Expansion of the RASopathies

The Ras/mitogen activated protein kinase (MAPK) pathway is essential in the regulation of cell cycle, differentiation, growth, cell senescence and apoptosis, all of which are critical to normal development. A class of neurodevelopmental disorders, RASopathies, is caused by germline mutations in genes of the Ras/MAPK pathway. Through the use of whole exome sequencing and targeted sequencing of selected genes in cohorts of panel-negative RASopathy patients, several new genes have been identified. These include: RIT1, SOS2, RASA2, RRAS and SYNGAP1, that likely represent new, albeit rare, causative RASopathy genes. In addition, A2ML1, LZTR1, MYST4, SPRY1 and MAP3K8 may represent new rare genes for RASopathies, but, additional functional studies regarding the mutations are warranted. In addition, recent reports have demonstrated that chromosomal copy number variation in regions encompassing Ras/MAPK pathway genes may be a novel pathogenetic mechanism expanding the RASopathies.