The Italian AICE-Genetics hemophilia a database: Results and correlation with clinical phenotype

Maurizio Margaglione, Giancarlo Castaman, Massimo Morfini, Angiola Rocino, Elena Santagostino, Giuseppe Tagariello, Anna Rita Tagliaferri, Ezio Zanon, Maria Patrizia Bicocchi, Giuseppe Castaldo, Flora Peyvandi, Rosa Santacroce, Francesca Torricelli, Elvira Grandone, Pier Mannuccio Mannucci, L. Contino, A. Accorsi, A. Scaraggi, N. Ciavarella, G. RodorigoR. Targhetta, G. Tagariello, D. Belvini, R. Salviato, R. Musso, G. Muleo, C. Biasoli, V. Rossi, S. Testa, G. L. Scapoli, D. Vincenti, M. Morfini, A. C. Molinari, M. P. Bicocchi, M. Girotto, G. Mariani, C. Ciabatta, M. T. Carloni, P. M. Mannucci, E. Santagostino, F. Peyvandi, F. Baudo, M. Marietta, C. Perricone, M. Schiavulli, A. Rocino, G. Di Minno, A. Coppola, M. Berrettini, E. Zanon, G. Mancuso, S. Siragusa, A. Tagliaferri, F. Rivolta, G. Gamba, A. Iorio, A. Dragani, M. C. Arbasi, A. Mancino, V. Trapani Lombardo, M. D'Incà, G. De Rossi, R. Landolfi, G. Mazzucconi, G. Piseddu, L. Perugini, M. Messina, G. Tamponi, P. Schinco, G. Rossetti, G. Barillari, A. Catalano, G. Feola, G. Gandini, G. Castaman, S. Giacomelli, R. Ghiotto

Research output: Contribution to journalArticlepeer-review


Background: The high mutational heterogeneity of hemophilia A is a challenge for the provision of genetic services.We plan to identify the mutation in patients with hemophilia A in order to create a confidential national database of mutations for the optimization of genetic services in Italy. Design and Methods: The factor VIII gene (F8) was analyzed in 1296 unrelated patients with hemophilia A using screening methods for intron 22 and 1 inversions and rare mutations (denaturing high performance liquid chromatography, conformation sensitive gel electrophoresis) and/or direct sequencing. Results: F8 mutations were identified in 874 (89%), 146 (89%), and 133 (94%) families with severe, moderate, or mild hemophilia A, respectively. Mutations predicting a null allele were responsible for 80%, 15%, and less than 1% of cases of severe, moderate, or mild hemophilia A, respectively. About 40% of missense and nonsense mutations occurred at a CpG site, arginines being most frequently affected. Of the small deletions or insertions, 29% occurred at one of two stretches of adenines, codons 1191-1194 (8As) and 1439-1441 (9As). Overall, these "hotspots" accounted for 31% of the point mutations in the patients with hemophilia A. Inhibitors developed in 22% of the patients with severe hemophilia A, 8% of those with moderate disease and in 4% of patients with mild hemophilia A. Patients who had severe hemophilia A and mutations predicting a null allele developed inhibitors more frequently (22 to 67%) than patients with missense mutations (5%). Conclusions: We report a wide spectrum of mutations in a large national database. The type of mutation was a strong predictor of the clinical phenotype. This database is expected to considerably improve the genetic counselling and medical care of families with hemophilia A in Italy.

Original languageEnglish
Pages (from-to)722-728
Number of pages7
Issue number5
Publication statusPublished - May 2008


  • F8 gene
  • Hemophilia A
  • Hotspots
  • Mutations
  • Phenotype

ASJC Scopus subject areas

  • Hematology


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