Convergent genetic and functional evidence implicate KCND3 in Brugada Syndrome
Liu, H.; Verkerk, A. O.; Lindenbaum, P.; Mengarelli, I.; Tuijnenburg, F.; Rahman, R. P.; Mauleekoonphairoj, J.; Kooyman, M.; Zimmerman, D.; Baron, E.; Krapels, I.; Volders, P. G.; Beekman, L.; Cazon Varela, L.; Ruiz Salas, A.; Tadros, R.; Al-Chalabi, A.; Veldink, J. H.; Thollet, A.; Charpentier, E.; Mabo, P.; Guicheney, P.; Leenhardt, A.; Houweling, A. C.; Tan, H. L.; Deleuze, J.-F.; Ochoa, J. P.; Coronel, R.; Wilders, R.; Wijeyeratne, Y. D.; Wongcharoen, W.; Chandanamattha, P.; Postema, P. G.; Gourraud, J.-B.; Schott, J.-J.; Dina, C.; Veerakul, G.; Sacher, F.; Mansourati, J.; Amin, A. S.; Pro
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Background: Dysfunction of the KCND3-encoded Kv4.3 channel, which carries the transient outward potassium current (Ito), 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 Kv4.3 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 Kv4.3 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 Ito 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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