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