Familial Moyamoya disease associated with dual RNF213 variants (R4810K and T1727M): A case report and genetic...

Moyamoya disease (MMD) is a progressive cerebrovascular disorder characterized by stenosis or occlusion of the distal internal carotid arteries, frequently observed in East Asian populations. The RNF213 R4810K variant is a well-established susceptibility factor for MMD; however, the pathogenic significance of other rare variants, such as T1727M, remains largely undefined. The co-occurrence and potential synergistic effects of dual RNF213 variants have rarely been documented.

We investigated a 3-generation family consisting of 17 members following the diagnosis of MMD in the proband. Comprehensive clinical evaluations, magnetic resonance angiography, and whole-exome sequencing were performed on symptomatic individuals, while targeted genotyping for RNF213 and other candidate variants was conducted on the remaining family members.

The proband was a 63-year-old woman with a history of ischemic and hemorrhagic cerebrovascular events. Genetic testing revealed 2 RNF213 variants, R4810K and T1727M, which were subsequently identified in 10 family members. Among these, 5 were diagnosed with MMD, 1 exhibited large-vessel occlusion with stroke symptoms, and 4 were asymptomatic but are currently under clinical surveillance. Additional rare variants were identified in HTRA1, PROS1, and F13A1, which may further modulate disease expression.

We report for the first time a multigenerational case with dual RNF213 variants (R4810K and T1727M) and modifiers in familial MMD. The findings underscore the importance of genetic screening in at-risk families and suggest that dual RNF213 mutations may increase disease penetrance. Further mechanistic studies are warranted to elucidate gene-gene interactions and the role of additional modifiers in MMD pathogenesis.