Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome

Giuseppe Zampino, Francesca Pantaleoni, Claudio Carta, Gilda Cobellis, Isabella Vasta, Cinzia Neri, Edgar A. Pogna, Emma De Feo, Angelica Delogu, Anna Sarkozy, Francesca Atzeri, Angelo Selicorni, Katherine A. Rauen, Cheryl S. Cytrynbaum, Rosanna Weksberg, Bruno Dallapiccola, Andrea Ballabio, Bruce D. Gelb, Giovanni Neri, Marco Tartaglia

Research output: Contribution to journalArticlepeer-review

106 Scopus citations


Activating mutations in v-Ha-ras Harvey rat sarcoma viral oncogene homolog (HRAS) have recently been identified as the molecular cause underlying Costello syndrome (CS). To further investigate the phenotypic spectrum associated with germline HRAS mutations and characterize their molecular diversity, subjects with a diagnosis of CS (N = 9), Noonan syndrome (NS; N = 36), cardiofaciocutaneous syndrome (CFCS; N = 4), or with a phenotype suggestive of these conditions but without a definitive diagnosis (N = 12) were screened for the entire coding sequence of the gene. A de novo heterozygous HRAS change was detected in all the subjects diagnosed with CS, while no lesion was observed with any of the other phenotypes. While eight cases shared the recurrent c.34G > A change, a novel c.436G > A transition was observed in one individual. The latter affected residue, p.Ala146, which contributes to guanosine triphosphate (GTP)/guanosine diphosphate (GDP) binding, defining a novel class of activating HRAS lesions that perturb development. Clinical characterization indicated that p.Gly12Ser was associated with a homogeneous phenotype. By analyzing the genomic region flanking the HRAS mutations, we traced the parental origin of lesions in nine informative families and demonstrated that de novo mutations were inherited from the father in all cases. We noted an advanced age at conception in unaffected fathers transmitting the mutation.

Original languageEnglish
Pages (from-to)265-272
Number of pages8
JournalHuman Mutation
Issue number3
StatePublished - Mar 2007


  • Costello syndrome
  • HRAS
  • Mutation analysis
  • Parental origin of de novo mutations


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