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

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSION

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.