title: Molecular analysis of Fanconi anemia: the experience of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Onco-Hematology.
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.
authors.affiliation: Department of Medical Sciences, University of Trieste, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: De Rocco
authors.affiliation: Department of Medical Sciences, University of Trieste, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Bottega
authors.affiliation: Clinical and Experimental Hematology Unit, G. Gaslini Children's Hospital, Genoa, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Cappelli
authors.affiliation: Human Genetics laboratory, "E.O. Ospedali Galliera", Genoa, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Cavani
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Criscuolo
authors.affiliation: Department of Medical Sciences, University of Trieste, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Nicchia
authors.affiliation: Clinical and Experimental Hematology Unit, G. Gaslini Children's Hospital, Genoa, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Corsolini
authors.affiliation: Pediatric Onco-Hematology, "Azienda Ospedaliero Universitaria Pisana", Pisa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Greco
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Borriello
authors.affiliation: Clinical and Experimental Hematology Unit, G. Gaslini Children's Hospital, Genoa, Italy.
authors.forename: Johanna
authors.initials: J
authors.lastname: Svahn
authors.affiliation: Institute for Maternal and Child Health - IRCCS Burlo Garofolo, Trieste, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Pillon
authors.affiliation: Pediatric Onco-Haematology Clinic, University of Padua, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mecucci
authors.affiliation: Hematology, University of Perugia, Perugia, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Casazza
authors.affiliation: Pediatric Onco-Hematology, "Azienda Ospedaliero Universitaria Pisana", Pisa, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Verzegnassi
authors.affiliation: Pediatric Onco-Hematology, "Fondazione IRCCS Policlinico San Matteo", Pavia, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cugno
authors.affiliation: Department of Pediatric and Pediatric Hematology, S.Camillo Hospital, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Locasciulli
authors.affiliation: Pediatric Onco-Hematology, ARNAS Civico Hospital, Palermo, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Farruggia
authors.affiliation: Pediatrics Unit, University of Milano-Bicocca, Fondazione MBBM, Ospedale San Gerardo, Monza, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Longoni
authors.affiliation: Department of Pediatric and Public Health Sciences, Sapienza Università di Roma, Firenze, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Ramenghi
authors.affiliation: Dipartimento di Biotecnologia Cellulari ed Ematologia, Sapienza Università di Roma, Firenze, Italy.
authors.forename: Walter
authors.initials: W
authors.lastname: Barberi
authors.affiliation: Pediatric Onco-Hematology, "Azienda Ospedaliero-Universitaria" Meyer, Firenze, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Tucci
authors.affiliation: Department of Pediatrics, Second University of Naples, Italy.
authors.forename: Silverio
authors.initials: S
authors.lastname: Perrotta
authors.affiliation: Department of Molecular Medicine, "La Sapienza" University, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Grammatico
authors.affiliation: 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.
authors.forename: Helmut
authors.initials: H
authors.lastname: Hanenberg
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Italy.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Della Ragione
authors.affiliation: Clinical and Experimental Hematology Unit, G. Gaslini Children's Hospital, Genoa, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Dufour
authors.affiliation: Department of Medical Sciences, University of Trieste, Italy Pediatric Onco-Hematology, "Azienda Ospedaliero Universitaria Pisana", Pisa, Italy anna.savoia@burlo.trieste.it.
authors.forename: Anna
authors.initials: A
authors.lastname: Savoia
mesh_terms: D019943:Amino Acid Substitution; D002460:Cell Line; D015331:Cohort Studies; D019295:Computational Biology; D030561:Databases, Nucleic Acid; D005199:Fanconi Anemia / Q000235:genetics*; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics*; D018703:Founder Effect; D005838:Genotype; D006801:Humans; D007558:Italy; D009030:Mosaicism; D009154:Mutation; D020641:Polymorphism, Single Nucleotide
chemical_list: D051856:Fanconi Anemia Complementation Group Proteins