HRAS mutations in Costello syndrome: Detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy

• Published in: American journal of medical genetics. Part A 2006-01, Vol.140A (1), p.8-16
• Main Authors: Estep, Anne L., Tidyman, William E., Teitell, Michael A., Cotter, Philip D., Rauen, Katherine A.
• Format: Article
• Language: English
• Subjects: Abnormalities, Multiple - genetics; Abnormalities, Multiple - pathology; Adolescent; Adult; Alleles; Base Sequence; Biological and medical sciences; cardio-facio-cutaneous syndrome; Cardiovascular Abnormalities - pathology; Child; Child, Preschool; Codon - genetics; Cohort Studies; Complex syndromes; constitutional mutation; Costello syndrome; Diseases of the osteoarticular system; DNA Mutational Analysis; Face - abnormalities; fibrosarcoma; Genes, ras - genetics; Genetic Predisposition to Disease - genetics; Genotype; HRAS mutations; Humans; Infant; Intellectual Disability - pathology; Medical genetics; Medical sciences; Musculoskeletal Abnormalities - pathology; Mutation; Neoplasms - genetics; Phenotype; ras pathway; rhabdomyosarcoma; Skin Abnormalities - pathology; Syndrome; Tumors of striated muscle and skeleton
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.31078

Costello syndrome (CS) is a complex developmental disorder involving characteristic craniofacial features, failure to thrive, developmental delay, cardiac and skeletal anomalies, and a predisposition to develop neoplasia. Based on similarities with other cancer syndromes, we previously hypothesized that CS is likely due to activation of signal transduction through the Ras/MAPK pathway [Tartaglia et al., 2003]. In this study, the HRAS coding region was sequenced for mutations in a large, well‐characterized cohort of 36 CS patients. Heterogeneous missense point mutations predicting an amino acid substitution were identified in 33/36 (92%) patients. The majority (91%) had a 34G → A transition in codon 12. Less frequent mutations included 35G → C (codon 12) and 37G → T (codon 13). Parental samples did not have an HRAS mutation supporting the hypothesis of de novo heterogeneous mutations. There is phenotypic variability among patients with a 34G → A transition. The most consistent features included characteristic facies and skin, failure to thrive, developmental delay, musculoskeletal abnormalities, visual impairment, cardiac abnormalities, and generalized hyperpigmentation. The two patients with 35G → C had cardiac arrhythmias whereas one patient with a 37G → T transversion had an enlarged aortic root. Of the patients with a clinical diagnosis of CS, neoplasia was the most consistent phenotypic feature for predicating an HRAS mutation. To gain an understanding of the relationship between constitutional HRAS mutations and malignancy, HRAS was sequenced in an advanced biphasic rhabdomyosarcoma/fibrosarcoma from an individual with a 34G → A mutation. Loss of the wild‐type HRAS allele was observed, suggesting tumorigenesis in CS patients is accompanied by additional somatic changes affecting HRAS. Finally, due to phenotypic overlap between CS and cardio‐facio‐cutaneuos (CFC) syndromes, the HRAS coding region was sequenced in a well‐characterized CFC cohort. No mutations were found which support a distinct genetic etiology between CS and CFC syndromes. © 2005 Wiley‐Liss, Inc.