[Association of Rare Variants and Moyamoya Disease].

Rare variants other than p.R4810K(rs112735431) have been identified in Asian and European patients with moyamoya disease. Several studies have consistently demonstrated that putative functional variants are significantly more prevalent in patients than in the general population, with the aid of bioinformatics tools, such as Combined Annotation-Dependent Depletion. Among these rare susceptibility variants, p.R4062Q(rs1555676035) has been repeatedly reported in severe pediatric cases with moyamoya disease. Three-dimensional structural analysis suggested that this may cause a loss of polar contact with the D4003 residue, leading to instability of the E3 ligase module in RNF213. Rare susceptibility variants tend to accumulate in this E3 module in pediatric cases, which may influence the severity of the clinical manifestations. Further research, including in vitro and in vivo functional analyses of the variants, is required to develop precision medicine.