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Whole-Exome Sequencing Improves Risk Assessments of Adult Moyamoya Disease.

E. Hong,E. J. Ha,D. Youn,Yuwhan Chung,K. Kim,S. Lee,W. Cho,Hyun-Seung Kang,J. Jeon,Jeong Eun Kim

Published 2026 in Journal of Clinical Neurology

ABSTRACT

BACKGROUND AND PURPOSE Whole-exome sequencing (WES) is a valuable tool for identifying causative mutations in adult moyamoya disease (MMD), thereby advancing our understanding of the genetic mechanisms underlying this condition. Here, we conducted the first WES-based association study aimed at identifying genetic modifiers implicated in MMD. METHODS This WES study involved 160 patients with MMD and 189 controls from a multicenter hospital-based biobank, and evaluated combined annotation-dependent depletion (CADD) scores. Mutant-allele frequencies were compared in 369,121 individuals derived from the UK Biobank (UKB) WES. Mutant-allele risk scores (MARSs) were created based on WES-identified mutations. Gene-based association analyses and pooled analyses in East-Asian populations were further performed. RESULTS Fourteen mutations reached the genome-wide significance criterion (p<5×10⁻⁸), among which the p.R4810K mutation in the ring finger protein 213 gene (RNF213) showed the strongest significance (odds ratio=117.4, p=8.54×10⁻²⁴). Notably, two mutations-p.G576S (alpha-glucosidase [GAA]) and p.D54N (charged multivesicular body protein 6 [CHMP6])-exhibited high CADD scores of 32 and 25, respectively, whereas the RNF213 p.R4810K mutation demonstrated a moderate deleteriousness score of 10.63. Fourteen mutations exhibited significant differences in allele frequencies between patients and UKB controlled data (p<1×10⁻⁸). The MARS9 model (incorporating nine missense mutations) showed better predictability for MMD (90.89%). The analysis of gene-based associations revealed four candidate genes: GAA, RNF213, CHMP6, and CARD14 (p=5×10⁻¹⁹ to 4×10⁻⁷). The subsequent pooled analyses validated four mutations in East Asian populations: p.V1195M, p.D1331G, p.S2334N, and p.R4810K (p<3×10⁻⁸). CONCLUSIONS This pioneering study has corroborated the significance of p.R4810K and identified several causative mutations predisposing patients to MMD, which helps to improve the understanding of its polygenetic nature.

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