Gain-of-function mutations of BRAF p.Q257R, MEK1 p.Y130C and MEK2 p.F57C are clinically associated with cardiofaciocutaneous (CFC) syndrome, KRAS p.T58I and RAF1 p.S257P mutations with Noonan syndrome, HRAS p.G12S mutation with Costello syndrome, NF1 mutation with LEOPARD syndrome, while loss-of-function mutations of the SPRED1 negative regulators rendering activated MAPK signaling is associated with Legius syndrome16 (Fig. 2). This evidence concerns the gene HRAS and Costello syndrome.