HRAS mutation analysis in Costello syndrome: Genotype and phenotype correlation

Karen W. Gripp, Angela E. Lin, Deborah L. Stabley, Linda Nicholson, Charles I. Scott, Daniel Doyle, Yoko Aoki, Yoichi Matsubara, Elaine H. Zackai, Pablo Lapunzina, Antonio Gonzalez-Meneses, Jennifer Holbrook, Cynthia A. Agresta, Iris L. Gonzalez, Katia Sol-Church

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155 Citations (Scopus)


Costello syndrome is a rare condition comprising mental retardation, distinctive facial appearance, cardiovascular abnormalities (typically pulmonic stenosis, hypertrophic cardiomyopathy, and/or atrial tachycardia), tumor predisposition, and skin and musculoskeletal abnormalities. Recently mutations in HRAS were identified in 12 Japanese and Italian patients with clinical information available on 7 of the Japanese patients. To expand the molecular delineation of Costello syndrome, we performed mutation analysis in 34 North American and 6 European (total 40) patients with Costello syndrome, and detected missense mutations in HRAS in 33 (82.5%) patients. All mutations affected either codon 12 or 13 of the protein product, with G12S occurring in 30 (90.9%) patients of the mutation-positive cases. In two patients, we found a mutation resulting in an alanine substitution in position 12 (G12A), and in one patient, we detected a novel mutation (G13C). Five different HRAS mutations have now been reported in Costello syndrome, however genotype-phenotype correlation remains incomplete.

Original languageEnglish
Pages (from-to)1-7
Number of pages7
JournalAmerican Journal of Medical Genetics, Part A
Volume140 A
Issue number1
Publication statusPublished - 2006 Jan 1


  • Bladder cancer
  • Gain-of-function
  • HRAS
  • Over-growth syndrome
  • Rhabdomyosarcoma


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