Costello syndrome (CS; MIM 214080) is a rare multiple congenital anomaly disorder in which individuals have characteristic dysmorphic craniofacial features, cardiac abnormalities, ectodermal and musculoskeletal anomalies, endocrinopathy, developmental delay, and a predisposition to neoplasia both benign and malignant. In this study, we examined a large, well-characterized cohort of patients with the clinical diagnosis of CS. We sequenced HRAS in 36 unrelated individuals with the clinical diagnosis of CS and three sets of parents and 10 normal controls. We screened for HRAS coding region mutations in an effort to define HRAS mutations in CS and attempt to establish a possible genotype-phenotype correlation. In addition, we sequenced HRAS to establish loss of heterozygosity in a rhabdomyosarcoma and fibrosarcoma from a CS patient. HRAS mutations were identified in 33 out of 36 (92%) patients with the clinical diagnosis of CS. Mutations were found in codon 12 or 13. Two different missense point mutations were identified in codon 12: 34G'A and 35G'C, predicting an amino acid substitution of gly12ser and gly12ala, respectively. The 34G'A transition mutation, the most common mutation observed in this cohort of patients, was found in 30 of 33 patients. Two patients were found to have a codon 12 35G'C transversion. One patient in the cohort had a codon 13 mutation: 37G'T transversion, predicting an amino acid substitution of gly13cys. Parental DNA samples from three CS patients with the 34G'A mutation did not harbor a mutation. HRAS was sequenced from DNA isolated from a rhabdomyosarcoma and fibrosarcoma from a patient who had the germline activating mutation 34GA. Sequence analysis demonstrated LOH of the wild-type allele of HRAS as demonstrated by detection of only 34A in exon 1. Our data show that the majority of Costello syndrome patients have de novo heterogeneous HRAS mutations. Furthermore, tumorigenesis in Costello syndrome patients is accompanied by additional somatic changes affecting the HRAS gene.
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