TY - JOUR
T1 - Chromosome fragility in patients with Fanconi anaemia: Diagnostic implications and clinical impact
AU - Castella, Maria
AU - Pujol, Roser
AU - Callén, Elsa
AU - Ramírez, Maria J.
AU - Casado, Joséé A.
AU - Talavera, Maria
AU - Ferro, Teresa
AU - Muñoz, Arturo
AU - Sevilla, Julián
AU - Madero, Luis
AU - Cela, Elena
AU - Beléndez, Cristina
AU - de Heredia, Cristina Díaz
AU - Olivé, Teresa
AU - de Toledo, José Sánchez
AU - Badell, Isabel
AU - Estella, Jesús
AU - Dasí, Ángeles
AU - Rodríguez-Villa, Antonia
AU - Gómez, Pedro
AU - Tapia, María
AU - Molinés, Antonio
AU - Figuera, Ángela
AU - Bueren, Juan A.
AU - Surrallés, Jordi
PY - 2011/4/1
Y1 - 2011/4/1
N2 - Background: Fanconi anaemia (FA) is a rare syndrome characterized by bone marrow failure, malformations and cancer predisposition. Chromosome fragility induced by DNA interstrand crosslink (ICL)-inducing agents such as diepoxybutane (DEB) or mitomycin C (MMC) is the 'gold standard' test for the diagnosis of FA. Objective: To study the variability, the diagnostic implications and the clinical impact of chromosome fragility in FA. Methods: Data are presented from 198 DEB-induced chromosome fragility tests in patients with and without FA where information on genetic subtype, cell sensitivity to MMC and clinical data were available. Results: This large series allowed quantification of the variability and the level of overlap in ICL sensitivity among patients with FA and the normal population. A new chromosome fragility index is proposed that provides a cut-off diagnostic level to unambiguously distinguish patients with FA, including mosaics, from non-FA individuals. Spontaneous chromosome fragility and its correlation with DEB-induced fragility was also analysed, indicating that although both variables are correlated, 54% of patients with FA do not have spontaneous fragility. The data reveal a correlation between malformations and sensitivity to ICL-inducing agents. This correlation was also statistically significant when the analysis was restricted to patients from the FA-A complementation group. Finally, chromosome fragility does not correlate with the age of onset of haematological disease. Conclusions: This study proposes a new chromosome fragility index and suggests that genome instability during embryo development may be related to malformations in FA, while DEB-induced chromosome breaks in T cells have no prognostic value for the haematological disease.
AB - Background: Fanconi anaemia (FA) is a rare syndrome characterized by bone marrow failure, malformations and cancer predisposition. Chromosome fragility induced by DNA interstrand crosslink (ICL)-inducing agents such as diepoxybutane (DEB) or mitomycin C (MMC) is the 'gold standard' test for the diagnosis of FA. Objective: To study the variability, the diagnostic implications and the clinical impact of chromosome fragility in FA. Methods: Data are presented from 198 DEB-induced chromosome fragility tests in patients with and without FA where information on genetic subtype, cell sensitivity to MMC and clinical data were available. Results: This large series allowed quantification of the variability and the level of overlap in ICL sensitivity among patients with FA and the normal population. A new chromosome fragility index is proposed that provides a cut-off diagnostic level to unambiguously distinguish patients with FA, including mosaics, from non-FA individuals. Spontaneous chromosome fragility and its correlation with DEB-induced fragility was also analysed, indicating that although both variables are correlated, 54% of patients with FA do not have spontaneous fragility. The data reveal a correlation between malformations and sensitivity to ICL-inducing agents. This correlation was also statistically significant when the analysis was restricted to patients from the FA-A complementation group. Finally, chromosome fragility does not correlate with the age of onset of haematological disease. Conclusions: This study proposes a new chromosome fragility index and suggests that genome instability during embryo development may be related to malformations in FA, while DEB-induced chromosome breaks in T cells have no prognostic value for the haematological disease.
U2 - https://doi.org/10.1136/jmg.2010.084210
DO - https://doi.org/10.1136/jmg.2010.084210
M3 - Article
VL - 48
SP - 242
EP - 250
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
SN - 0022-2593
ER -