From the Population Health Research Institute, the Thrombosis & Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada (N.G., M.C., R.L., P.M.-S., G.P.).
the Centre for Medical Informatics, Usher Institute, The University of Edinburgh, United Kingdom (D.E.H., K.R.).
Stroke. 2020 Apr;51(4):1290-1293. doi: 10.1161/STROKEAHA.119.028840. Epub 2020 Feb 28.
Background and Purpose- Mendelian stroke confers a high lifetime risk for mutation carriers; however, ethnicity-specific prevalence estimates have been difficult to establish. Methods- Eighteen genes responsible for Mendelian stroke were investigated using the Genome Aggregation Database. Genome Aggregation Database participants belonged to 1 of 7 populations: African/African-American, Latino/Admixed American, Ashkenazi Jewish, East Asian, Finnish European, non-Finnish European, and South Asian. Rare nonsynonymous variants from 101 635 participants free of neurological disease were examined for each ethnicity. Mutations were categorized according to 3 nested classes: pathogenic clinical variants, likely damaging variants based on in silico prediction, and all nonsynonymous variants. Results- , , , , , , , , , , , and harbored pathogenic clinical variants in Genome Aggregation Database. Across all 18 genes, total nonsynonymous carrier frequency was found to be high in 5 ethnicities (African/African-American, Latino/Admixed American, East Asian, non-Finnish European, and South Asian; 28.5%-37.5%) while lower total frequencies were estimated for in silico-predicted likely damaging variants (14.9%-19.7%) and pathogenic clinical variants (0.7%-2.8%). Overall, East Asian exhibited the highest total pathogenic clinical mutation carrier frequency (2.8%). pathogenic clinical variants were most prevalent among East Asian (0.8%). Pathogenic variants, causal for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, were most frequent among East Asian (1.1%) and South Asian (1.2%). East Asian also demonstrated the highest carrier rate for (0.8%). Finnish European exhibited the greatest frequency (0.2%), while pathogenic variants were most prevalent in African/African-American (0.3%). Conclusions- Especially, among pathogenic clinical variants, Mendelian stroke genetic prevalence differed significantly between populations. These prevalence estimates may serve as guides for screening and risk profiling in patients worldwide, particularly for understudied non-European populations.
背景与目的- 孟德尔氏中风使突变携带者终生面临高风险；然而，种族特异性的患病率估计一直难以确定。方法- 使用基因组聚合数据库（Genome Aggregation Database）研究了 18 个导致孟德尔氏中风的基因。基因组聚合数据库参与者属于 7 个群体之一：非洲/非裔美国人、拉丁裔/混合裔美国人、阿什肯纳兹犹太人、东亚人、芬兰裔欧洲人、非芬兰裔欧洲人和南亚人。对来自 101535 名无神经系统疾病的参与者的罕见非同义变异进行了检查。根据 3 个嵌套类别对每种种族的突变进行分类：致病性临床变异、基于计算机预测的可能有害变异以及所有非同义变异。结果- 、 、 、 、 、 、 、 、 、 以及 在基因组聚合数据库中携带致病性临床变异。在所有 18 个基因中，5 个种族（非洲/非裔美国人、拉丁裔/混合裔美国人、东亚人、非芬兰裔欧洲人和南亚人）的总非同义携带者频率很高（28.5%-37.5%），而计算预测的可能有害变异（14.9%-19.7%）和致病性临床变异（0.7%-2.8%）的总频率较低。总的来说，东亚的总致病性临床突变携带者频率最高（2.8%）。在东亚，致病性 变异最常见（0.8%）。致病性 变异，导致大脑常染色体显性动脉病伴皮质下梗死和白质脑病，在东亚（1.1%）和南亚（1.2%）中最为常见。东亚也显示出 （0.8%）的最高携带者率。芬兰裔欧洲人的 频率最高（0.2%），而非洲/非裔美国人的致病性变异最为常见（0.3%）。结论- 特别是在致病性临床变异方面，孟德尔氏中风的遗传患病率在不同人群之间存在显著差异。这些患病率估计可以作为全球患者筛查和风险评估的指南，特别是对研究较少的非欧洲人群。
