title: Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease.
abstract: 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. Genotype-phenotype 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.
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Miyatake
authors.forename: N
authors.initials: N
authors.lastname: Miyake
authors.forename: H
authors.initials: H
authors.lastname: Touho
authors.forename: A
authors.initials: A
authors.lastname: Nishimura-Tadaki
authors.forename: Y
authors.initials: Y
authors.lastname: Kondo
authors.forename: I
authors.initials: I
authors.lastname: Okada
authors.forename: Y
authors.initials: Y
authors.lastname: Tsurusaki
authors.forename: H
authors.initials: H
authors.lastname: Doi
authors.forename: H
authors.initials: H
authors.lastname: Sakai
authors.forename: H
authors.initials: H
authors.lastname: Saitsu
authors.forename: K
authors.initials: K
authors.lastname: Shimojima
authors.forename: T
authors.initials: T
authors.lastname: Yamamoto
authors.forename: M
authors.initials: M
authors.lastname: Higurashi
authors.forename: N
authors.initials: N
authors.lastname: Kawahara
authors.forename: H
authors.initials: H
authors.lastname: Kawauchi
authors.forename: K
authors.initials: K
authors.lastname: Nagasaka
authors.forename: N
authors.initials: N
authors.lastname: Okamoto
authors.forename: T
authors.initials: T
authors.lastname: Mori
authors.forename: S
authors.initials: S
authors.lastname: Koyano
authors.forename: Y
authors.initials: Y
authors.lastname: Kuroiwa
authors.forename: M
authors.initials: M
authors.lastname: Taguri
authors.forename: S
authors.initials: S
authors.lastname: Morita
authors.forename: Y
authors.initials: Y
authors.lastname: Matsubara
authors.forename: S
authors.initials: S
authors.lastname: Kure
authors.forename: N
authors.initials: N
authors.lastname: Matsumoto
mesh_terms: D000251:Adenosine Triphosphatases; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D015415:Biomarkers; D002544:Cerebral Infarction / Q000209:etiology; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D004827:Epilepsy / Q000150:complications; D005190:Family; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000150:complications / Q000523:psychology; D008297:Male; D008875:Middle Aged; D009072:Moyamoya Disease / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D020769:Posterior Cerebral Artery / Q000473:pathology; D011237:Predictive Value of Tests; D012727:Sex Characteristics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D004247:DNA; C557998:RNF213 protein, human; D044767:Ubiquitin-Protein Ligases; D000251:Adenosine Triphosphatases