RNF213 p.R4810K variant in moyamoya disease in adults and children from a Malaysian tertiary center

Background: Ring finger protein 213 (RNF213) is a major susceptibility gene for moyamoya disease (MMD). A single nucleotide variant known as c.14429G>A (p.R4810K, rs112735431) is strongly associated with MMD, weakly associated with moyamoya syndrome (MMS) and intracranial atherosclerosis (ICAS) in East Asians. The percentage of patients carrying p.R4810K and the effect sizes vary between different racial backgrounds. We aimed to investigate the prevalence of p.R4810K in MMD, MMS, and ICAS patients in Malaysia. Methods: We genotyped p.R4810K in DNA extracted from 9 MMD, 13 MMS, 15 ICAS cases, and 45 controls using TaqMan SNP genotyping assay. Clinical and neuroradiological data was collected for each patient and the distribution of genotype frequencies compared between cases and controls and tested for association. Results: Two of seven (28.6%) Chinese MMD cases had heterozygous p.R4810K (GA) genotype. The remaining MMD cases (5 Chinese and 2 Malays), all 13 MMS, 15 ICAS cases and 45 controls had homozygous wild-type (GG) genotype. Higher frequency of GA genotype was observed in Chinese MMD patients compared with controls, indicating an association between p.R4810K and Chinese MMD subgroup under a dominant model (P=0.0398). Conclusion: This is the first study reporting p.R4810K in a multiracial Asian population. The p.R4810K missense mutation was detected in MMD cases of Chinese descent in Malaysia. Further studies are needed to identify other susceptibility variants and genes in Malaysian patients with moyamoya and ICAS.