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.
- MeSH
- dítě MeSH
- dospělí MeSH
- faciální stigmatizace * MeSH
- fenotyp MeSH
- kožní abnormality * genetika MeSH
- lidé MeSH
- MAP kinasa-kinasa 1 genetika MeSH
- MAP kinasa-kinasa 2 genetika MeSH
- mentální retardace MeSH
- mnohočetné abnormality * genetika MeSH
- mutace * MeSH
- mutační analýza DNA MeSH
- protoonkogenní proteiny B-raf genetika MeSH
- protoonkogenní proteiny genetika MeSH
- ras proteiny genetika MeSH
- syndrom MeSH
- vrozené srdeční vady * genetika MeSH
- vývojové poruchy u dětí MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH