Global Assessment of Mendelian Stroke Genetic Prevalence in 101 635 Individuals From 7 Ethnic Groups

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.