RASopathies (Noonan, LEOPARD, Costello) [27 genes]

RAS genes play an important role in the mitogen-activated protein kinase-dependent signaling pathway (MAPK), a metabolic pathway that regulates cell proliferation, differentiation, survival and death or apoptosis. Germinal mutations described in some of these genes cause developmental anomalies in the subject (depending on the affected gene), which often overlap clinically, with an autosomal dominant inheritance pattern. Therefore, all patients share a variable degree of intellectual disability, cardiac anomalies, facial dysmorphism, skin anomalies, and predisposition to develop cancer (RASopathies).

• The most widely known pathology in this group is Noonan syndrome, with an estimated incidence between 1/1,000 and 1/2,500 live births.

• Subjects under suspicion or clinical diagnosis of Noonan, LEOPARD, Costello, Legius or cardiofaciocutaneous syndrome. There is frequent clinical overlapping among these syndromes (these patients share a variable degree of intellectual disability, cardiac anomalies, facial dysmorphism, skin anomalies, and predisposition to develop cancer); therefore the genetic study would facilitate differential diagnosis. All these syndromes share an autosomal dominant pattern of inheritance.
• Familial study: A search for the mutation previously identified in a proband (relatives of patients with Noonan, LEOPARD, Costello, Legius or cardiofaciocutaneous syndrome, in which a mutation has been previously identified).

The probability of identifying a causal mutation when a patient has been diagnosed with one of these syndromes is high, over 70% in all cases. It can range from 70%-80% for one mutation or relevant variant in case of Noonan syndrome to 88%-98% in the case of Legius syndrome.