The KCNJ8-S422L variant previously associated with J-wave syndromes is found at an increased frequency in Ashkenazi Jews

Krishna R. Veeramah, Tatiana M. Karafet, Daniel Wolf, Ricardo A. Samson, Michael F. Hammer

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


J-wave syndromes have been associated with increased risk of ventricular fibrillation and sudden cardiac death. Previous studies have identified the KCNJ8-S422L variant in heterozygous form in individuals with J-wave syndromes. Its absence in over 1500 controls, coupled with in vitro analysis, have led to the conclusion that S422L is pathogenic. We previously performed whole-genome sequencing in a family quartet of Ashkenazi Jewish decent with no history of J-wave syndrome. Re-examination of these data reveals that both parents are heterozygous for the S422L variant, while the 12-year old son carries two copies-thus representing the first reported case of a S422L homozygote. In order to examine whether the S422L mutation might segregate at appreciable frequencies in specific populations, we genotyped the variant in a panel consisting of 722 individuals from 22 European, Middle Eastern non-Jewish, Ashkenazi Jewish, and non-Ashkenazi Jewish populations. We found that the S422L allele was at a significantly higher frequency in Ashkenazi Jews (∼4%) compared with other populations in our survey, which have frequencies <0.25%. We also performed ECGs in both male members of the family quartet. The homozygous boy demonstrated no clinically significant ECG abnormalities, while the heterozygous father presented with a subtle J-wave point elevation. Our results suggest that either (a) previous studies implicating S422L as pathogenic for J-wave syndromes failed to appropriately account for European population structure and the variant is likely benign, or (b) Ashkenazi Jews may be at significantly increased risk of J-wave syndromes and ultimately sudden cardiac death.

Original languageEnglish (US)
Pages (from-to)94-98
Number of pages5
JournalEuropean Journal of Human Genetics
Issue number1
StatePublished - Jan 2014


  • Brugada syndrome
  • J-wave syndromes
  • early repolarization syndromes
  • idiopathic ventricular fibrillation
  • sudden cardiac arrest

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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