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 Academic Article uri icon

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  • BACKGROUND: J-wave ECG patterns are associated with an increased risk of sudden arrhythmic death, and experimental evidence supports a transient outward current (I(to))-mediated mechanism of J-wave formation. This study aimed to determine the frequency of genetic mutations in genes encoding the I(to) in patients with J waves on ECG. METHODS AND RESULTS: Comprehensive mutational analysis was performed on I(to)-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 I(to) 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 I(to)-encoding genes seem to be an uncommon cause of sudden cardiac arrest in patients with apparent J-wave syndromes.


  • Perrin, Mark J
  • Adler, Arnon
  • Green, Sharon
  • Al-Zoughool, Foad
  • Doroshenko, Petro
  • Orr, Nathan
  • Uppal, Shaheen
  • Healey, Jeffrey Sean
  • Birnie, David
  • Sanatani, Shubhayan
  • Gardner, Martin
  • Champagne, Jean
  • Simpson, Chris
  • Ahmad, Kamran
  • van den Berg, Maarten P
  • Chauhan, Vijay
  • Backx, Peter H
  • van Tintelen, J Peter
  • Krahn, Andrew D
  • Gollob, Michael H

publication date

  • December 2014

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