Evaluation of genes encoding for the transient outward current (Ito) identifies the KCND2 gene as a cause of J-wave syndrome associated with sudden cardiac death

Background-J-wave ECG patterns are associated with an increased risk of sudden arrhythmic death, and experimental evidence supports a transient outward current (Ito)-mediated mechanism of J-wave formation. This study aimed to determine the frequency of genetic mutations in genes encoding the Ito in patients with J waves on ECG. Methods and Results-Comprehensive mutational analysis was performed on Ito-encoding KCNA4, KCND2, and KCND3 genes, as well as the previously described J-wave-associated KCNJ8 gene, in 51 unrelated patients with ECG evidence defining a J-wave syndrome. Only patients with a resuscitated cardiac arrest or type 1 Brugada ECG pattern were included for analysis. A rare genetic mutation of the KCND2 gene, p.D612N, was identified in a single patient. Co-expression of mutant and wild-type KCND2 with KChIP2 in HEK293 cells demonstrated a gain-of-function phenotype, including an increase in peak Ito density of 48% (P<0.05) in the heterozygous state. Using computer modeling, this increase in Ito resulted in loss of the epicardial action potential dome, predicting an increased ventricular transmural Ito gradient. The previously described KCNJ8-S422L mutation was not identified in this cohort of patients with ECG evidence of J-wave syndrome. Conclusions-These findings are the first to implicate the KCND2 gene as a novel cause of J-wave syndrome associated with sudden cardiac arrest. However, genetic defects in Ito-encoding genes seem to be an uncommon cause of sudden cardiac arrest in patients with apparent J-wave syndromes.