Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome

A. L. Schulz, B. Albrecht, C. Arici, I. van der Burgt, A. Buske, G. Gillessen-Kaesbach, R. Heller, D. Horn, C. A. Hübner, G. C. Korenke, R. König, W. Kress, K. Krüger, P. Meinecke, J. Mücke, B. Plecko, E. Rossier, P. Schinzel, A. Schulze, E. SeemanovaH. Seidel, S. Spranger, B. Tuysuz, S. Uhrig, D. Wieczorek, Kerstine Kutsche*, W. Zenker

*Corresponding author for this work
76 Citations (Scopus)

Abstract

Cardio-facio-cutaneous (CFC) and Costello syndrome (CS) are congenital disorders with a significant clinical overlap. The recent discovery of heterozygous mutations in genes encoding components of the RAS-RAF-MAPK pathway in both CFC and CS suggested a similar underlying pathogenesis of these two disorders. While CFC is heterogeneous with mutations in BRAF, MAP2K1, MAP2K2 and KRAS, HRAS alterations are almost exclusively associated with CS. We carried out a comprehensive mutation analysis in 51 CFC-affected patients and 31 individuals with CS. Twelve different BRAF alterations were found in twenty-four patients with CFC (47.0%), two MAP2K1 mutations in five (9.8%) and two MAP2K2 sequence variations in three CFC-affected individuals (5.9%), whereas three patients had a KRAS alteration (5.9%). We identified four different missense mutations of HRAS in twenty-eight cases with CS (90.3%), while KRAS mutations were detected in two infants with a phenotype meeting criteria for CS (6.5%). In 14 informative families, we traced the parental origin of HRAS alterations and demonstrated inheritance of the mutated allele exclusively from the father, further confirming a paternal bias in the parental origin of HRAS mutations in CS. Careful clinical evaluation of patients with BRAF and MAP2K1/2 alterations revealed the presence of slight phenotypic differences regarding craniofacial features in MAP2K1 - and MAP2K2-mutation positive individuals, suggesting possible genotype-phenotype correlations.

Original languageEnglish
JournalClinical Genetics
Volume73
Issue number1
Pages (from-to)62-70
Number of pages9
ISSN0009-9163
DOIs
Publication statusPublished - 01.01.2008

Research Areas and Centers

  • Research Area: Medical Genetics

Fingerprint

Dive into the research topics of 'Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome'. Together they form a unique fingerprint.

Cite this