Convergent genetic and functional evidence implicate KCND3 in Brugada Syndrome
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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.
