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SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome
  1. Martin Zenker1,
  2. Denise Horn2,
  3. Dagmar Wieczorek3,
  4. Judith Allanson4,
  5. Silke Pauli5,
  6. Ineke van der Burgt6,
  7. Helmuth-Guenther Doerr7,
  8. Harald Gaspar8,
  9. Michael Hofbeck9,
  10. Gabriele Gillessen-Kaesbach10,
  11. Andreas Koch11,
  12. Peter Meinecke12,
  13. Stefan Mundlos2,
  14. Anja Nowka13,
  15. Anita Rauch1,
  16. Silke Reif14,
  17. Christian von Schnakenburg15,
  18. Heide Seidel16,
  19. Lars-Erik Wehner5,
  20. Christiane Zweier1,
  21. Susanne Bauhuber1,
  22. Verena Matejas1,
  23. Christian P Kratz15,
  24. Christoph Thomas17,
  25. Kerstin Kutsche13
  1. 1Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Germany
  2. 2Institute of Medical Genetics, Charité, University Medicine of Berlin, Berlin, Germany
  3. 3Institut für Humangenetik, Universität Duisburg-Essen, Essen, Germany
  4. 4Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada
  5. 5Institute of Human Genetics, University of Goettingen, Goettingen, Germany
  6. 6Department of Human Genetics, University Medical Center St Radboud, Nijmegen, The Netherlands
  7. 7Department of Pediatric Endocrinology, University Children’s Hospital, Erlangen, Germany
  8. 8Institute of Medical Genetics, University of Zurich, Zurich, Switzerland
  9. 9University Children’s Hospital, Pediatric Cardiology, Tuebingen, Germany
  10. 10Institut für Humangenetik, Universität zu Lübeck, Lübeck, Germany
  11. 11Department of Pediatric Cardiology, University Children’s Hospital, Erlangen, Germany
  12. 12Medizinische Genetik, Altonaer Kinderkrankenhaus, Hamburg, Germany
  13. 13Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
  14. 14Institut für Humangenetik und Medizinische Biologie, Universität Halle, Germany
  15. 15Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany
  16. 16Institute of Human Genetics, Ludwig-Maximilian University, Munich, Germany
  17. 17Max Planck Institute of Molecular Physiology, Department of Structural Biology, Dortmund, Germany
  1. Correspondence to:
 Martin Zenker
 MD, Institute of Human Genetics, University of Erlangen-Nuremberg, Schwabachanlage 10, 91054 Erlangen, Germany; mzenker{at}


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.

  • CFCS, cardio-facio-cutaneous syndrome
  • DH-PH, Dbl homology–pleckstrin homology
  • GEF, guanine exchange factor
  • NS, Noonan syndrome
  • OMIM, Online Mendelian Inheritance in Man
  • congenital heart defect
  • pulmonic stenosis
  • short stature
  • ras pathway

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  • Competing interests: None declared.

  • Parental/guardian informed consent was obtained for publication of figure 2.

  • Published Online First 23 June 2007