349 ZYX is a Novel Candidate Gene in Moyamoya Pathogenesis

INTRODUCTION: Moyamoya disease (MMD) is characterized by progressive bilateral stenosis in the proximal branches of the internal carotid arteries with compensatory angiogenesis. It is common in Japanese population; accounting for one fifth of pediatric stroke cases associated with arteriopathies. Although the etiology remains largely unknown, genetic factors have been implicated in the pathophysiology of MMD. METHODS: We performed gene-based mutational burden analysis using WES results of 23 MMD patients and a control cohort of 8380 Japanese individuals obtained from jMorp (8.3 kjpn). We performed a case-control analysis by comparing the enrichment of rare (Japanese minor allele frequency <2.5e-4) and deleterious variants including loss of function (LoF) variants (stop gain, start loss, frameshift, splice acceptor and splice donor) and missense variants annotated as “deleterious” in MetaSVM (D-Mis). RESULTS: We identified ZYX gene, encoding a focal adhesion molecule Zyxin, top significantly enriched gene in MMD cohort (two tailed Fisher's P = 1.52E-5; OR 77.55 [95% CI 13.91–291.69]), with three individuals were found to carry a heterozygous LoF and two missense mutations in ZYX gene. ZYX expression was found above 96th percentile for an ‘arterial-enrichment ratio’ calculated using GtEX portal, suggesting its critical role in vascular cell types. CONCLUSIONS: In this study, we identified ZYX as a novel candidate gene in Moyamoya pathogenesis. Zyxin is a known focal adhesion molecule involved in mechanosensation in the vasculature, while its implication in MMD has not been previously reported.