Modeling the Non-NF1 RASopathies

The RASopathies are genetic disorders caused by germline pathogenic variants in one of the genes that encode RAS/MAPK pathway components. These disorders, which include neurofibromatosis Type 1 (NF1), Noonan syndrome, cardio-facio-cutaneous syndrome, Costello syndrome, and Legius syndrome, among others, have overlapping clinical features, such as congenital heart disease, vascular or lymphatic anomalies, neurocognitive impairment, and cancer predisposition. Here, we describe the existing preclinical models of the non-NF1 RASopathies, including both those made by genetic modification of model organisms such as zebrafish, Drosophila, and mice, and those derived from patients. Further, we describe models of emerging RASopathy-associated variants and models of other syndromes caused by alterations in the RAS/MAPK pathway. These models have advanced our understanding of the basic biology of the RAS/MAPK pathway and the pathogenesis of the RASopathies. Additionally, these models have facilitated the preclinical testing of drugs that target the RAS/MAPK pathway, allowing these agents to be considered as potential treatments for patients with RASopathies.