Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
J Hum Genet. 2012 Dec;57(12):804-6. doi: 10.1038/jhg.2012.105. Epub 2012 Aug 30.
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.
烟雾病（MMD）是一种罕见的脑血管疾病，其特征是颈内动脉末端及其分支进行性闭塞。由于家族性发病的高发生率，因此推测存在遗传背景。同胞病例通常表现出相似的临床病程。最近，RNF213 被确定为第一个 MMD 易感性基因。RNF213 的 c.14576G>A 变体显著增加了 MMD 的风险，优势比为 190.8。此外，该变体的临床表型与剂量之间存在很强的关联。本研究描述了 RNF213 中存在纯合子和杂合子 c.14576G>A 变体的同胞 MMD 病例，以及不同的临床病程和疾病严重程度。c.14576G>A 变体的纯合子表现为发病年龄早且疾病进展迅速，导致严重的广泛分布的血管病变引起明显的神经功能缺损。相比之下，该变体的杂合子表现为发病年龄较晚且临床病程较轻，无不可逆性脑损伤，血管病变分布有限。这是首例具有不同 RNF213 变体剂量的同胞 MMD 病例报告，表明其对临床表型的遗传影响，即使在具有相似遗传背景的成员中也是如此。
