Whole-exome sequencing in moyamoya patients of Northern-European origin identifies gene variants involved in Nitric Oxide metabolism: A pilot study

INTRODUCTION: Moyamoya disease (MMD) is a chronic cerebrovascular steno-occlusive disease of largely unknown etiology. Variants in the RNF213 gene are strongly associated with MMD in East-Asia. In MMD patients of Northern-European origin, no predominant susceptibility variants have been identified so far. RESEARCH QUESTION: Are there specific candidate genes associated with MMD of Northern-European origin, including the known RNF213 gene? Can we establish a hypothesis for MMD phenotype and associated genetic variants identified for further research? MATERIAL AND METHODS: Adult patients of Northern-European origin, treated surgically for MMD at Oslo University Hospital between October 2018 to January 2019 were asked to participate. WES was performed, with subsequent bioinformatic analysis and variant filtering. The selected candidate genes were either previously reported in MMD or known to be involved in angiogenesis. The variant filtering was based on variant type, location, population frequency, and predicted impact on protein function. RESULTS: Analysis of WES data revealed nine variants of interest in eight genes. Five of those encode proteins involved in nitric oxide (NO) metabolism: NOS3, NR4A3, ITGAV, GRB7 and AGXT2. In the AGXT2 gene, a de novo variant was detected, not previously described in MMD. None harboured the p.R4810K missense variant in the RNF213 gene known to be associated with MMD in East-Asian patients. DISCUSSION AND CONCLUSION: Our findings suggest a role for NO regulation pathways in Northern-European MMD and introduce AGXT2 as a new susceptibility gene. This pilot study warrants replication in larger patient cohorts and further functional investigations.