Molecular Genetics of Costello Syndrome

Abstract

The molecular basis of Costello syndrome (CS) is heterozygous germline mutations in HRAS . Over 95% of patients with CS have been found to have mutations in codon 12 or codon 13, with over 80% having the single mutation c.34G>A, p.(Gly12Ser). The mutational spectrum is similar, but not identical, to that observed for somatic HRAS mutations in cancer. These mutations result in constitutive activation of the HRAS protein. The function of HRAS as a molecular switch is therefore perturbed, resulting in increased downstream Ras‐MAPK pathway activity. The severity of clinical features of CS in any given individual may be influenced by which mutation is present, with mutations more commonly observed in cancer, such as p.(Gly12Val), which have more dramatic effects at the cellular level, tending to lead to a more severe presentation. As for other germline disorders, however, much variability is seen, which may be due to further genomic and other modifying factors. Key Concepts: Germline gain of function mutations in HRAS cause Costello syndrome (CS). Somatic gain‐of‐function HRAS mutations (often with more extreme biochemical effects) are also found in cancer. HRAS p.(Gly12Ser) is the cause of CS in 80% of patients diagnosed with this condition. CS is associated with advanced paternal age. Spermatogonia in the testes of older fathers may be enriched for mutations conferring a proliferative advantage, such as the HRAS mutations that underlie CS.