Abstract
Deregulated RAS signaling is associated with increasing numbers of congenital diseases usually referred to as RASopathies. The spectrum of genes and mutant alleles causing these diseases has been significantly expanded in recent years. This progress has triggered new challenges, including the origin and subsequent selection of the mutations driving these diseases, the specific pathobiological programs triggered by those mutations, the type of correlations that exist between the genotype and the clinical features of patients, and the ancillary genetic factors that influence the severity of the disease in patients. These issues also directly impinge on the feasibility of using RAS pathway drugs to treat RASopathy patients. Here, we will review the main developments and pending challenges in this research topic.