RNF213 R4810K Variant in Suspected Unilateral Moyamoya Disease Predicts Contralateral Progression

Abstract

Background Early‐stage unilateral moyamoya disease (MMD) is difficult to discriminate from isolated intracranial atherosclerotic stenosis, and identification of contralateral progression may aid in the diagnosis of MMD. The RNF213 (ring finger protein 213) R4810K variant is a strong genetic susceptibility factor for MMD; however, the role of contralateral progression in unilateral MMD is unknown. Methods and Results Patients who had undergone RNF213 R4810K genotyping with suspected unilateral MMD between January 2017 and August 2021 from 2 tertiary university hospitals were retrospectively reviewed. We compared the clinical features and radiographic outcomes of patients with and without this variant. The risk factors of contralateral progression in patients with suspected unilateral MMD were evaluated. The RNF213 R4810K variant was observed in 72 of 123 patients with suspected unilateral MMD, all of which were heterozygous. The allele frequency of the R4810K variant was significantly higher in the suspected unilateral MMD group compared with the historical control group (29.3% versus 1.2%; P <0.0001). Family history of MMD was significantly more common in patients with the variant than in those without (17% versus 4%; P =0.003). Eleven of 72 patients with the variant developed contralateral progression, whereas only 1 of 51 patients without the variant developed contralateral progression during a median follow‐up period of 28 months (log‐rank test; P =0.03). The presence of the RNF213 R4810K variant significantly correlated with contralateral progression (adjusted odds ratio, 6.39 [95% CI, 1.11–36.63]; P =0.04). Conclusions Contralateral progression is more likely to occur in patients with suspected unilateral MMD with the RNF213 R4810K variant than in those without the variant. However, because our study used a small sample size, this finding should be carefully interpreted and requires further studies with more patients and longer follow‐up periods.

Recent Advances for Global Perspectives on Etiology, Pathophysiology, Clinical Presentations, and Management of Moyamoya Disease

“…Recent research has identified several susceptibility genes, including individuals diagnosed with familial moyamoya disease, that have the 95% p. R4810K variant in the RNF213 gene [3]. Studies have found that Moyamoya disease is more common in individuals of Asian descent, with a higher prevalence observed in Japan where the condition was first discovered [4]. Interestingly, MMD is linked to have an association with mutations in human RNF213 and ACTA2 genes.…”

“…MMD has a bimodal distribution, with peaks between the ages of 5 to 10 years in children and then between ages 30 -50 years in adults; the population of patients from the second peak is smaller than the first. MMD has a family history, which is positive in 10% -15% of patients with initial onset followed by slow progression [4] [5]. According to a prospective study involving 23 patients diagnosed with ischemic MMD using DSA, it was discovered that TGFβ1 is crucial in facilitating the development of collateral blood vessels by increasing the expression of VEGF in ischemic MMD.…”