Veeramah Krishna R, Karafet Tatiana M, Wolf Daniel, Samson Ricardo A, Hammer Michael F
Division of Biotechnology, Arizona Research Laboratories, University of Arizona, Tucson, AZ, USA.
Department of Pediatrics, College of Medicine, University of Arizona, Tucson, AZ, USA.
Eur J Hum Genet. 2014 Jan;22(1):94-8. doi: 10.1038/ejhg.2013.78. Epub 2013 May 1.
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.
J波综合征与心室颤动和心源性猝死风险增加有关。先前的研究已在患有J波综合征的个体中鉴定出杂合形式的KCNJ8 - S422L变体。在超过1500名对照中未发现该变体，再加上体外分析，得出S422L具有致病性的结论。我们之前对一个没有J波综合征病史的阿什肯纳兹犹太裔家庭四人组进行了全基因组测序。重新检查这些数据发现，父母双方均为S422L变体的杂合子，而12岁的儿子携带两个拷贝——因此代表了首例报道的S422L纯合子病例。为了研究S422L突变是否可能在特定人群中以可观的频率分离，我们对一个由来自22个欧洲、中东非犹太、阿什肯纳兹犹太和非阿什肯纳兹犹太人群的722名个体组成的样本进行了该变体的基因分型。我们发现，与我们调查中的其他人群（频率<0.25%）相比，阿什肯纳兹犹太人中S422L等位基因的频率显著更高（约4%）。我们还对这个家庭四人组的男性成员进行了心电图检查。纯合子男孩未表现出临床上显著的心电图异常，而异合子父亲则有轻微的J波点抬高。我们的结果表明，要么（a）先前将S422L认定为J波综合征致病因素的研究未能适当考虑欧洲人群结构，该变体可能是良性的；要么（b）阿什肯纳兹犹太人可能患J波综合征以及最终心源性猝死的风险显著增加。
