Genetic Biomarkers for Moyamoya Disease Beyond Angiography

Moyamoya disease (MMD) is a chronic, progressive cerebrovascular disorder characterized by idiopathic steno-occlusive changes involving the distal internal carotid arteries or proximal middle cerebral arteries, accompanied by the formation of fragile collateral vessels.1,2 Although its angiographic features are well recognized, the underlying etiology of MMD remains incompletely understood.MMD shows a marked ethnic and geographic predilection, with a substantially higher incidence in East Asian populations, particularly in Korea, Japan and China, compared with Western countries.3 Annual incidence of these three countries are increasing.4 A bimodal age distribution is observed, with incidence peaks at approximately 10 years and 30-40 years, accompanied by differing clinical presentations.3,5 In adults, clinical presentations are heterogeneous, ranging from transient ischemic attacks to ischemic or hemorrhagic stroke, often with a more variable disease course than that observed in pediatric patients.Despite its characteristic vascular morphology, the diagnosis of MMD in adults is frequently challenging in clinical practice.Intracranial atherosclerotic disease, inflammatory vasculopathies, radiation-induced arteriopathy, and other nonatherosclerotic steno-occlusive disorders may resemble MMD, particularly in cases of unilateral involvement, earlystage disease, or in patients with conventional vascular risk factors.Reliance on imaging findings alone may therefore be insufficient for accurate differentiation in certain patient populations.2 Given that treatment strategies, prognosis, and follow-up differ across these conditions, there is a growing interest in adjunctive diagnostic approaches.In this context, the identification of reliable biomarkers, including genetic markers, has been proposed as a complementary strategy to improve diagnostic accuracy and to better characterize the underlying biology of moyamoya vasculopathy.2,6 Ring finger protein 213 (RNF213) p.Arg4810Lys (p.R4810K, rs112735431) variant is a major genetic risk factor for MMD.This RNF213 variant has been implicated not only in the diagnosis of MMD but also in the risk of stroke recurrence.7 Additional RNF213 variants, including p.A4399T (rs148731719), 8 p.A5021V (rs138130613), p.D4863N, p.E4950D, p.D5160E, and p.E5176G have also been identified as being associated with increased risk of MMD. 9 However, in Korea, a single-center observational study demonstrated that RNF213 p.R4810K was the only variant among thirty RNF213 variants that showed strong association with MMD. 10 These findings have underscored the need to find other genetic risk factors.The recent whole-exome sequencing-based association study in adult MMD provides relevant insights into the genetic contributors to disease susceptibility.6 This study also confirmed the strong association of the RNF213 p.R4810K variant with adult MMD, particularly in East Asian populations.Additional coding variants in genes such as GAA (alpha-glucosidase) and CHMP6 (charged multivesicular body protein 6) within the 17q25.3locus were identified.Importantly, by integrating multiple missense variants into a mutant allele risk score, the authors demonstrated improved discriminative performance for MMD compared