title: The KCNJ8-S422L variant previously associated with J-wave syndromes is found at an increased frequency in Ashkenazi Jews.
abstract: 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.
authors: Division of Biotechnology, Arizona Research Laboratories, University of Arizona, Tucson, AZ, USA.
authors: Krishna R
authors: KR
authors: Veeramah
authors: Division of Biotechnology, Arizona Research Laboratories, University of Arizona, Tucson, AZ, USA.
authors: Tatiana M
authors: TM
authors: Karafet
authors: Division of Biotechnology, Arizona Research Laboratories, University of Arizona, Tucson, AZ, USA.
authors: Daniel
authors: D
authors: Wolf
authors: Department of Pediatrics, College of Medicine, University of Arizona, Tucson, AZ, USA.
authors: Ricardo A
authors: RA
authors: Samson
authors: Division of Biotechnology, Arizona Research Laboratories, University of Arizona, Tucson, AZ, USA.
authors: Michael F
authors: MF
authors: Hammer
mesh_terms: D002648:Child; D016757:Death, Sudden, Cardiac / Q000209:etiology; D005060:Europe; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D005838:Genotype; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007585:Jews / Q000235:genetics*; D054086:KATP Channels / Q000235:genetics*; D008297:Male; D009154:Mutation; D012307:Risk Factors; D014693:Ventricular Fibrillation / Q000235:genetics* / Q000473:pathology
chemical_list: D054086:KATP Channels; C092520:uK-ATP-1 potassium channel
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