Non-Atherosclerotic and Genetic Intracranial Stenoses: Diagnostic Challenges and Emerging Genetic Insights

Intracranial arterial stenosis is a major cause of ischemic stroke worldwide. It is particularly prevalent among Asian populations. Intracranial arterial stenosis was traditionally considered as a manifestation of atherosclerotic disease. Subsequent research has documented it as a heterogeneous group of vasculopathies with diverse underlying mechanisms. Advanced high-resolution vessel wall imaging and genetic studies have revealed that non-atherosclerotic intracranial arteriopathies occur more commonly than previously recognized. In addition, these arteriopathies often exhibit overlapping clinical and imaging features with atherosclerotic stenosis. In this narrative review, we summarize the representative non-atherosclerotic causes of intracranial arterial stenosis, focusing on their characteristic clinical contexts, imaging hallmarks, and key points for differential diagnosis. Particular attention is given to phenotypic overlap that complicates strict etiological classification in routine clinical practice. We further discuss emerging evidence supporting a genetic contribution to intracranial arterial vulnerability, with particular emphasis on the ring finger protein 213 (RNF213) gene. Originally identified as a major susceptibility gene for moyamoya disease, RNF213 has since been implicated in a broader spectrum of intracranial arterial stenosis, including lesions conventionally classified as atherosclerotic. In addition, accumulating evidence suggests that RNF213-associated vascular phenotypes are not confined to intracranial circulation but may also involve extracranial arterial beds, supporting the concept of RNF213-related vasculopathy. Clinical and imaging studies have indicated that RNF213 variant carriers exhibit distinctive features, such as negative vascular remodeling and accelerated disease progression. Overall, these observations support a conceptual framework in which intracranial arterial stenosis represents a continuum of overlapping phenotypes shaped by genetic susceptibility and acquired modifiers. A 2-hit hypothesis integrating RNF213-related vascular vulnerability with secondary factors such as inflammation, atherosclerosis, or metabolic disorders may provide a unifying model for understanding disease heterogeneity and guiding future research and therapeutic strategies.