Table 1 Noonan syndrome causative genes and associated phenotype
From: New insights on Noonan syndrome’s clinical phenotype: a single center retrospective study
Gene | Phenotype | Genotype-phenotype correlation described in literature |
|---|---|---|
PTPN11 | NS | Classical NS, due to PTPN11 gain-of-function variants. In this the highest incidence of pulmonary valve stenosis is described. In some cases, JMML risk is increased |
NS-ML | Mainly caused by PTPN11 loss-of-function variants, frequently associated with multiple lentigines, facial dysmorphism and ECG conduction abnormalities | |
SOS1 | NS | Less short stature and intellectual disability. Follicular keratosis is common |
SOS2 | NS | Similar to SOS1 phenotype, with higher incidence of lymphatic abnormalities |
RAF1 | NS, but variable | Highest incidence of hypertrophic cardiomyopathy |
RIT1 | NS, but variable | Normal growth, and intellect. High incidence of cardiac abnormalities; particularly, hypertrophic cardiomyopathy is common |
LZTR1 | NS, but variable | In autosomal recessive forms, lymphatic abnormalities and hypertrophic cardiomyopathy are common. In autosomal dominant forms, phenotype is generally milder |
NRAS | NS | Classical NS |
RRAS2 | NS | Classical NS |
MRAS | NS | Classical NS with common hypertrophic cardiomyopathy |
SHOC2 | NS-LAH | Sparse hair, hyperpigmented skin, eczema, keratosis pilaris; short stature is a common feature |
KRAS | Some NS/CFC | Higher rate of intellectual disability |
BRAF | Some NS/CFC | Intellectual disability is common, as for skin and hair abnormalities |