Global Assessment of Mendelian Stroke Genetic Prevalence in 101 635 Individuals From 7 Ethnic Groups
Global Assessment of Mendelian Stroke Genetic Prevalence in 101 635 Individuals From 7 Ethnic Groups
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DOI：
10.1161/strokeaha.119.028840
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发表时间：
2020-04-01
期刊：
影响因子：
8.3
通讯作者：
Pare, Guillaume
中科院分区：
文献类型：
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作者：
Grami, Nickrooz;Chong, Michael;Pare, Guillaume
背景和目的孟德尔中风赋予突变携带者的高终身风险，然而，种族特异性患病率估计已难以建立。方法18个基因负责孟德尔中风进行了调查，使用基因组聚合数据库。基因组聚合数据库参与者属于7个人群之一：非洲人/非裔美国人，拉丁美洲人/混血美国人，德系犹太人，东亚人，芬兰欧洲人，非芬兰欧洲人和南亚人。对来自101635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。结果ABCC 6、KRIT 1、CECR 1、COL 3A 1、COL 4A 1、COL 4A 2、COLGALT 1、GLA、HTRA 1、NOTCH 3、RNF 213和TREX 1在基因组聚合数据库中均为致病性临床变异。在所有18个基因中，发现5个种族（非洲人/非裔美国人、拉丁美洲人/混血美国人、东亚人、非芬兰欧洲人和南亚人; 28.5%-37.5%）的总非同义携带者频率较高，而计算机预测的可能损害性变体（14.9%-19.7%）和致病性临床变体（0.7%-2.8%）的总频率估计较低。总体而言，东亚人表现出最高的总致病性临床突变携带者频率（2.8%）。ABCC 6致病性临床变异在东亚人群中最常见（0.8%）。致病性NOTCH 3变异体是常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病的病因，在东亚人（1.1%）和南亚人（1.2%）中最常见。东亚人也表现出RNF 213的最高携带率（0.8%）。芬兰欧洲人表现出最大的HTRA 1频率（0.2%），而COL 4A 1致病性变异是最普遍的非洲/非洲裔美国人（0.3%）。结论，特别是在致病性临床变异，孟德尔中风的遗传患病率在人群之间有显着差异。这些患病率估计值可作为全球患者筛查和风险分析的指南，特别是对于研究不足的非欧洲人群。
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.