hal",
      "url": "https://hal.science/hal-05840486v1"
    },
    {
      "first_seen": "2026-10-30T12:20:10Z",
      "native_id": "10.64898/2026.09.30.26364181",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.09.30.26364181v1"
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  "subjects": [
    {
      "field": "biology",
      "origin": "hal:0.sdv",
      "subfield": "general"
    },
    {
      "field": "medicine",
      "origin": "medrxiv:cardiovascular medicine",
      "subfield": "cardiovascular"
    }
  ],
  "title": "Convergent genetic and functional evidence implicate KCND3 in Brugada Syndrome",
  "title_text": "Convergent genetic and functional evidence implicate KCND3 in Brugada Syndrome",
  "type": "preprint",
  "updated_at": "2026-10-30T12:20:10Z",
  "url": "https://research.draconitic.com/paper/4m5dnc0445565",
  "venue": "medRxiv",
  "versions": []
}