Genetic epidemiology of moyamoya disease and CADASIL in over 120,000 healthy Korean individuals: Insights into cerebrovascular disorders

Abstract

Background East Asia has one of the highest global stroke burdens. Genetically, moyamoya disease (MMD) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) contribute to this burden. This study investigated the allele frequencies and estimated the genetic prevalence of RNF213 and NOTCH3 variants in a large Korean population. Methods Between July 2021 and August 2024, 129,933 individuals who underwent health checkups were included. RNF213 p.Arg4810Lys and three NOTCH3 variants, p.Arg544Cys, p.Arg640Cys, and p.Arg75Pro, were analyzed using next-generation sequencing. Allele frequencies were calculated, and genetic prevalence was estimated using the Hardy-Weinberg equilibrium. Results The allele frequency of RNF213 p.Arg4810Lys was 1.08%, with 13 homozygotes. The estimated genetic prevalence of MMD was 1 in 47 individuals. For NOTCH3, the allele frequencies were 0.07% for p.Arg544Cys, 0.07% for p.Arg640Cys, and 0.04% for p.Arg75Pro, corresponding to an estimated genetic prevalence of CADASIL of 1 in 277 individuals. Eight individuals carried both the RNF213 and NOTCH3 variants. Conclusion This large-scale study highlights the substantial genetic burden of RNF213 and NOTCH3 variants in Koreans, which partially contributes to the high stroke burden in East Asia. These findings emphasize the importance of population-specific genetic studies to optimize cerebrovascular disorder management in East Asia.