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.
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.
Authors: Judith Reina-Castillón; Roser Pujol; Marcos López-Sánchez; Benjamín Rodríguez-Santiago; Miriam Aza-Carmona; Juan Ramón González; José Antonio Casado; Juan Antonio Bueren; Julián Sevilla; Isabel Badel; Albert Català; Cristina Beléndez; María Ángeles Dasí; Cristina Díaz de Heredia; Jean Soulier; Detlev Schindler; Luis Alberto Pérez-Jurado; Jordi Surrallés Journal: Blood Adv Date: 2017-01-23
Authors: Fernanda Gutierrez-Rodrigues; Sushree S Sahoo; Marcin W Wlodarski; Neal S Young Journal: Best Pract Res Clin Haematol Date: 2021-06-27 Impact factor: 3.670
Authors: John H Fargo; Andrzej Rochowski; Neelam Giri; Sharon A Savage; Susan B Olson; Blanche P Alter Journal: Cytogenet Genome Res Date: 2014-09-11 Impact factor: 1.636
Authors: Irene Catucci; Ana Osorio; Brita Arver; Guido Neidhardt; Massimo Bogliolo; Federica Zanardi; Mirko Riboni; Simone Minardi; Roser Pujol; Jacopo Azzollini; Bernard Peissel; Siranoush Manoukian; Giovanna De Vecchi; Stefano Casola; Jan Hauke; Lisa Richters; Kerstin Rhiem; Rita K Schmutzler; Karin Wallander; Therese Törngren; Åke Borg; Paolo Radice; Jordi Surrallés; Eric Hahnen; Hans Ehrencrona; Anders Kvist; Javier Benitez; Paolo Peterlongo Journal: Genet Med Date: 2017-08-24 Impact factor: 8.822