TY - JOUR
T1 - Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease
AU - Miyatake, S.
AU - Miyake, N.
AU - Touho, H.
AU - Nishimura-Tadaki, A.
AU - Kondo, Y.
AU - Okada, I.
AU - Tsurusaki, Y.
AU - Doi, H.
AU - Sakai, H.
AU - Saitsu, H.
AU - Shimojima, K.
AU - Yamamoto, T.
AU - Higurashi, M.
AU - Kawahara, N.
AU - Kawauchi, H.
AU - Nagasaka, K.
AU - Okamoto, N.
AU - Mori, T.
AU - Koyano, S.
AU - Kuroiwa, Y.
AU - Taguri, M.
AU - Morita, S.
AU - Matsubara, Y.
AU - Kure, S.
AU - Matsumoto, N.
N1 - Funding Information:
Dr. Miyatake reports no disclosures. Dr. Miyake is funded by research grants from the Ministry of Health, Labour and Welfare, and a Grant-in-Aid for Young Scientists from the Japan Society for the Promotion of Science. Dr. Touho, Dr. Nishimura-Tadaki, Dr. Kondo, Dr. Okada, Dr. Tsurusaki, Dr. Doi, and Dr. Sakai report no disclosures. Dr. Saitsu is funded by research grants from the Ministry of Health, Labour and Welfare and a Grant-in-Aid for Young Scientists from the Japan Society for the Promotion of Science. Dr. Shimojima reports no disclosures. Dr. Yamamoto is funded by a research grant, Scientific Research (c) from the Japan Ministry of Education, Science, Sports and Culture. Dr. Higurashi, Dr. Kawahara, Dr. Kawauchi, Dr. Nagasaka, Dr. Okamoto, Dr. Mori, Dr. Koyano, Dr. Kuroiwa, Dr. Taguri, Dr. Morita, Dr. Matsubara, and Dr. Kure report no disclosures. Dr. Matsumoto serves on editorial advisory boards for Clinical Genetics, Journal of Human Genetics, and American Journal of Medical Genetics Part A and is funded by research grants from the Ministry of Health, Labour and Welfare, the Japan Science and Technology Agency, a Grant-in-Aid for Scientific Research on Innovative Areas-(Foundation of Synapse and Neurocircuit Pathology)-from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, and a grant from the Takeda Science Foundation.
PY - 2012/3/13
Y1 - 2012/3/13
N2 - Objective: RNF213 was recently reported as a susceptibility gene for moyamoya disease (MMD). Our aim was to clarify the correlation between the RNF213 genotype and MMD phenotype. Methods: The entire coding region of the RNF213 gene was sequenced in 204 patients with MMD, and corresponding variants were checked in 62 pairs of parents, 13 mothers and 4 fathers of the patients, and 283 normal controls. Clinical information was collected. Genotypephenotype correlations were statistically analyzed. Results: The c.14576G>A variant was identified in 95.1% of patients with familial MMD, 79.2% of patients with sporadic MMD, and 1.8% of controls, thus confirming its association with MMD, with an odds ratio of 259 and p < 0.001 for either heterozygotes or homozygotes. Homozygous c.14576G>A was observed in 15 patients but not in the controls and unaffected parents. The incidence rate for homozygotes was calculated to be >78%. Homozygotes had a significantly earlier age at onset compared with heterozygotes or wild types (median age at onset 3, 7, and 8 years, respectively). Of homozygotes, 60% were diagnosed with MMD before age 4, and all had infarctions as the first symptom. Infarctions at initial presentation and involvement of posterior cerebral arteries, both known as poor prognostic factors for MMD, were of significantly higher frequency in homozygotes than in heterozygotes and wild types. Variants other than c.14576G>A were not associated with clinical phenotypes. Conclusions: The homozygous c.14576G>A variant in RNF213 could be a good DNA biomarker for predicting the severe type of MMD, for which early medical/surgical intervention is recommended, and may provide a better monitoring and prevention strategy.
AB - Objective: RNF213 was recently reported as a susceptibility gene for moyamoya disease (MMD). Our aim was to clarify the correlation between the RNF213 genotype and MMD phenotype. Methods: The entire coding region of the RNF213 gene was sequenced in 204 patients with MMD, and corresponding variants were checked in 62 pairs of parents, 13 mothers and 4 fathers of the patients, and 283 normal controls. Clinical information was collected. Genotypephenotype correlations were statistically analyzed. Results: The c.14576G>A variant was identified in 95.1% of patients with familial MMD, 79.2% of patients with sporadic MMD, and 1.8% of controls, thus confirming its association with MMD, with an odds ratio of 259 and p < 0.001 for either heterozygotes or homozygotes. Homozygous c.14576G>A was observed in 15 patients but not in the controls and unaffected parents. The incidence rate for homozygotes was calculated to be >78%. Homozygotes had a significantly earlier age at onset compared with heterozygotes or wild types (median age at onset 3, 7, and 8 years, respectively). Of homozygotes, 60% were diagnosed with MMD before age 4, and all had infarctions as the first symptom. Infarctions at initial presentation and involvement of posterior cerebral arteries, both known as poor prognostic factors for MMD, were of significantly higher frequency in homozygotes than in heterozygotes and wild types. Variants other than c.14576G>A were not associated with clinical phenotypes. Conclusions: The homozygous c.14576G>A variant in RNF213 could be a good DNA biomarker for predicting the severe type of MMD, for which early medical/surgical intervention is recommended, and may provide a better monitoring and prevention strategy.
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U2 - 10.1212/WNL.0b013e318249f71f
DO - 10.1212/WNL.0b013e318249f71f
M3 - Article
C2 - 22377813
AN - SCOPUS:84859929899
VL - 78
SP - 803
EP - 810
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 11
ER -