PT  - JOURNAL ARTICLE
AU  - Martin Zenker
AU  - Denise Horn
AU  - Dagmar Wieczorek
AU  - Judith Allanson
AU  - Silke Pauli
AU  - Ineke van der Burgt
AU  - Helmuth-Guenther Doerr
AU  - Harald Gaspar
AU  - Michael Hofbeck
AU  - Gabriele Gillessen-Kaesbach
AU  - Andreas Koch
AU  - Peter Meinecke
AU  - Stefan Mundlos
AU  - Anja Nowka
AU  - Anita Rauch
AU  - Silke Reif
AU  - Christian von Schnakenburg
AU  - Heide Seidel
AU  - Lars-Erik Wehner
AU  - Christiane Zweier
AU  - Susanne Bauhuber
AU  - Verena Matejas
AU  - Christian P Kratz
AU  - Christoph Thomas
AU  - Kerstin Kutsche
TI  - <em>SOS1</em> is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome
AID  - 10.1136/jmg.2007.051276
DP  - 2007 Oct 01
TA  - Journal of Medical Genetics
PG  - 651--656
VI  - 44
IP  - 10
4099  - http://jmg.bmj.com/content/44/10/651.short
4100  - http://jmg.bmj.com/content/44/10/651.full
SO  - J Med Genet2007 Oct 01; 44
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.