TY - JOUR
T1 - The KCNJ8-S422L variant previously associated with J-wave syndromes is found at an increased frequency in Ashkenazi Jews
AU - Veeramah, Krishna R.
AU - Karafet, Tatiana M.
AU - Wolf, Daniel
AU - Samson, Ricardo A.
AU - Hammer, Michael F.
PY - 2014/1
Y1 - 2014/1
N2 - 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.
AB - 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.
KW - Brugada syndrome
KW - J-wave syndromes
KW - early repolarization syndromes
KW - idiopathic ventricular fibrillation
KW - sudden cardiac arrest
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U2 - 10.1038/ejhg.2013.78
DO - 10.1038/ejhg.2013.78
M3 - Article
C2 - 23632791
AN - SCOPUS:84890791465
SN - 1018-4813
VL - 22
SP - 94
EP - 98
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 1
ER -