RNF213 p.Arg4810Lys Wild Type is Associated with De Novo Hemorrhage in Asymptomatic Hemispheres with Moyamoya Disease

Abstract

Clinical implications of RNF213 genetic variants, other than p.Arg4810Lys, in moyamoya disease (MMD), remain unclear. This study aimed to investigate the association of RNF213 variants with clinical phenotypes in MMD. This retrospective cohort study collected data regarding the clinical characteristics of 139 patients with MMD and evaluated the angioarchitectures of 253 hemispheres using digital subtraction angiography at diagnosis. All RNF213 exons were sequenced, and the associations of clinical characteristics and angiographical findings with p.Arg4810Lys, p.Ala4399Thr, and other rare variants (RVs) were examined. Among 139 patients, 100 (71.9%) had p.Arg4810Lys heterozygote (GA) and 39 (28.1%) had the wild type (GG). Fourteen RVs were identified and detetcted in 15/139 (10.8%) patients, and p.Ala4399Thr was detected in 17/139 (12.2%) patients. Hemispheres with GG and p.Ala4399Thr presented with significantly less ischemic events and more hemorrhagic events at diagnosis (p = 0.001 and p = 0.028, respectively). In asymptomatic hemispheres, those with GG were more susceptible to de novo hemorrhage than those with GA (adjusted hazard ratio [aHR] 5.36) with an increased risk when accompanied by p.Ala4399Thr or RVs (aHR 15.22 and 16.60, respectively). Within the choroidal anastomosis-positive hemispheres, GG exhibited a higher incidence of de novo hemorrhage than GA (p = 0.004). The GG of p. Arg4810Lys was a risk factor for de novo hemorrhage in asymptomatic MMD hemispheres. This risk increased with certain other variants and is observed in choroidal anastomosis-positive hemispheres. A comprehensive evaluation of RNF213 variants and angioarchitectures is essential for predicting the phenotype of asymptomatic hemispheres in MMD.

Keywords: RNF213; Genotype; Moyamoya disease; Phenotype.

Fig. 1

Kaplan–Meier curves for de novo ischemia and hemorrhage in asymptomatic hemispheres. Kaplan–Meier curves for de novo ischemia (a) and de novo hemorrhage (b) in the asymptomatic hemispheres. PCA involvement is a risk factor for de novo ischemia in terms of angiographical features, whereas choroidal PA is associated with de novo hemorrhage. GG/p.Ala4399Thr and GG/RV were significant risk factors for de novo hemorrhage compared to GA regarding the genotype groups. Kaplan–Meier curves analyzed by the other angiographical features and other factors (sex, HT, DM, HL, and smoking) are shown in Supplementary Fig. S3. P-values were calculated using the log-rank tests. GA, heterozygote of p.Arg4810Lys; GG, wild type of p.Arg4810Lys; PA, periventricular anastomosis; PCA, posterior cerebral artery; RV, rare variant

Fig. 2

Kaplan–Meier curves for de novo hemorrhage in asymptomatic hemispheres with or without choroidal periventricular anastomosis. Kaplan–Meier curves for de novo hemorrhage in asymptomatic hemispheres with (a) or without (b) choroidal PA. The log-rank test revealed that GG was significantly more susceptible to de novo hemorrhage than GA within the hemispheres with choroidal PA. Conversely, there was no significant difference by genotype in the hemispheres without PA. aHR, adjusted hazard ratio; CI, Confidence interval; GA, heterozygote of p.Arg4810Lys; GG, wild type of p.Arg4810Lys; PA, periventricular anastomosis