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RNF213-related susceptibility of Japanese CADASIL patients to intracranial arterial stenosis


Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), caused by NOTCH3, primarily affects small cerebral arteries; however, stenosis of major intracranial arteries has occasionally been reported. Recent studies identified a close association between the c.14576G>A (p.R4859K, rs112735431) variant of the ring finger protein 213 (RNF213) gene and sporadic intracranial arterial stenosis (ICAS). To determine whether RNF213 is associated with ICAS in CADASIL, we genotyped rs112735431 for 124 patients with CADASIL. The c.14576G>A carrier rate in CADASIL patients with ICAS (4/17; 23.5%) was significantly higher compared with those without ICAS (2/107; 1.9%) (P = 0.0032). Among patients with ICAS, frequency of territorial infarction was significantly higher in c.14576G>A carriers (75.0%) than in non-carriers (20.0%) (P = 0.0410). In addition, rate of ≥50% stenosis or occlusion tended to be higher in c.14576G>A carriers (4/4; 100%) than in non-carriers (6/13; 46.2%) (P = 0.1029). We conclude that RNF213 is a gene associated with susceptibility to ICAS in CADASIL patients. MRA follow-up and close observation are necessary for CADASIL patients with the RNF213 variant, as they may be predisposed to ICAS.

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This work was supported by the construction and application of a database for CADASIL, a hereditary small-vessel disease, by the Japan Agency for Medical Research and Development (AMED), and by a grant-in-aid for Research on Intractable Disease “Research group on medical infrastructure for adult-onset leukoencephalopathy” from the Japanese Ministry of Health, Labor, and Welfare, Japan. We thank all participants in this study. This work forms part of the master’s thesis of Yeung WTE.

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Correspondence to Toshiki Mizuno.

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Yeung, W.T.E., Mizuta, I., Watanabe-Hosomi, A. et al. RNF213-related susceptibility of Japanese CADASIL patients to intracranial arterial stenosis. J Hum Genet 63, 687–690 (2018).

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