Abstract Background and aims The Jeju Genome Project (JGP) is a population-based genomic initiative integrating whole-genome sequencing with clinical data from community-dwelling adults in Jeju, South Korea. We aimed to investigate the prevalence, genotype distribution, and stroke burden associated with pathogenic NOTCH3 variants in a community-based genomic cohort. Methods Of 5,309 JGP participants, 3,001 apparently healthy community-dwelling adults were included. Whole-genome sequencing was performed using standard high-throughput platforms with a mean depth of 36.5×. Pathogenic and likely pathogenic NOTCH3 variants were identified based on ClinVar annotations. Demographic characteristics, vascular risk factors, family history of stroke, and self-reported stroke history were compared between variant carriers and non-carriers. Results Among 3,001 individuals, 39 (1.3%) carried pathogenic or likely pathogenic NOTCH3 variants. The mean age of carriers was 53.9 ± 15.3 years, and 33.3% were male, with no significant differences compared with non-carriers. Genotype distribution was dominated by the p.Arg544Cys variant (87.2%), followed by p.Arg578Cys (5.1%), p.Arg75Pro (5.1%), and p.Arg640Cys (2.6%), consistent with a strong regional founder effect. Only one carrier reported a prior history of stroke, with no significant difference compared with non-carriers (2.6% vs. 0.8%, p=0.289). Conclusions In this population-based cohort, pathogenic NOTCH3 variants were identified in more than 1% of individuals, whereas the observed burden of clinical stroke was remarkably low. These findings suggest substantial age-dependent penetrance and highlight the need for long-term follow-up to clarify lifetime stroke risk and modifying vascular factors among NOTCH3 variant carriers detected through population-based genomic screening. Conflict of interest Jay Chol Choi: nothing to disclose. Hyeon Ju Kim: nothing to disclose. JeHoon Jun: nothing to disclose. Sungwoong Jho: nothing to disclose.
Choi et al. (2026) studied this question.