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The Italian AICE-Genetics hemophilia A database: results and correlation with clinical phenotype

¹ Genetica Medica, Università di Foggia
² Unità di Emostasi e Trombosi, I.R.C.C.S. "Casa Sollievo della Sofferenza", S. Giovanni Rotondo
³ Divisione di Ematologia, "S. Bortolo" Hospital, Vicenza
⁴ Centro Regionale Riferimento Coagulopatie Congenite, Azienda Ospedaliero-Universitaria Careggi, Firenze
⁵ Hemophilia and Thrombosis Center, "San Giovanni Bosco" Hospital, Napoli
⁶ "Angelo Bianchi Bonomi" Hemophilia and Thrombosis Center, University of Milan and IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation, Milan
⁷ Servizio Trasfusionale, Castelfranco Veneto Hospital (TV), ASL 8 Regione Veneto, Castelfranco Veneto
⁸ Regional Reference for Inherited Bleeding Disorders, University Hospital of Parma
⁹ Dipartimento di Scienze Mediche e Chirurgiche, Università di Padova
¹⁰ Laboratorio di Ematologia ed Emofilia, IV Divisione di Pediatria, Istituto Gaslini, Genova
¹¹ Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli "Federico II", CEINGE Biotecnologie Avanzate, Napoli
¹² SOD Diagnostica Genetica, Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy

Correspondence: Maurizio Margaglione, MD, Cattedra di Genetica Medica, Dipartimento di Scienze Biomediche, Università degli Studi di Foggia, viale Pinto, 71100 Foggia, Italy. E-mail: m.margaglione{at}unifg.it

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.

Key words: hemophilia A, F8 gene, mutations, hotspots, phenotype.