Genetics of Moyamoya Beyond RNF213: Monogenic Moyamoya Syndromes

Abstract

Moyamoya angiopathy (MMA), in addition to its idiopathic form, so-called moyamoya disease (MMD), is also part of a broad spectrum of various diseases. In that situation, it is designated by the term moyamoya syndrome (MMS). Most MMS have a strong genetic component and include a heterogeneous group of monogenic disorders with highly variable clinical features and patterns of inheritance and penetrance. The recognition of known monogenic MMS entities and the delineation of novel ones are of major importance for disease prognosis, clinical care, accurate genetic counseling, gene identification, and MMA pathomechanisms understanding. In this chapter, we will focus on (i) RASopathies, a well-known group of Mendelian diseases whose gene identification established the role of the RAS/MAPK pathway in MMA, despite the low prevalence of MMA in those conditions and on (ii) some recently identified very rare Mendelian conditions with a highly penetrant MMA. We will also emphasize the importance of novel high-throughput methodologies to identify the genes involved in the numerous yet uncharacterized MMS.