Molecular analysis of Fanconi anemia: the experience of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Onco-Hematology.

Daniela De Rocco, Roberta Bottega, Enrico Cappelli, Simona Cavani, Maria Criscuolo, Elena Nicchia, Fabio Corsolini, Chiara Greco, Adriana Borriello, Johanna Svahn, Marta Pillon, Cristina Mecucci, Gabriella Casazza, Federico Verzegnassi, Chiara Cugno, Anna Locasciulli, Piero Farruggia, Daniela Longoni, Ugo Ramenghi, Walter Barberi, Fabio Tucci, Silverio Perrotta, Paola Grammatico, Helmut Hanenberg, Fulvio Della Ragione, Carlo Dufour, Anna Savoia

Journal: Haematologica 2015;99(6):1022-31

PMID: 24584348

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Abstract

Fanconi anemia is an inherited disease characterized by congenital malformations, pancytopenia, cancer predisposition, and sensitivity to cross-linking agents. The molecular diagnosis of Fanconi anemia is relatively complex for several aspects including genetic heterogeneity with mutations in at least 16 different genes. In this paper, we report the mutations identified in 100 unrelated probands enrolled into the National Network of the Italian Association of Pediatric Hematoly and Oncology. In approximately half of these cases, mutational screening was carried out after retroviral complementation analyses or protein analysis. In the other half, the analysis was performed on the most frequently mutated genes or using a next generation sequencing approach. We identified 108 distinct variants of the FANCA, FANCG, FANCC, FANCD2, and FANCB genes in 85, 9, 3, 2, and 1 families, respectively. Despite the relatively high number of private mutations, 45 of which are novel Fanconi anemia alleles, 26% of the FANCA alleles are due to 5 distinct mutations. Most of the mutations are large genomic deletions and nonsense or frameshift mutations, although we identified a series of missense mutations, whose pathogenetic role was not always certain. The molecular diagnosis of Fanconi anemia is still a tiered procedure that requires identifying candidate genes to avoid useless sequencing. Introduction of next generation sequencing strategies will greatly improve the diagnostic process, allowing a rapid analysis of all the genes.

Address: Department of Medical Sciences, University of Trieste, Italy.; Clinical and Experimental Hematology Unit, G. Gaslini Children's Hospital, Genoa, Italy.; Human Genetics laboratory, "E.O. Ospedali Galliera", Genoa, Italy.; Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Italy.; Pediatric Onco-Hematology, "Azienda Ospedaliero Universitaria Pisana", Pisa, Italy.; Institute for Maternal and Child Health - IRCCS Burlo Garofolo, Trieste, Italy.; Pediatric Onco-Haematology Clinic, University of Padua, Italy.; Hematology, University of Perugia, Perugia, Italy.; Pediatric Onco-Hematology, "Fondazione IRCCS Policlinico San Matteo", Pavia, Italy.; Department of Pediatric and Pediatric Hematology, S.Camillo Hospital, Rome, Italy.; Pediatric Onco-Hematology, ARNAS Civico Hospital, Palermo, Italy.; Pediatrics Unit, University of Milano-Bicocca, Fondazione MBBM, Ospedale San Gerardo, Monza, Italy.; Department of Pediatric and Public Health Sciences, Sapienza Università di Roma, Firenze, Italy.; Dipartimento di Biotecnologia Cellulari ed Ematologia, Sapienza Università di Roma, Firenze, Italy.; Pediatric Onco-Hematology, "Azienda Ospedaliero-Universitaria" Meyer, Firenze, Italy.; Department of Pediatrics, Second University of Naples, Italy.; Department of Molecular Medicine, "La Sapienza" University, Rome, Italy.; Department of Otorhinolaryngology & Head/Neck Surgery, Heinrich Heine University School of Medicine, Duesseldorf, Germany Pediatric Hematology/Oncology, Wells Center for Pediatric Research, Department of Pediatrics, The Riley Hospital, Indiana University School of Medicine, Indianapolis, IN, USA Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Medical Sciences, University of Trieste, Italy Pediatric Onco-Hematology, "Azienda Ospedaliero Universitaria Pisana", Pisa, Italy [email protected].

DOI: 10.3324/haematol.2014.104224

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MeSH Terms: Amino Acid Substitution, Cell Line, Cohort Studies, Computational Biology, Databases, Nucleic Acid, Fanconi Anemia, Fanconi Anemia Complementation Group Proteins, Founder Effect, Genotype, Humans, Italy, Mosaicism, Mutation, Polymorphism, Single Nucleotide