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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease
S Miyatake1, N Miyake, H Touho
1Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
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.
Insights
The RNF213 gene's c.14576G>A variant strongly associates with moyamoya disease (MMD). Homozygous carriers often experience severe MMD with early onset and infarctions, suggesting it as a biomarker for aggressive disease.
Area of Science:
- Genetics
- Neurology
- Vascular Diseases
Background:
- Moyamoya disease (MMD) is a rare cerebrovascular disorder.
- RNF213 has been identified as a key susceptibility gene for MMD.
Purpose of the Study:
- To investigate the correlation between RNF213 gene variants and the clinical presentation of MMD.
- To determine the diagnostic and prognostic value of specific RNF213 genotypes in MMD patients.
Main Methods:
- Sequencing of the RNF213 coding region in 204 MMD patients and controls.
- Analysis of genotype-phenotype correlations, including age at onset and initial symptoms.
- Statistical analysis of variant frequencies and clinical outcomes.
Main Results:
- The c.14576G>A variant was highly prevalent in MMD patients (95.1% familial, 79.2% sporadic) compared to controls (1.8%).
- Homozygous c.14576G>A carriers exhibited significantly earlier onset (median 3 years) and a higher frequency of infarctions and posterior cerebral artery involvement.
- Other RNF213 variants did not show significant associations with MMD phenotypes.
Conclusions:
- The homozygous c.14576G>A variant in RNF213 serves as a potential DNA biomarker for predicting severe MMD.
- Early intervention strategies may be beneficial for individuals identified with this homozygous genotype.
- This finding aids in developing better monitoring and prevention approaches for severe moyamoya disease.
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