Abstract TP382: Ethnicities, Genetic Backgrounds, and the Location of Internal Carotid Artery Stenosis in Patients with Moyamoya Disease

Introduction: Moyamoya disease (MMD) is a rare cerebrovascular disease causing nonatherosclerotic intracranial arterial stenosis in children and young adults. Recent investigations have found that some genetic variants, such as RNF213 p.R4810K variant among East Asian populations, play an important role in MMD. Previously, we have identified a subset of patients with unique imaging features characterized by stenosis of the internal carotid artery (ICA) localized proximal to the terminal portion of ICA (non-terminal ICA), differing from the typical stenosis in MMD. This non-terminal stenosis was more common in Caucasian than in Asian patients; thus, investigating this unique feature may elucidate novel pathophysiology of MMD, especially in non-Asian population. Herein, we investigated the genetic background of non-terminal ICA stenosis in diverse ethnicities. Methods: We selected 46 sporadic nonhemorrhagic bilateral MMD patients aged 18-50 years old with diverse ethnic backgrounds and no significant comorbidities (Fig. 1). MRAs of each patient were visually assessed to evaluate the location of stenosis in ICAs and were categorized as “terminal stenosis” or “non-terminal stenosis”. Blood samples were analyzed for known single-nucleotide polymorphisms with risk of MMD in RNF213, ZXDC, DIAPH1, ACTA2, and GUCY1A1. Results: Representative images of patients with terminal ICA stenosis and non-terminal ICA stenosis were shown in Fig. 2. Non-terminal ICA stenosis was more frequent in Caucasians (5/15, 33.3%) compared to Asians (2/13, 15.4%) and other ethnicities (2/19, 10.5%). Genetic analysis revealed RNF213 p.R4810K variant only in Asian patients with terminal stenosis (Table 1). Among patients with non-terminal stenosis, ZXDC p.P562L variant was detected in two Caucasian patients; however, this variant was also detected in two Hispanic patients with terminal ICA stenosis. Two Black patients with terminal stenosis exhibited DIAPH1 c.534-2A>G variant, but no variants of DIAPH1 , ACTA2, and GUCY1A1 were detected in patients with non-terminal ICA stenosis Conclusion: Previously established variants of disease-causing genes, particularly RNF213 p.R4810K mutation, are insufficient to explain non-terminal ICA stenosis, an atypical feature of MMD. Future genomic analysis focusing on other rare genetic variants and epigenetic analysis may clarify the factors inducing this unique phenotype.