RT Journal Article SR Electronic T1 SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 651 OP 656 DO 10.1136/jmg.2007.051276 VO 44 IS 10 A1 Martin Zenker A1 Denise Horn A1 Dagmar Wieczorek A1 Judith Allanson A1 Silke Pauli A1 Ineke van der Burgt A1 Helmuth-Guenther Doerr A1 Harald Gaspar A1 Michael Hofbeck A1 Gabriele Gillessen-Kaesbach A1 Andreas Koch A1 Peter Meinecke A1 Stefan Mundlos A1 Anja Nowka A1 Anita Rauch A1 Silke Reif A1 Christian von Schnakenburg A1 Heide Seidel A1 Lars-Erik Wehner A1 Christiane Zweier A1 Susanne Bauhuber A1 Verena Matejas A1 Christian P Kratz A1 Christoph Thomas A1 Kerstin Kutsche YR 2007 UL http://jmg.bmj.com/content/44/10/651.abstract AB 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 gain-of-function mutations in molecules belonging to the same pathway, NS and CFCS scarcely overlap genotypically.