title: Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome.
abstract: 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.
authors.affiliation: Istituto di Clinica Pediatrica, Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zampino
authors.forename: Francesca
authors.initials: F
authors.lastname: Pantaleoni
authors.forename: Claudio
authors.initials: C
authors.lastname: Carta
authors.forename: Gilda
authors.initials: G
authors.lastname: Cobellis
authors.forename: Isabella
authors.initials: I
authors.lastname: Vasta
authors.forename: Cinzia
authors.initials: C
authors.lastname: Neri
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Pogna
authors.forename: Emma
authors.initials: E
authors.lastname: De Feo
authors.forename: Angelica
authors.initials: A
authors.lastname: Delogu
authors.forename: Anna
authors.initials: A
authors.lastname: Sarkozy
authors.forename: Francesca
authors.initials: F
authors.lastname: Atzeri
authors.forename: Angelo
authors.initials: A
authors.lastname: Selicorni
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Rauen
authors.forename: Cheryl S
authors.initials: CS
authors.lastname: Cytrynbaum
authors.forename: Rosanna
authors.initials: R
authors.lastname: Weksberg
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
authors.forename: Giovanni
authors.initials: G
authors.lastname: Neri
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000328:Adult; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D011905:Genes, ras; D005820:Genetic Testing; D014644:Genetic Variation; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D020125:Mutation, Missense; D010290:Parents; D010375:Pedigree; D010641:Phenotype; D013577:Syndrome