What Is a RASopathy?

A RASopathy is a medical genetic syndrome that is caused by germline mutations in genes that encode components or regulators of the well-studied oncogenic RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway. These syndromes include neurofibromatosis type-1, Noonan syndrome, Noonan syndrome with multiple lentigines, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, cardio-facio-cutaneous syndrome, Legius syndrome, SYNGAP1 syndrome, and central conducting lymphatic anomalies. Because the common underlying pathogenic mechanism is RAS/MAPK pathway dysregulation during development, the RASopathies have many common overlapping clinical features that assist in defining the RASopathies as a cohesive syndromic group. The RAS pathway has been robustly studied in cancer and is known to play a critical role in the regulation of proliferation, differentiation, the cell cycle, and cell senescence, all of which are important to normal human development. With overlapping clinical phenotypic features and a unifying pathogenic mechanism of RAS/MAPK pathway activation and dysregulation, the possible use of small molecule inhibitors, readily available for cancer treatment, is currently being considered for systemic treatment of RASopathies.