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J Hum Genet. 2012 Dec;57(12):804-6. doi: 10.1038/jhg.2012.105. Epub 2012 Aug 30.

Sibling cases of moyamoya disease having homozygous and heterozygous c.14576G>A variant in RNF213 showed varying clinical course and severity.

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Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.


Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by progressive occlusion of the terminal portion of the internal carotid arteries and their branches. A genetic background was under speculation, because of the high incidence of familial occurrence. Sibling cases usually exhibit a similar clinical course. Recently, RNF213 was identified as the first MMD susceptibility gene. The c.14576G>A variant of RNF213 significantly increases the MMD risk, with an odds ratio of 190.8. Furthermore, there is a strong association between clinical phenotype and the dosage of this variant. The present study described sibling MMD cases having homozygous and heterozygous c.14576G>A variant in RNF213, as well as different clinical course and disease severity. The homozygote of c.14576G>A variant showed an early onset age and rapid disease progress, which resulted in significant neurological deficits with severe and wide distribution of vasculopathy. In contrast, the heterozygote of the variant showed a relatively late-onset age and mild clinical course without irreversible brain lesions with limited distribution of vasculopathy. This is the first report of sibling MMD cases with different doses of the RNF213 variant, showing its genetic impact on clinical phenotype even in members with similar genetic background.

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