• World Neurosurg · Jul 2019

    Rare and low-frequency variants in RNF213 confer susceptibility to moyamoya syndrome associated with hyperthyroidism.

    • Shunsuke Nomura, Hiroyuki Akagawa, Koji Yamaguchi, Tatsuya Ishikawa, Akitsugu Kawashima, Hidetoshi Kasuya, Maki Mukawa, Tadashi Nariai, Taketoshi Maehara, Yoshikazu Okada, and Takakazu Kawamata.
    • Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan; Tokyo Women's Medical University Institute for Integrated Medical Sciences (TIIMS), Tokyo, Japan.
    • World Neurosurg. 2019 Jul 1; 127: e460-e466.

    BackgroundMoyamoya syndrome (MMS), distinguished from definite moyamoya disease (MMD), is characterized by moyamoya vasculopathy thought to develop secondary to underlying conditions (e.g., hyperthyroidism). Recent studies have shown that a proportion of East Asian (EAS) patients with MMS possess the p.R4810K variant of RNF213 (rs112735431), the foremost susceptibility variant among EAS patients with MMD. We evaluated the association between hyperthyroidism-associated MMS (hMMS) and sequence variants in RNF213.MethodsWe performed next-generation sequencing of RNF213 in 15 patients with hMMS. Candidate coding variants for the association analysis were defined by allelic frequencies of <1%, based on the p.R4810K frequency in the Japanese population. The association with hMMS was tested using a collapsing method, and 260 unrelated EAS women from the 1000 Genomes Project served as population-based controls.ResultsAll patients were female, reflecting female predominance in both moyamoya and hyperthyroid conditions. Five candidate missense variants in RNF213 were identified in 8 of 15 patients (53.3%): p.C118R, p.R4062Q, and p.R4810K as heterozygous; and p.A3468V and p.S3986N as compound heterozygous with p.R4810K. Among 260 EAS female controls, 36 (13.8%) had putatively functional variants. All identified variants were missense variants and were significantly overrepresented among patients compared with EAS controls (permuted P = 0.00010; odds ratio = 7.03; 95% confidence interval, 2.09-24.3).ConclusionsRare and low-frequency missense variants in RNF213 confer susceptibility to both MMD and hMMS. This finding indicates that susceptibility variants in RNF213 may require additional clinical factors with an effect equivalent to hyperthyroidism in order to develop moyamoya vasculopathy.Copyright © 2019 Elsevier Inc. All rights reserved.

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