Ethnic variation and the relevance of homozygous RNF 213 p.R4810.K variant in the phenotype of Indian Moya moya disease.

Arun K,C M Shafeeque,Sylaja P N,Moinak Banerjee,Jayanand B Sudhir,Klaus Brusgaard

doi:10.1371/journal.pone.0243925

Abstract

Polymorphisms in Ring Finger Protein 213 (RNF 213) gene have been detected to confer genetic susceptibility to Moya moya disease (MMD) in the East Asian population. We investigated the frequency of RNF 213 gene polymorphism and its association with MMD phenotypes in the Indian population. A case-control study for RNF 213 polymorphism involving 65 MMD patients, 75 parents, and 120 controls were performed. A total of 21 SNPs were screened, of which 17 SNPs were monomorphic. Allelic and genotypic frequency of all polymorphic SNPs were assessed and its association with MMD phenotypes was evaluated. The median age of symptom onset was 9 (range 2-17) and 37 years (range 20-58) in paediatric and adult patients respectively. A strong association was observed with RNF 213 rs112735431(p.R4810K) and MMD. Out of 65 patients with MMD, five patients carried the homozygous risk AA genotype. None of the healthy controls carried this homozygous mutation. The mutant allele was detected in MMD patients from Tamil Nadu and North eastern states of India (p = <0.0001). All the patients carrying the mutant allele had an early age of onset (p = <0.0001), higher incidence of bilateral disease (p = <0.002), positive family history (p = 0.03), higher Suzuki angiographic stage (≥3) (p<0.0006) and recurrent neurological events (ischemic strokes and TIAs) (p = <0.009). The homozygous rs112735431(p.R4810K) variant in RNF 213 variant not only predicts the risk for MMD but can also predict the phenotypic variants.

Highlights

Moya moya disease (MMD) is a rare chronic cerebrovascular disorder characterized by progressive bilateral occlusion of the supra-clinoid internal carotid artery (ICA) and its main branches with associated development of fine collateral networks, adjacent to the site of occlusion in the deep areas of the brain [1]
A strong association was observed with Ring Finger Protein 213 (RNF 213) rs112735431(p.R4810K) and MMD
The mutant allele was detected in MMD patients from Tamil Nadu and North eastern states of India (p =

Summary

Introduction

Moya moya disease (MMD) is a rare chronic cerebrovascular disorder characterized by progressive bilateral occlusion of the supra-clinoid internal carotid artery (ICA) and its main branches with associated development of fine collateral networks, adjacent to the site of occlusion in the deep areas of the brain [1]. Studies have demonstrated that single nucleotide polymorphisms in the RNF 213 gene had a strong association with the onset of MMD in both familial and sporadic cases [4, 5]. In the East Asian population, the founder variant RNF 213 p.R4810K was much more frequently found in MMD patients (Japanese, 90.1%; Korean, 78.9%; Chinese, 23.1%) than the general population (Japanese, 2.5%; Korean, 2.7%; Chinese, 0.9%) [5, 6]. Polymorphisms in Ring Finger Protein 213 (RNF 213) gene have been detected to confer genetic susceptibility to Moya moya disease (MMD) in the East Asian population. We investigated the frequency of RNF 213 gene polymorphism and its association with MMD phenotypes in the Indian population

Results

Discussion

Conclusion