Genotype-Phenotype Correlation of the RNF213 R4810K Variant in Moyamoya Disease

Abstract

The R4810K variant of ring finger protein 213 (RNF213) was identified as a strong genetic susceptibility factor for moyamoya disease (MMD) in the East Asian population [1,2]. The RNF213 R4810K variant is associated with significantly early age of onset and the severity of clinical disease phenotypes [3-5]. However, its association with various other clinical presentations and long-term patient outcomes has not been fully established [6,7]. This study aimed to investigate the influence of the RNF213 R4810K variant on clinical phenotypes and long-term outcomes in Korean patients with MMD. This retrospective study involved 311 Korean patients with MMD who had undergone RNF213 genotyping at two tertiary university hospitals between January 2017 and August 2021. A flowchart for the selection of MMD with RNF213 genotyping is shown in Supplementary Figure 1. The detailed methodology is described in the Supplementary Methods. Briefly, clinical manifestations including cerebral infarction, transient ischemic attack (TIA), intracranial hemorrhage/intraventricular hemorrhage (ICH/IVH), seizure, and angiographic characteristics including bilateral vasculopathy, posterior cerebral artery (PCA) involvement, and Suzuki grade were assessed at diagnosis of MMD. The association between the RNF213 R4810K variant and clinical/angiographic characteristics at MMD diagnosis was investigated. Moreover, among patients with at least 3 months of follow-up, we evaluated the influence of the RNF213 R4810K variant on long-term clinical outcomes and the results of revascularization after bypass surgery. This study was reviewed and approved by Severance Hospital Yonsei University Health System Institutional Review Board (3-2021-0443). The requirement for written informed consent was waived due to the retrospective study design. The clinical and angiographic characteristics of 311 patients with MMD are summarized in Supplementary Table 1. The distribution of age peaked twice—at ages 5-9 and 45-49 years—with a higher frequency in the adult peak (Supplementary Figure 2A). Compared to adult MMD patients, pediatric MMD patients more frequently presented with ischemic manifestations and seizures and had a higher proportion of bilateral vasculopathy. The correlation between clinical characteristics and the RNF213 R4810K variant in MMD is summarized in Table 1 and Supplementary Figure 3. The age at onset of homozygotes was significantly lower than those of heterozygotes and the wild-type (Supplementary Figure 2B). The proportion of patients who underwent revascularization surgery showed a dosage-dependent pattern of the variant, being the highest in homozygotes (60% in AA, 34% in GA, and 16% in GG; P for trend <0.001). Seizure as the initial clinical manifestation was more common in homozygotes than in heterozygotes or those with the wild-type variant (40% vs. 3%, P=0.03; 40% vs. 3%, P=0.06; respectively). Homozygotes were more susceptible to PCA involvement than heterozygotes and wild-type (80% vs. 20%, P=0.02; 80% vs. 10%, P<0.01; respectively). PCA involvement showed a dose-dependent pattern of the variant, being the highest in homozygotes (80% in AA, 20% in GA, and 10% in GG; P for trend <0.001). The results of the subgroup analysis of genotype-phenotype correlations for RNF213 R4810K variant with the age at onset are described in the Supplementary Results, Supplementary Tables 2-4, and Supplementary Figure 3.