Identification of a new Jnk-activating familial SOS1 and a de novo RAF1 mutations in a Noonan syndrome patient

Noonan syndrome is an autosomal dominant genetic disease characterized by congenital heart defects, short stature and characteristic facial features. Mutations in PTPN11, RAF1, SOS1, KRAS, and NRAS are responsible for 60-75% of the cases, thus additional genes, are expected to be involved in Noonan syndrome pathogenesis. The genotype/ phenotype correlation has been hindered by the relatively few reported genotyped cases. Expanding the case numbers will benefit the clinical community. A mutation analysis has been performed on RAF1, SOS1 and on the SOS1-interacting GRB2, in twenty-four NS patients previously found to be negative for PTPN11 and KRAS mutations. We identified four mutations in SOS1 and one in RAF1, while no GRB2 variants have been found. Interestingly the RAF1 mutation was present in a patient also carrying a newly identified p.R497Q familial SOS1 mutation, segregating with a typical NS SOS1 cutaneous phenotype. The new SOS1 mutations have been predicted to dysregulate the protein activity by bioinformatics. Functional analysis demonstrated the R497Q-SOS1 mutation leads to Jnk activation, but had no effect on the Ras effector Erk1. We propose that this variant might contribute to the onset of the peculiar ectodermal traits displayed by the proband amidst the more classical NS presentation. The characteristic cutaneous traits, frequently shown by NS patients carrying SOS1 mutations, might be associated to the activation of both Jnk/Erk pathways. To our knowledge, this is the first reported case of a NS patient harbouring mutations in two NS genes, allowing us to propose a genotype/phenotype correlation in the family