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Background  A founder variant of   RNF 213 , p.R4810K (c.14429G>A, rs112735431), was recently identified as a major genetic risk factor for moyamoya disease ( MMD ) in Japan. Although the association of p.R4810K was reported to be highly significant and reproducible, the disease susceptibility of other   RNF 213  variants remains largely unknown. In the present study, we systematically evaluated the coding variants detected in Japanese patients and controls for associations with  MMD .    Methods and Results  To detect variants of   RNF 213 , all coding exons were sequenced in 27 Japanese  MMD  patients without p.R4810K. We also validated all previously reported variants in our case–control samples and tested for associations in combination with previous Japanese study cohorts, including the 1000 Genomes Project data set, as population‐based controls. Forty‐six missense variants other than p.R4810K were identified among 370 combined patients and 279 combined controls in Japan. Sixteen of 46 variants were polymorphisms with minor allele frequency >1%, and, after conditioning on the p.R4810K genotype, were not associated with  MMD . We conducted a variable threshold test using Combined Annotation‐Dependent Depletion on the remaining 30 rare variants (minor allele frequency <1%), and the results showed that the frequency of potentially functional variants was significantly higher in patients than in controls (permutation, minimum  P =0.045).    Conclusions  Not only p.4810K but also other functional missense variants of   RNF 213  conferred susceptibility to  MMD . Our analysis also revealed that ≈20% of Japanese  MMD  patients did not harbor susceptibility variants of   RNF 213 , indicating the presence of other susceptibility genes for  MMD .

Systematic Validation of RNF 213 Coding Variants in Japanese Patients With Moyamoya Disease