To investigate mutation spectrums and their correlations to phenotypes in Noonan syndrome (NS) and NS-related disorders that share functional alterations of the Ras-mitogen-activated protein kinase pathway.

Clinical characteristics and genotypes of 10 previously known and 2 candidate genes, SPRY1-4 and SPRED1, were investigated in 59 patients with NS, 17 with cardiofaciocutaneous syndrome, 5 with Costello syndrome, and 2 with LEOPARD syndrome.

PTPN11 (39.0%), SOS1 (20.3%), RAF1 (6.8%), KRAS (5.1%), and BRAF (1.7%) mutations were identified in NS; BRAF (41.2%), SHOC2 (23.5%), and MEK1 (5.9%) mutations in cardiofaciocutaneous syndrome; and HRAS and PTPN11 mutations in Costello syndrome and LEOPARD syndrome, respectively. No additional mutations were identified in 28.9% of NS and 35.3% of cardiofaciocutaneous syndrome. Functional characterizations of 2 RAF1 novel variants, p.P261T and p.S259T, and one SOS1 variant, p.K170E, showed enhanced activity of Ras-mitogen-activated protein kinase pathway. Normal stature was frequent in SOS1 mutations, hypertrophic cardiomyopathy in RAF1, and developmental delay in RAF1, BRAF, or SHOC2 mutations.

By identifying genotype-phenotype correlations, our study highlights the role of molecular genetic testing in the process of differential diagnosis of NS and NS-related disorders. Pathophysiologies that underlie these correlations are needed to be investigated in terms of their effects on Ras-mitogen-activated protein kinase pathway.