Difference in Clinical Phenotype, Mutation Position, and Structural Change of RNF213 Rare Variants Between Pediatric...

Area of Science:

• Genetics
• Neurology
• Biochemistry

Background:

• Moyamoya disease (MMD) is a rare cerebrovascular disorder.
• The RNF213 gene, particularly the p.R4810K variant, is strongly associated with MMD.
• The impact of rare RNF213 variants beyond p.R4810K on MMD remains unclear.

Purpose of the Study:

• To investigate the clinical phenotypes associated with rare RNF213 variants in MMD patients.
• To analyze the genotype-phenotype correlation of these variants.
• To explore the structural impact of rare variants on the RNF213 protein using 3D modeling.

Main Methods:

• Targeted resequencing of all coding exons of the RNF213 gene in 151 Japanese MMD patients.
• Clinical phenotype investigation and statistical genotype-phenotype correlation analysis.
• Three-dimensional (3D) modeling of human RNF213 to assess structural changes caused by variants.

Main Results:

• The p.R4810K homozygous variant was found in 6.6%, heterozygous in 73.5%, and wild type in 19.9% of patients.
• Fifteen rare variants were identified in 10.6% of patients.
• Pediatric patients with rare variants (excluding p.R4810K homozygous) showed a significantly higher frequency of cerebral infarction at onset (50.0%) compared to those with only heterozygous p.R4810K or no variants (3.9%).
• Rare variants in pediatric patients were predominantly located in the E3 module, causing salt bridge loss, unlike in adult patients.
• Clinical phenotypes and structural changes differed between pediatric and adult MMD patients with rare RNF213 variants.

Conclusions:

• Rare RNF213 variants, in addition to the founder p.R4810K variant, significantly influence MMD clinical phenotypes.
• These rare variants can cause structural destabilization of the RNF213 protein.
• Distinct genotype-phenotype correlations and structural impacts exist for rare variants in pediatric versus adult MMD patients.