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Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations
  1. Martin Zenker1,*,
  2. Katarina Lehmann2,*,
  3. Anna Leana Schulz3,
  4. Helmut Barth4,
  5. Dagmar Hansmann5,
  6. Rainer Koenig6,
  7. Rudolf Korinthenberg7,
  8. Martina Kreiss-Nachtsheim8,
  9. Peter Meinecke9,
  10. Susanne Morlot10,
  11. Stefan Mundlos2,
  12. Anne S Quante11,
  13. Salmo Raskin12,
  14. Dirk Schnabel13,
  15. Lars-Erik Wehner14,
  16. Christian P Kratz7,
  17. Denise Horn2,*,
  18. Kerstin Kutsche3,*
  1. 1Institute of Human Genetics, University of Erlangen-Nuremberg, Germany
  2. 2Institute of Medical Genetics, Charité, University Medicine of Berlin, Germany
  3. 3Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
  4. 4Zentrum für Kinder-und Jugendmedizin, Klinik für Neonatologie und Neuropädiatrie, Marburg, Germany
  5. 5Pränatalmedizin und Medizinische Genetik, Meckenheim, Germany
  6. 6Institute of Human Genetics, University of Frankfurt, Germany
  7. 7Department of Paediatrics and Adolescent Medicine, University of Freiburg, Germany
  8. 8Institute of Human Genetics, Friedrich-Wilhelms-University of Bonn, Germany
  9. 9Medizinische Genetik, Altonaer Kinderkrankenhaus, Hamburg, Germany
  10. 10Praxis für Humangenetik, Ärztliche Partnerschaft Wagner-Stibbe Hannover, Germany
  11. 11Institute of Human Genetics, Heinrich-Heine-University of Düsseldorf, Germany
  12. 12Laboratorio Genetika, Alameda Augusto Stellfeld, Curitiba Parana, Brazil
  13. 13Institute of Paediatric Endocrinology, University Children’s Hospital, University Medicine of Berlin, Germany
  14. 14Institute of Human Genetics, University of Göttingen, Germany
  1. Correspondence to:
 Dr Kerstin Kutsche
 Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Butenfeld 42, 22529 Hamburg, Germany; kkutsche{at}


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.

  • CFC, cardio-facio-cutaneous syndrome
  • GAP, GTPase activating protein

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  • * M Zenker, K Lehmann, D Horn and K Kutsche are equally contributing first and senior authors.

  • Competing interests: None.

  • Electronic database information See Gene at for KRAS genomic (accession number NC_000012), cDNA (accession numbers NM_004985 and NM_033360) and K-Ras amino acid (accession numbers NP_004976 and NP_203524) sequences; for N-Ras (accession number NP_002515) and H-Ras (accession numbers NP_005334 and NP_789765) amino acid sequences. See Catalogue of Somatic Mutations in Cancer (COSMIC) at for somatic mutations observed in KRAS.

  • Published Online First 20 October 2006