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- ABCC6, KRIT1, CECR1, COL3A1, COL4A1, COL4A2, COLGALT1, GLA, HTRA1, NOTCH3, RNF213, and TREX1 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%). ABCC6 pathogenic clinical variants were most prevalent among East Asian (0.8%). Pathogenic NOTCH3 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 RNF213 (0.8%). Finnish European exhibited the greatest HTRA1 frequency (0.2%), while COL4A1 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.

中文翻译：

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对来自7个种族的101635名个体的孟德尔卒中遗传发生率进行全球评估。

背景和目的-孟德尔中风可给突变携带者带来终身风险；但是，很难确定针对特定种族的患病率。方法-使用基因组聚集数据库研究了负责孟德尔中风的18个基因。基因组聚集数据库参与者属于以下7个人群中的1个：非洲裔/非裔美国人，拉丁美洲裔/混血儿，阿什肯纳兹犹太人，东亚，芬兰欧洲，非芬兰欧洲和南亚。对每种种族检查了来自101 635名无神经系统疾病的参与者的罕见非同义变体。根据3个嵌套类别对突变进行分类：致病性临床变体，基于计算机预测的可能具有破坏性的变体以及所有非同义变体。结果-ABCC6，KRIT1，CECR1，COL3A1，COL4A1，COL4A2，COLGALT1，GLA，HTRA1，NOTCH3，RNF213和TREX1在基因组聚合数据库中包含病原性临床变体。在所有18个基因中，发现5个种族（非洲/非裔美国人，拉丁裔/混合美国人，东亚，非芬兰欧洲和南亚； 28.5％-37.5％）的总非同义载波频率很高，但总数较低估计了计算机预测的可能具有破坏性的变异（14.9％-19.7％）和致病性临床变异（0.7％-2.8％）的频率。总体而言，东亚地区表现出最高的总致病性临床突变携带者频率（2.8％）。ABCC6致病性临床变异在东亚地区最为普遍（0.8％）。致病性NOTCH3变异是脑性常染色体显性遗传动脉病伴皮质下梗死和白脑病的病因，在东亚（1.1％）和南亚（1.2％）中最常见。东亚地区也显示出RNF213的最高携带率（0.8％）。芬兰欧洲人表现出最大的HTRA1频率（0.2％），而COL4A1病原体变异在非洲/非裔美国人中最为普遍（0.3％）。结论-特别是在致病性临床变异中，孟德尔卒中的遗传流行率在人群之间存在显着差异。这些患病率估计值可以作为全球患者筛查和风险分析的指南，尤其是对于未被研究的非欧洲人群。孟德尔卒中的遗传流行率在人群之间存在显着差异。这些患病率估计值可以作为全球患者筛查和风险分析的指南，尤其是对于未被研究的非欧洲人群。孟德尔卒中的遗传流行率在人群之间存在显着差异。这些患病率估计值可以作为全球患者筛查和风险分析的指南，尤其是对于未被研究的非欧洲人群。