Convergent genetic and functional evidence implicate KCND3 in Brugada Syndrome

Background: Dysfunction of the KCND3-encoded Kv4.3 potassium channel, which carries the transient outward current (Ito), has long been suspected to contribute to Brugada Syndrome (BrS). Recent genome-wide association studies have implicated KCND3, but the role of rare variation in the gene has remained uncertain and clinically unactionable.

Methods: The researchers performed genome sequencing in 983 BrS probands from Europe and Thailand. Putative gain-of-function rare variants in KCND3 identified in patients were functionally characterized with patch-clamp analysis of Kv4.3 current properties using a HEK293 cell heterozygous model. Biobank datasets were also used to assess 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. Terminal exon rare variants were significantly enriched in cases compared with study controls (p=0.004) and population controls (p=2.0e-6). Four of five KCND3 case variants studied showed significant gain-of-function effects versus wild-type and putative benign variants, including increased Ito amplitude for p.Leu586Val and p.Ala634Thr and slower inactivation for p.Gly600Arg, p.Ala654Thr, and p.Ala634Thr. Analysis of p.Gly600Arg carriers in the UK Biobank and All of Us found significant enrichment of the protective KCND3 expression-reducing allele of the GWAS lead SNP rs12090194, suggesting a possible epistatic common-rare variant interaction that modifies penetrance in carriers.

Conclusions: Gain-of-function rare variants at the C-terminus of KCND3 are associated with BrS in a small proportion of cases. Determining both rare and common variant status in BrS patients and their relatives may provide information about disease risk.