ß 2005 Wiley-Liss, Inc. American Journal of Medical Genetics 140A:8–16 (2006) Rapid Publication HRAS Mutations in Costello Syndrome: Detection of Constitutional Activating Mutations in Codon 12 and 13 and Loss of Wild-Type Allele in Malignancy Anne L. Estep, 1 William E. Tidyman, 2 Michael A. Teitell, 3 Philip D. Cotter, 4,5 and Katherine A. Rauen 1,5 * 1 Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 2 Department of Anatomy, University of California San Francisco, San Francisco, California 3 Department of Pathology and Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California 4 Department of Pathology, Children’s Hospital and Research Center at Oakland, Oakland, California 5 Department of Pediatrics, Division of Medical Genetics, University of California San Francisco, San Francisco, California Received 26 October 2005; Accepted 14 November 2005 Costello syndrome (CS) is a complex developmental disorder involving characteristic craniofacial features, failure to thrive, developmental delay, cardiac and skeletal anoma- lies, 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 predict- ing 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 rhabdomyo- Editor’s Note The following paper by Estep and colleagues was submitted to the Journal only a few weeks after the preceding paper by Gripp et al. also published in this issue. Both investigations address in detail the frequency of HRAS mutations in large series of patients with Costello syndrome, and both present timely data. Editorial perusal of this work raised an interesting dilemma that will likely be more commonplace in the future: both groups of investigators had collected samples at the same International Costello Syndrome meetings in 2001, 2003, and 2005. The AJMG Editors considered it important to understand the degree of overlap of patients in each study and requested the respective corresponding authors to provide the blinded identity (initials only) of their patients. Both complied. From this information, we could determine that there were 20 patients that participated in both in- vestigations. We have resolved that these two studies have investigated at least 56 patients with Costello syndrome. Notably the frequency of mutation- positive patients was high in both studies, and both demonstrate a similar mutation type and location. Grant sponsor: NIH grant; Grant numbers: HD048502, CA90571, CA107300; Grant sponsor: CIRP Mt. Zion Health Fund; Grant sponsor: CMISE (a NASA URETI award NCC 2-1364); Grant sponsor: Leukemia and Lymphoma Society Scholar award. *Correspondence to: Katherine A. Rauen, Ph.D., M.D., UCSF Compre- hensive Cancer Center, Cancer Research Institute, 2340 Sutter Street, Room S429, Box 0128, San Francisco, CA, 94115. E-mail: rauen@cc.ucsf.edu DOI 10.1002/ajmg.a.31078