Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China National Clinical Research Center for Neurological Diseases; and.
McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
J Neurosurg. 2017 Apr;126(4):1106-1113. doi: 10.3171/2016.2.JNS152173. Epub 2016 Apr 29.
OBJECTIVE Moyamoya disease (MMD) is a rare, genetically heterogeneous cerebrovascular disease. The authors conducted a genetic study of really interesting new gene (RING) finger protein 213 ( RNF213); actin alpha 2 ( ACTA2); BRCA1/BRCA2-containing complex subunit 3 ( BRCC3); and guanylate cyclase 1, soluble, alpha 3 ( GUCY1A3) as well as a clinical phenotype analysis in Chinese MMD patients to determine whether genetic differences are responsible for the different clinical features that appear in MMD in different ethnicities. METHODS A panel was designed to identify disease-causing mutations in MMD genes and those involved in related disorders ( RNF213, ACTA2, BRCC3, and GUCY1A3). The panel was used to detect disease-causing mutations in 255 Chinese MMD patients. Genotype and allele frequencies were compared between patients and 300 controls. A mutation segregation analysis was performed in 34 families, and genotype-phenotype correlations were made. RESULTS Twenty-seven rare missense variants of RNF213 were identified and were not found in controls. Among them, p.R4810K was identified in 31.4% of patients (80 of 255) with MMD. Significantly higher frequencies of the A allele and G/A genotype of p.R4810K were observed in MMD patients compared with controls (χ = 104.166, p < 0.000). Twenty-five rare variants were identified in 10.6% of patients (27 of 255) without p.R4810K variants. Segregation analysis supported an association between MMD and 3 variants. No possible disease-causing mutations were identified in ACTA2, BRCC3, or GUCY1A3. Compared with patients without the rare variants in RNF213, the p.R4810K heterozygous patients were younger at diagnosis (25 vs 29 years old, p = 0.049) and had more familial cases (24% vs 4.4%, p = 0.000), ischemic cases (81.3% vs 67.5%, p = 0.037), and involvement of the posterior cerebral artery (52% vs 32.5%, p = 0.007). CONCLUSIONS RNF213 is the major susceptibility gene in Chinese MMD patients. The spectrum of rare variants identified in Chinese MMD patients was diverse. Compared to patients without the rare variants in RNF213, the p.R4810K heterozygous patients exhibited different clinical features.
目的 烟雾病（MMD）是一种罕见的、遗传异质性的脑血管疾病。作者对真核起始因子 213（RING）（RNF213）、肌动蛋白α2（ACTA2）、BRCA1/BRCA2 复合物亚基 3（BRCC3）和鸟苷酸环化酶 1，可溶性，α3（GUCY1A3）进行了基因研究，并对中国 MMD 患者进行了临床表型分析，以确定遗传差异是否导致不同种族的 MMD 出现不同的临床特征。
方法 设计了一个小组来确定 MMD 基因和相关疾病（RNF213、ACTA2、BRCC3 和 GUCY1A3）中的致病突变。该小组用于检测 255 名中国 MMD 患者的致病突变。将患者与 300 名对照的基因型和等位基因频率进行比较。对 34 个家系进行了突变分离分析，并进行了基因型-表型相关性分析。
结果 在 RNF213 中发现了 27 种罕见的错义变异，在对照组中未发现。其中，p.R4810K 在 31.4%（80/255）的 MMD 患者中发现。与对照组相比，MMD 患者中 p.R4810K 的 A 等位基因和 G/A 基因型频率显著升高（χ=104.166，p<0.000）。在没有 p.R4810K 变异的 10.6%（27/255）的患者中发现了 25 种罕见变异。分离分析支持 MMD 与 3 种变异有关。在 ACTA2、BRCC3 或 GUCY1A3 中未发现可能的致病突变。与没有 RNF213 罕见变异的患者相比，p.R4810K 杂合子患者的诊断年龄更小（25 岁与 29 岁，p=0.049），家族病例更多（24%与 4.4%，p=0.000），缺血性病例更多（81.3%与 67.5%，p=0.037），后循环受累更多（52%与 32.5%，p=0.007）。
结论 RNF213 是中国 MMD 患者的主要易感基因。在中国 MMD 患者中发现的罕见变异谱是多样化的。与没有 RNF213 罕见变异的患者相比，p.R4810K 杂合子患者表现出不同的临床特征。
