{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T06:33:44Z","timestamp":1791095624072,"version":"4.1.0"},"reference-count":38,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2005,12,13]],"date-time":"2005-12-13T00:00:00Z","timestamp":1134432000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2006,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    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.,\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"#bib34\">2003<\/jats:ext-link>\n                    ]. In this study, the\n                    <jats:italic>HRAS<\/jats:italic>\n                    coding region was sequenced for mutations in a large, well\u2010characterized 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\u2009\u2192\u2009A transition in codon 12. Less frequent mutations included 35G\u2009\u2192\u2009C (codon 12) and 37G\u2009\u2192\u2009T (codon 13). Parental samples did not have an\n                    <jats:italic>HRAS<\/jats:italic>\n                    mutation supporting the hypothesis of de novo heterogeneous mutations. There is phenotypic variability among patients with a 34G\u2009\u2192\u2009A 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\u2009\u2192\u2009C had cardiac arrhythmias whereas one patient with a 37G\u2009\u2192\u2009T 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\n                    <jats:italic>HRAS<\/jats:italic>\n                    mutation. To gain an understanding of the relationship between constitutional\n                    <jats:italic>HRAS<\/jats:italic>\n                    mutations and malignancy,\n                    <jats:italic>HRAS<\/jats:italic>\n                    was sequenced in an advanced biphasic rhabdomyosarcoma\/fibrosarcoma from an individual with a 34G\u2009\u2192\u2009A mutation. Loss of the wild\u2010type\n                    <jats:italic>HRAS<\/jats:italic>\n                    allele was observed, suggesting tumorigenesis in CS patients is accompanied by additional somatic changes affecting\n                    <jats:italic>HRAS<\/jats:italic>\n                    . Finally, due to phenotypic overlap between CS and cardio\u2010facio\u2010cutaneuos (CFC) syndromes, the\n                    <jats:italic>HRAS<\/jats:italic>\n                    coding region was sequenced in a well\u2010characterized CFC cohort. No mutations were found which support a distinct genetic etiology between CS and CFC syndromes. \u00a9 2005 Wiley\u2010Liss, Inc.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.31078","type":"journal-article","created":{"date-parts":[[2005,12,21]],"date-time":"2005-12-21T18:50:04Z","timestamp":1135191004000},"page":"8-16","source":"Crossref","is-referenced-by-count":153,"title":["<i>HRAS<\/i>\n                    mutations in Costello syndrome: Detection of constitutional activating mutations in codon 12 and 13 and loss of wild\u2010type allele in malignancy"],"prefix":"10.1002","volume":"140A","author":[{"given":"Anne L.","family":"Estep","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William E.","family":"Tidyman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Teitell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip D.","family":"Cotter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine A.","family":"Rauen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2005,12,13]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9896(199901)187:1<82::AID-PATH248>3.0.CO;2-8"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-2264(199912)26:4<275::AID-GCC1>3.0.CO;2-3"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1641"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.17.6902"},{"key":"e_1_2_7_6_1","first-page":"4682","article-title":"ras oncogenes in human cancer: A review","volume":"49","author":"Bos 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