Association of RNF213 Variants With Periventricular Anastomosis in Moyamoya Disease

Background: The pathogenic mechanisms of periventricular anastomosis (PA) in moyamoya disease remain unknown. Here, we aimed to describe the angiographic profiles of PA and their relationships with really interesting new gene (RING) finger protein 213 (RNF213) genotypes.

Methods: We conducted a retrospective cohort study of moyamoya disease patients consecutively recruited between June 2019 and January 2021 in Beijing Tiantan Hospital, Capital Medical University, China. C-terminal region of RNF213 was sequenced. Angiographic characteristics of PA vessels (lenticulostriate artery, thalamotuberal artery, thalamoperforating artery, anterior choroidal artery, and posterior choroidal artery) were compared between different groups of RNF213 genotypes. The dilatation and extension of PA vessels were measured by using PA score (positive, score 1-5; negative, score 0). Multivariate regression analysis was conducted to assess variables associated with PA score. In addition, gene expression of RNF213 in human brain regions was evaluated from the Allen Human Brain Atlas.

Results: Among 260 patients (484 hemispheres), 71.2% carried no RNF213 rare and novel variants, 20.0% carried p.R4810K heterozygotes, and 8.8% carried other rare and novel variants. PA scores in patients with p.R4810K and other rare and novel variants were significantly higher than in wild-type patients (P<0.001). Age (odds ratio [OR], 0.958 [95% CI, 0.942-0.974]; P<0.001), platelet count (OR, 0.996 [95% CI, 0.992-0.999]; P=0.027), p.R4810K variant (OR, 2.653 [95% CI, 1.514-4.649]; P=0.001), other rare and novel variants (OR, 3.197 [95% CI, 1.012-10.094]; P=0.048), Suzuki stage ≥4 (OR, 1.941 [95% CI, 1.138-3.309]; P=0.015), and posterior cerebral artery involvement (OR, 1.827 [95% CI, 1.020-3.271]; P=0.043) were significantly correlated with PA score. High expression of RNF213 was detected in the periventricular area.

Conclusions: RNF213 variants were confirmed to be associated with PA in moyamoya disease. Individuals with RNF213 p.R4810K heterozygotes and other C-terminal region rare variants exhibited different angiographic phenotypes, compared with wild-type patients.