RASopathies – Noonan syndrome and differential diagnosis [53 genes]

Noonan syndrome is a disorder characterized by mental retardation, short stature, facial dysmorphism, and a broad spectrum of congenital heart defects. Facial features are a broad forehead, hypertelorism, downward-sloping palpebral fissures, and low-set ears rotated posteriorly. Cardiac involvement is present in up to 90% of patients. Pulmonary stenosis and hypertrophic cardiomyopathy are the most common forms of heart disease, but other malformations are also seen. Other relatively usual features are multiple skeletal defects (thoracic and spinal deformities), cryptorchidism, and hemorrhagic diathesis.

Noonan syndrome: 1 / 1,000-2,500 (ORPHA:648).

The benefits derived from a genetic diagnosis in this context can range from family genetic counseling, typical of genetic studies in general, to the prevention of associated comorbidities or their early detection, as myeloproliferative neoplasms associated with certain mutations in specific genes. Thus, the genetic information within this clinical spectrum is for diagnosis but also relevant prognostic information and allows personalized monitoring of the patient based on their genotype.

Service indicated when, due to the phenotypic findings, Noonan or at least the clinical spectrum of RASopathies is suspected. Due to the high number of genes related to this phenotype, the exome approach is currently considered indicated, preferably including other superimposable entities within the Noonan-like clinical spectrum.

The analysis of the genes currently known to be involved in a Noonan phenotype makes it possible to identify the genetic cause in approximately 90% of cases with a clinical diagnosis. Other genes not clearly related to date seem to be involved in at least a small number of cases without molecular diagnosis.