Molecular Genetics of Noonan Syndrome and Other RASopathies

RASopathies are caused by variants in more than 20 genes functionally converging toward the upregulation of intracellular signaling through the RAS/mitogen-associated protein kinase (MAPK) cascade. These disorders are largely transmitted as autosomal dominant traits, though recessive forms are emerging. More than 10 genes have been causally linked to Noonan syndrome, the most common and clinically variable RASopathy; genetic heterogeneity characterizes also cardio-facio-cutaneous syndrome and Noonan syndrome with loose anagen hair, also known as Mazzanti syndrome. On the other hand, allelic heterogeneity also occurs, as in the case of PTPN11, KRAS, and BRAF. A large proportion of cases result from de novo mutations; however, families transmitting the disorder are common in Noonan syndrome. In RASopathies, increased RAS/MAPK signaling can result from the upregulated activity of various GTPases of the RAS family, increased function of signal transducers positively controlling RAS activity or favoring RAS interactions with RAF kinases, functional upregulation of the three tiers belonging to the MAPK cascade, or inefficient signaling switch-off operating at different levels. While the MAPK cascade is virtually upregulated in almost all RASopathies, upregulation of the PI3K-AKT-mTOR pathway also represents an alternative driver or contributing mechanism. Genetic evidence also suggests the involvement of signaling dysregulation via other networks (e.g., small RHO GTPases signaling) to disease pathogenesis. Here, we summarize key concepts on the molecular genetics of these disorders, discussing the involved genes and the molecular circuits implicated in RAS/MAPK signaling dysregulation, including those that had previously remained uncharacterized due to their minor impact on oncogenesis.