LETTER TO JMG

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

Martin Zenker¹, Denise Horn², Dagmar Wieczorek³, Judith Allanson⁴, Silke Pauli⁵, Ineke van der Burgt⁶, Helmuth-Guenther Doerr⁷, Harald Gaspar⁸, Michael Hofbeck⁹, Gabriele Gillessen-Kaesbach¹⁰, Andreas Koch¹¹, Peter Meinecke¹², Stefan Mundlos², Anja Nowka¹³, Anita Rauch¹, Silke Reif¹⁴, Christian von Schnakenburg¹⁵, Heide Seidel¹⁶, Lars-Erik Wehner⁵, Christiane Zweier¹, Susanne Bauhuber¹, Verena Matejas¹, Christian P Kratz¹⁵, Christoph Thomas¹⁷, Kerstin Kutsche¹³

¹ Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Germany
² Institute of Medical Genetics, Charité, University Medicine of Berlin, Berlin, Germany
³ Institut für Humangenetik, Universität Duisburg-Essen, Essen, Germany
⁴ Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada
⁵ Institute of Human Genetics, University of Goettingen, Goettingen, Germany
⁶ Department of Human Genetics, University Medical Center St Radboud, Nijmegen, The Netherlands
⁷ Department of Pediatric Endocrinology, University Children’s Hospital, Erlangen, Germany
⁸ Institute of Medical Genetics, University of Zurich, Zurich, Switzerland
⁹ University Children’s Hospital, Pediatric Cardiology, Tuebingen, Germany
¹⁰ Institut für Humangenetik, Universität zu Lübeck, Lübeck, Germany
¹¹ Department of Pediatric Cardiology, University Children’s Hospital, Erlangen, Germany
¹² Medizinische Genetik, Altonaer Kinderkrankenhaus, Hamburg, Germany
¹³ Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
¹⁴ Institut für Humangenetik und Medizinische Biologie, Universität Halle, Germany
¹⁵ Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany
¹⁶ Institute of Human Genetics, Ludwig-Maximilian University, Munich, Germany
¹⁷ Max Planck Institute of Molecular Physiology, Department of Structural Biology, Dortmund, Germany

Correspondence to:
Martin Zenker
MD, Institute of Human Genetics, University of Erlangen-Nuremberg, Schwabachanlage 10, 91054 Erlangen, Germany; mzenker{at}humgenet.uni-erlangen.de

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.

Abbreviations: CFCS, cardio-facio-cutaneous syndrome; DH-PH, Dbl homology–pleckstrin homology; GEF, guanine exchange factor; NS, Noonan syndrome; OMIM, Online Mendelian Inheritance in Man

Keywords: congenital heart defect; pulmonic stenosis; short stature; ras pathway

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