Convergent genetic and functional evidence implicate KCND3 in Brugada Syndrome
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.
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BibTeX
@misc{liu2026convergent,
title = {{Convergent genetic and functional evidence implicate KCND3 in Brugada Syndrome}},
author = {Henan Liu and Arie O Verkerk and Pierre Lindenbaum and Isabella Mengarelli and Fenna Tuijnenburg and Rezbieara P Rahman and John Mauleekoonphairoj and Maarten Kooyman and Dominic Zimmerman and Estelle Baron and Ingrid Krapels and Paul G Volders and Leander Beekman and Laura Cazón Varela and Amalio Ruiz Salas and Rafik Tadros and Ammar Al-Chalabi and Jan H Veldink and Aurélie Thollet and Eric Charpentier and Philippe Mabo and Pascale Guicheney and Antoine Leenhardt and Arjan C Houweling and Hanno L Tan and Jean François Deleuze and Juan Pablo Ochoa and Ruben Coronel and Ronald Wilders and Yanushi D Wijeyeratne and Wanwarang Wongcharoen and Pakorn Chandanamattha and Pieter G Postema and Jean-Baptiste Gourraud and Jean-Jacques Schott and Christian Dina and Gumpanart Veerakul and Frederic Sacher and Jacques Mansourati and Ahmad S Amin and Vincent Probst and Arthur A Wilde and Richard Redon and Pier D Lambiase and Elijah R Behr and Apichai Khongphatthanayothin and Koonlawee Nademanee and Julien Barc and Roddy Walsh and Connie R Bezzina},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.30.26364181},
url = {https://hal.science/hal-05840486v1},
note = {CC BY-NC 4.0},
}
RIS
TY - UNPB
TI - Convergent genetic and functional evidence implicate KCND3 in Brugada Syndrome
AU - Henan Liu
AU - Arie O Verkerk
AU - Pierre Lindenbaum
AU - Isabella Mengarelli
AU - Fenna Tuijnenburg
AU - Rezbieara P Rahman
AU - John Mauleekoonphairoj
AU - Maarten Kooyman
AU - Dominic Zimmerman
AU - Estelle Baron
AU - Ingrid Krapels
AU - Paul G Volders
AU - Leander Beekman
AU - Laura Cazón Varela
AU - Amalio Ruiz Salas
AU - Rafik Tadros
AU - Ammar Al-Chalabi
AU - Jan H Veldink
AU - Aurélie Thollet
AU - Eric Charpentier
AU - Philippe Mabo
AU - Pascale Guicheney
AU - Antoine Leenhardt
AU - Arjan C Houweling
AU - Hanno L Tan
AU - Jean François Deleuze
AU - Juan Pablo Ochoa
AU - Ruben Coronel
AU - Ronald Wilders
AU - Yanushi D Wijeyeratne
AU - Wanwarang Wongcharoen
AU - Pakorn Chandanamattha
AU - Pieter G Postema
AU - Jean-Baptiste Gourraud
AU - Jean-Jacques Schott
AU - Christian Dina
AU - Gumpanart Veerakul
AU - Frederic Sacher
AU - Jacques Mansourati
AU - Ahmad S Amin
AU - Vincent Probst
AU - Arthur A Wilde
AU - Richard Redon
AU - Pier D Lambiase
AU - Elijah R Behr
AU - Apichai Khongphatthanayothin
AU - Koonlawee Nademanee
AU - Julien Barc
AU - Roddy Walsh
AU - Connie R Bezzina
PY - 2026
DA - 2026/09/30
PB - medRxiv
DO - 10.64898/2026.09.30.26364181
UR - https://hal.science/hal-05840486v1
AB - 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.
ER -