Kim Eun-Hee, Yum Mi-Sun, Ra Young-Shin, Park Jun Bum, Ahn Jae Sung, Kim Gu-Hwan, Goo Hyun Woo, Ko Tae-Sung, Yoo Han-Wook
Department of Pediatrics;
Departments of 3 Neurosurgery and.
J Neurosurg. 2016 May;124(5):1221-7. doi: 10.3171/2015.4.JNS142900. Epub 2015 Oct 2.
OBJECT Moyamoya disease (MMD) is an idiopathic cerebrovascular occlusive disorder prevalent in East Asia. In the pathogenesis of MMD, the important role of genetic factors is being elucidated, and RNF213 has recently been identified as a susceptibility gene for MMD. The aim of this retrospective study was to investigate the RNF213 genotype in patients with MMD and to determine their genotype-phenotype associations. METHODS The study involved 165 Korean MMD patients from 155 unrelated families who were diagnosed with MMD at a single center from 1995 to 2013. Their demographic, radiological, and clinical findings were evaluated. Direct sequencing of the major RNF213 single nucleotide polymorphisms was performed. The association of the common RNF213 variant with MMD risk was evaluated using historical controls for comparison. Correlations between RNF213 genotype and phenotype were statistically analyzed. RESULTS The c.14429G>A (p.R4810K) variant was identified in 125 (75.8%) of 165 MMD patients. Most patients (112) were heterozygous, and 13 patients had 2 copies of the c.14429G>A variant. A novel heterozygous variant, c.12086A>G (p.Q4029R), was found in 1 additional patient. The minor allele frequency of the c.14429G>A variant was significantly higher in the MMD group (138 [41.8%] of 330 patients) than in the control group (8 [1.36%] of 588 subjects; p < 0.001). The c.14429G>A (p.R4810K) variant significantly increased the risk of MMD in Korean patients, with an OR of 52.11 (p < 0.001) compared with controls. Moreover, c.14429G>A (p.R4810K) genotypes occurred more frequently in patients with a family history of MMD. The homozygous variant was highly associated with early-onset MMD (age at onset < 5 years), cerebral infarction at diagnosis, and cognitive impairment in long-term outcome. CONCLUSIONS The findings indicate that the c.14429G>A (p.R4810K) allele of RNF213 is strongly associated with Korean patients with MMD. The homozygous c.14429G>A (p.R4810K) variant is particularly related to early-onset MMD, severe symptomatic manifestations at diagnosis, and poor prognosis. This genotypic variant may be a useful biomarker for early-onset MMD or unstable MMD with cerebral infarction, which requires early diagnosis and revascularization treatment.
烟雾病（MMD）是一种在东亚地区流行的特发性脑血管闭塞性疾病。在烟雾病的发病机制中，遗传因素的重要作用正在被阐明，最近RNF213已被确定为烟雾病的一个易感基因。这项回顾性研究的目的是调查烟雾病患者的RNF213基因型，并确定其基因型与表型的关联。方法：该研究纳入了1995年至2013年在单一中心确诊为烟雾病的165例韩国烟雾病患者，他们来自155个无亲缘关系的家庭。评估了他们的人口统计学、影像学和临床资料。对主要的RNF213单核苷酸多态性进行直接测序。使用历史对照进行比较，评估常见RNF213变异与烟雾病风险的关联。对RNF213基因型与表型之间的相关性进行统计学分析。结果：在165例烟雾病患者中的125例（75.8%）中鉴定出c.14429G>A（p.R4810K）变异。大多数患者（112例）为杂合子，13例患者有2个拷贝的c.14429G>A变异。在另外1例患者中发现了一个新的杂合变异，c.12086A>G（p.Q4029R）。c.14429G>A变异的次要等位基因频率在烟雾病组（330例患者中的138例[41.8%]）显著高于对照组（588例受试者中的8例[1.36%]；p<0.001）。与对照组相比，c.14429G>A（p.R4810K）变异显著增加了韩国患者患烟雾病的风险，OR为52.11（p<0.001）。此外，c.14429G>A（p.R4810K）基因型在有烟雾病家族史的患者中更频繁出现。纯合变异与早发型烟雾病（发病年龄<5岁）、诊断时的脑梗死以及长期预后中的认知障碍高度相关。结论：研究结果表明，RNF213的c.14429G>A（p.R4810K）等位基因与韩国烟雾病患者密切相关。纯合的c.14429G>A（p.R4810K）变异尤其与早发型烟雾病、诊断时严重的症状表现以及预后不良有关。这种基因型变异可能是早发型烟雾病或伴有脑梗死的不稳定烟雾病的一个有用生物标志物，这需要早期诊断和血管重建治疗。
