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Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases
  1. B Kerr1,
  2. M-A Delrue2,
  3. S Sigaudy3,
  4. R Perveen1,
  5. M Marche4,
  6. I Burgelin4,
  7. M Stef4,
  8. B Tang1,
  9. O B Eden5,
  10. J O’Sullivan1,
  11. A De Sandre-Giovannoli3,
  12. W Reardon6,
  13. C Brewer7,
  14. C Bennett8,
  15. O Quarell9,
  16. E M’Cann10,
  17. D Donnai1,
  18. F Stewart11,
  19. R Hennekam12,
  20. H Cavé13,
  21. A Verloes14,
  22. N Philip3,
  23. D Lacombe2,
  24. N Levy3,
  25. B Arveiler4,
  26. G Black14
  1. 1Academic Unit of Medical Genetics and Regional Genetic Service, Central Manchester and Manchester University Hospitals NHS Trust, Manchester, UK
  2. 2Service de Génétique Médicale, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
  3. 3Department de Génétique Médicale, Hopital d’enfants de la Timoine, Universite de la Mediterranee, Marseille, France
  4. 4Laboratoire de Génétique Humaine, Développement et Cancer, EA 3669, Université Victor Segalen Bordeaux 2, Bordeaux, France
  5. 5Department of Paediatric Oncology, Central Manchester and Manchester University Hospitals NHS Trust, Manchester, UK
  6. 6National Centre for Medical Genetics, Our Lady’s Hospital for Sick Children, Dublin, Republic of Ireland
  7. 7Clinical Genetics Department, Royal Devon and Exeter Hospital, Exeter, UK
  8. 8Department of Clinical Genetics, St James’s University Hospital, Leeds, UK
  9. 9Sheffield Centre for Human Genetics, Sheffield Children’s Hospital, Sheffield, UK
  10. 10Department of Clinical Genetics, Royal Liverpool Children’s Hospital, Liverpool, UK
  11. 11Clinical Genetics Service, Belfast City Hospital, Belfast, UK
  12. 12Department of Pediatrics and Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands
  13. 13Service de Génétique, Hôpital Robert Debré, Paris, France
  14. 14Centre for Molecular Medicine, Faculty of Medical and Health Sciences, University of Manchester, Manchester, UK
  1. Correspondence to:
 Dr B Kerr
 Academic Unit of Medical Genetics and Regional Genetic Service, St Mary’s Hospital, Hathersage Road, Manchester M13 0JN, UK; bronwyn.kerr


Background: Costello syndrome (CS) is a rare multiple congenital abnormality syndrome, associated with failure to thrive and developmental delay. One of the more distinctive features in childhood is the development of facial warts, often nasolabial and in other moist body surfaces. Individuals with CS have an increased risk of malignancy, suggested to be about 17%. Recently, mutations in the HRAS gene on chromosome 11p13.3 have been found to cause CS.

Methods: We report here the results of HRAS analysis in 43 individuals with a clinical diagnosis of CS.

Results: Mutations were found in 37 (86%) of patients. Analysis of parental DNA samples was possible in 16 cases for both parents and in three cases for one parent, and confirmed the mutations as de novo in all of these cases. Three novel mutations (G12C, G12E, and K117R) were found in five cases.

Conclusions: These results confirm that CS is caused, in most cases, by heterozygous missense mutations in the proto-oncogene HRAS. Analysis of the major phenotypic features by mutation suggests a potential correlation between malignancy risk and genotype, which is highest for patients with an uncommon (G12A) substitution. These results confirm that mutation testing for HRAS is a reliable diagnostic test for CS.

  • CFC, cardiofaciocutaneous
  • CS, Costello syndrome
  • NS, Noonan syndrome
  • Costello syndrome
  • HRAS mutations
  • malignancy

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  • Published Online First 27 January 2006

  • The first three authors contributed equally to this work.Members of the Costello Syndrome Collaboration Group; Drs N Gregerson, E Sheridan, M Porteus, A Fryer, A Brady, K Becker, M Till, A David, G Vittu, D Heron, S Odent, B Leheup, A Munnich.

  • Competing interests: there are no competing interests.