Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations
Year: 2006
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Noonan syndrome, cardio-facio-cutaneous syndrome (CFC) and Costello syndrome constitute a group of developmental disorders with an overlapping pattern of congenital anomalies. Each of these conditions can be caused by germline mutations in key components of the highly conserved Ras-MAPK pathway, possibly reflecting a similar pathogenesis underlying the three disorders. Germline mutations in KRAS have recently been identified in a small number of patients with Noonan syndrome and CFC. METHODS AND RESULTS: 260 patients were screened for KRAS mutations by direct sequencing. Overall, we detected KRAS mutations in 12 patients, including three known and eight novel sequence alterations. All mutations are predicted to cause single amino acid substitutions. Remarkably, our cohort of individuals with KRAS mutations showed a high clinical variability, ranging from Noonan syndrome to CFC, and also included two patients who met the clinical criteria of Costello syndrome. CONCLUSION: Our findings reinforce the picture of a clustered distribution of disease associated KRAS germline alterations. We further defined the phenotypic spectrum associated with KRAS missense mutations and provided the first evidence of clinical differences in patients with KRAS mutations compared with Noonan syndrome affected individuals with heterozygous PTPN11 mutations and CFC patients carrying a BRAF, MEK1 or MEK1 alteration, respectively. We speculate that the observed phenotypic variability may be related, at least in part, to specific genotypes and possibly reflects the central role of K-Ras in a number of different signalling pathways.
Source: Journal of Medical Genetics
Authors: Martin Zenker, Katarina Lehmann, Anna Leana Schulz, Helmut Barth, Dagmar Hansmann, Rainer Koenig, Rudolf Korinthenberg, Martina Kreiss-Nachtsheim, Peter Meinecke, Susanne Morlot, Stefan Mundlos, Anne S Quante, Salmo Raskin, Dirk Schnabel, Lars-Erik Wehner, Christian P Kratz, Denise Horn, Kerstin Kutsche
Institutions: Friedrich-Alexander-Universität Erlangen-Nürnberg, Charité – Universitätsmedizin Berlin, University Medical Center Hamburg-Eppendorf, Goethe University Frankfurt, University of Freiburg, University of Bonn, Altonaer Kinderkrankenhaus, Heinrich Heine University Düsseldorf, University of Göttingen
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2008762441