Zenker, Martin; Horn, Denise; Wieczorek, Dagmar; Allanson, Judith; Pauli, Silke; van der Burgt, Ineke; Doerr, Helmuth-Guenther; Gaspar, Harald; Hofbeck, Michael; Gillessen-Kaesbach, Gabriele; Kock, Andreas; Meinecke, Peter; Mundlos, Stefan; Nowka, Anja; Rauch, Anita; Reif, Silke; Schnakenburg, Christian von; Seidel, Heide; Wehner, Lars-Erik; Zweier, Christiane; Bauhuber, Susanne; Matejas, Verena; Kratz, Christian P.; Thomas, Christoph; Kutsche, Kerstin
SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome.
In: Journal of Medical Genetics, Vol. 44: pp. 651-656
Background: Heterozygous gain-of-function mutations in various
genes encoding proteins of the Ras-MAPK signalling
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 discoveries
in patients with NS, but 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, who had
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
patients classified as having CFCS was found to carry a
pathogenic sequence change in this gene.
Conclusion: We have 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 that of CFCS.
These findings corroborate that, despite being caused by gainof-
function mutations in molecules belonging to the same
pathway, NS and CFCS scarcely overlap genotypically.