title: RNF213 as the major susceptibility gene for Chinese patients with moyamoya disease and its clinical relevance.
abstract: 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 (χ2= 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.
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China National Clinical Research Center for Neurological Diseases; and.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China National Clinical Research Center for Neurological Diseases; and.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China National Clinical Research Center for Neurological Diseases; and.
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China National Clinical Research Center for Neurological Diseases; and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China National Clinical Research Center for Neurological Diseases; and.
authors.forename: Shuo
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China National Clinical Research Center for Neurological Diseases; and.
authors.forename: Lanbing
authors.initials: L
authors.lastname: Yu
authors.affiliation: 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.
authors.forename: Chaoxia
authors.initials: C
authors.lastname: Lu
authors.affiliation: 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.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China National Clinical Research Center for Neurological Diseases; and.
authors.forename: Jizong
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000199:Actins / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000235:genetics*; D000328:Adult; D044466:Asian People; D000072017:Deubiquitinating Enzymes; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009072:Moyamoya Disease / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D000071756:Soluble Guanylyl Cyclase / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; C000605661:GUCY1A1 protein, human; D008565:Membrane Proteins; C557998:RNF213 protein, human; D044767:Ubiquitin-Protein Ligases; C518017:BRCC3 protein, human; D000072017:Deubiquitinating Enzymes; D000251:Adenosine Triphosphatases; D000071756:Soluble Guanylyl Cyclase
keywords: MAF = minor allele frequency; MMD = moyamoya disease; MMS = moyamoya syndrome; NGS = next-generation sequencing; PCA = posterior cerebral artery; RING = really interesting new gene; RNF213; clinical features; mRS = modified Rankin Scale; moyamoya disease; variant; vascular disorders