Abstract

Background: Heterozygous gain-of-function mutations in various genes encoding proteins of the Ras-MAPK signaling cascade have been identified as the genetic basis of Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFCS). Mutations of SOS1, the gene encoding a guanine nucleotide exchange factor for Ras, have been the most recent discovery in patients with NS, however, this gene has not been studied in patients with CFCS.

Methods and Results: We investigated SOS1 in a large cohort of patients with disorders of the NS-CFCS spectrum, previously tested negative for mutations in PTPN11, KRAS, BRAF, MEK1, and MEK2. Missense mutations of SOS1 were discovered in 28% of patients with NS. In contrast, none of the individuals classified as CFCS was found to carry a pathogenic sequence change in this gene.

Conclusion: We confirmed SOS1 as the second major gene for NS. Patients carrying mutations in this gene have a distinctive phenotype with frequent ectodermal anomalies such as keratosis pilaris and curly hair. However, the clinical picture associated with SOS1 mutations is different from CFCS. These findings corroborate that, despite being caused by gain-of-function mutations in molecules belonging to the same pathway, NS and CFCS hardly overlap genotypically.