Whole-Exome Sequencing Improves Risk Assessments of Adult Moyamoya Disease

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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 WESbased 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 WESidentified 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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