title: Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Human Genetics, University of Erlangen-Nuremberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.forename: Katarina
authors.initials: K
authors.lastname: Lehmann
authors.forename: Anna Leana
authors.initials: AL
authors.lastname: Schulz
authors.forename: Helmut
authors.initials: H
authors.lastname: Barth
authors.forename: Dagmar
authors.initials: D
authors.lastname: Hansmann
authors.forename: Rainer
authors.initials: R
authors.lastname: Koenig
authors.forename: Rudolf
authors.initials: R
authors.lastname: Korinthenberg
authors.forename: Martina
authors.initials: M
authors.lastname: Kreiss-Nachtsheim
authors.forename: Peter
authors.initials: P
authors.lastname: Meinecke
authors.forename: Susanne
authors.initials: S
authors.lastname: Morlot
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.forename: Anne S
authors.initials: AS
authors.lastname: Quante
authors.forename: Salmo
authors.initials: S
authors.lastname: Raskin
authors.forename: Dirk
authors.initials: D
authors.lastname: Schnabel
authors.forename: Lars-Erik
authors.initials: LE
authors.lastname: Wehner
authors.forename: Christian P
authors.initials: CP
authors.lastname: Kratz
authors.forename: Denise
authors.initials: D
authors.lastname: Horn
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kutsche
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D005060:Europe; D005260:Female; D011905:Genes, ras; D014644:Genetic Variation; D018095:Germ-Line Mutation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D009634:Noonan Syndrome / Q000235:genetics*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases