The Molecular Basis of Costello Syndrome

Costello syndrome is a rare tumor predisposition syndrome with a distinctive phenotype overlapping with Noonan and cardio-facio-cutaneous syndromes. Based on this information its genetic cause was identified as heterozygous HRAS mutations. HRAS is a well-known oncogene, and aberrant activation of the gene product due to specific point mutations affecting glycines in positions 12 and 13 is often found in sporadic tumors. As the germline mutations in Costello syndrome affect similar codons, a similar effect on the gene product can be inferred. Substitutions of glycine 12 or 13 account for 95% of Costello syndrome mutations. The common changes (G12S, G12A) result in the typical phenotype, whereas the presentation of presumably more strongly activating mutations (G12V) appears to be more severe. Mutations affecting amino acids other than G12 or G13 occurred in one individual each (Q22K, T58I, E63K, K117R, A146T, A146V), and may be associated with a less typical phenotype. The vast majority of mutations arose in the paternal germline, but two were maternally derived. Somatic mosaicism for the G12S mutation was seen in one individual. While germline mosaicism is the likely cause for reported Costello syndrome sibling pairs, this has not been molecularly confirmed.