SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome

• Published in: Journal of medical genetics Vol. 44; no. 10; pp. 651 - 656
• Main Authors: Zenker, Martin, Horn, Denise, Wieczorek, Dagmar, Allanson, Judith, Pauli, Silke, van der Burgt, Ineke, Doerr, Helmuth-Guenther, Gaspar, Harald, Hofbeck, Michael, Gillessen-Kaesbach, Gabriele, Koch, Andreas, Meinecke, Peter, Mundlos, Stefan, Nowka, Anja, Rauch, Anita, Reif, Silke, von Schnakenburg, Christian, Seidel, Heide, Wehner, Lars-Erik, Zweier, Christiane, Bauhuber, Susanne, Matejas, Verena, Kratz, Christian P, Thomas, Christoph, Kutsche, Kerstin
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.10.2007; BMJ; BMJ Publishing Group LTD; BMJ Group
• Subjects: Amino Acid Sequence; Biological and medical sciences; Body Height; cardio-facio-cutaneous syndrome; CFCS; congenital heart defect; Constriction, Pathologic; Dbl homology–pleckstrin homology; DH-PH; Female; Fundamental and applied biological sciences. Psychology; GEF; General aspects. Genetic counseling; Genes; Genetics of eukaryotes. Biological and molecular evolution; guanine exchange factor; Heart Diseases - congenital; Heart Diseases - genetics; Heterozygote; Humans; Letter to JMG; Male; Medical genetics; Medical sciences; Molecular and cellular biology; Molecular Sequence Data; Mutation; Noonan syndrome; Noonan Syndrome - genetics; OMIM; Online Mendelian Inheritance in Man; Patients; Polymorphism; Proteins; pulmonic stenosis; ras Guanine Nucleotide Exchange Factors - metabolism; ras pathway; Sequence Homology, Amino Acid; short stature; Skin Diseases - genetics; SOS1 Protein - genetics; SOS1 Protein - physiology; Syndrome; Germany; Human; Skin disease; Cardio facio cutaneous syndrome; Nitric oxide; Cardiovascular disease; Genetics; Major gene
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.2007.051276

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.