2. Academic Validation
  3. Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome

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

  • Clin Genet. 2008 Jan;73(1):62-70. doi: 10.1111/j.1399-0004.2007.00931.x.
A L Schulz 1,  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,  G Krüger,  P Meinecke,  J Mücke,  B Plecko,  E Rossier,  A Schinzel,  A Schulze,  E Seemanova,  H Seidel,  S Spranger,  B Tuysuz,  S Uhrig,  D Wieczorek,  K Kutsche,  M Zenker
Affiliations

Affiliation

  • 1 Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
PMID: 18042262 DOI: 10.1111/j.1399-0004.2007.00931.x
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.

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