PT  - JOURNAL ARTICLE
AU  - Martin Zenker
AU  - Katarina Lehmann
AU  - Anna Leana Schulz
AU  - Helmut Barth
AU  - Dagmar Hansmann
AU  - Rainer Koenig
AU  - Rudolf Korinthenberg
AU  - Martina Kreiss-Nachtsheim
AU  - Peter Meinecke
AU  - Susanne Morlot
AU  - Stefan Mundlos
AU  - Anne S Quante
AU  - Salmo Raskin
AU  - Dirk Schnabel
AU  - Lars-Erik Wehner
AU  - Christian P Kratz
AU  - Denise Horn
AU  - Kerstin Kutsche
TI  - Expansion of the genotypic and phenotypic spectrum in patients with <em>KRAS</em> germline mutations
AID  - 10.1136/jmg.2006.046300
DP  - 2007 Feb 01
TA  - Journal of Medical Genetics
PG  - 131--135
VI  - 44
IP  - 2
4099  - http://jmg.bmj.com/content/44/2/131.short
4100  - http://jmg.bmj.com/content/44/2/131.full
SO  - J Med Genet2007 Feb 01; 44
AB  - 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.