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.
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.
Authors: 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 Journal: Am J Med Genet A Date: 2006-01-01 Impact factor: 2.802
Authors: Karen W Gripp; Charles I Scott; Linda Nicholson; Donna M McDonald-McGinn; J Daniel Ozeran; Marilyn C Jones; Angela E Lin; Elaine H Zackai Journal: Am J Med Genet Date: 2002-02-15
Authors: Markéta Sutajová; Ursula Neukirchen; Peter Meinecke; Andrew E Czeizel; László Tímár; Enikö Sólyom; Andreas Gal; Kerstin Kutsche Journal: Genomics Date: 2004-05 Impact factor: 5.736
Authors: Angela E Lin; Paul D Grossfeld; Robert M Hamilton; Leslie Smoot; Karen W Gripp; Virginia Proud; Rosanna Weksberg; Patricia Wheeler; Jonathan Picker; Mira Irons; Elaine Zackai; Bradley Marino; Charles I Scott; Linda Nicholson Journal: Am J Med Genet Date: 2002-08-01
Authors: Karen W Gripp; Lindsey A Morse; Marni Axelrad; Kathryn C Chatfield; Aaron Chidekel; William Dobyns; Daniel Doyle; Bronwyn Kerr; Angela E Lin; David D Schwartz; Barbara J Sibbles; Dawn Siegel; Suma P Shankar; David A Stevenson; Mihir M Thacker; K Nicole Weaver; Sue M White; Katherine A Rauen Journal: Am J Med Genet A Date: 2019-06-20 Impact factor: 2.802
Authors: Michael Klüppel; Payman Samavarchi-Tehrani; Kela Liu; Jeffrey L Wrana; Aleksander Hinek Journal: Eur J Hum Genet Date: 2012-02-08 Impact factor: 4.246
Authors: Angela E Lin; Barbara O'Brien; Laurie A Demmer; Kristina K Almeda; Cynthia L Blanco; Patrick F Glasow; Charles I Berul; Robert Hamilton; A Micheil Innes; Julie L Lauzon; Katia Sol-Church; Karen W Gripp Journal: Prenat Diagn Date: 2009-07 Impact factor: 3.050
Authors: Karen W Gripp; Katia Sol-Church; Patroula Smpokou; Gail E Graham; David A Stevenson; Heather Hanson; David H Viskochil; Laura C Baker; Bridget Russo; Nick Gardner; Deborah L Stabley; Verena Kolbe; Georg Rosenberger Journal: Am J Med Genet A Date: 2015-04-25 Impact factor: 2.802
Authors: Karen W Gripp; Katherine M Robbins; Brandon S Sheffield; Anna F Lee; Millan S Patel; Stephen Yip; Daniel Doyle; Deborah Stabley; Katia Sol-Church Journal: Am J Med Genet A Date: 2015-11-17 Impact factor: 2.802