Identification of 217 unreported mutations in the F8 gene in a group of 1,410 unselected Italian patients with hemophilia A |
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| Authors: | R. Santacroce M. Acquila D. Belvini G. Castaldo I. Garagiola S. H. Giacomelli A. M. Lombardi B. Minuti F. Riccardi R. Salviato L. Tagliabue E. Grandone M. Margaglione |
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| Affiliation: | (1) Cattedra di Genetica Medica, Dipartimento di Scienze Biomediche, Università degli Studi di Foggia, viale Pinto, Foggia, 71100, Italy;(2) Laboratorio di Ematologia ed Emofilia, IV Divisione di Pediatria, Istituto Gaslini, Genova, Italy;(3) Servizio Trasfusionale, Castelfranco Veneto Hospital (TV), ASL 8 Regione Veneto, Veneto, Italy;(4) Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli “Federico II”, CEINGE Biotecnologie Avanzate, Napoli, Italy;(5) “Angelo Bianchi Bonomi” Hemophilia and Thrombosis Center, University of Milan and IRCCS Maggiore Hospital, Mangiagalli and regina Elena Foundation, Milan, Italy;(6) Divisione di Ematologia, “S. Bortolo” Hospital, Vicenza, Italy;(7) Dipartimento di Scienze Mediche e Chirurgiche, Università di Padova, Padova, Italy;(8) SOD Diagnostica Genetica, Azienda Ospedaliero-Universitaria Careggi Firenze, Firenze, Italy;(9) UOS di Genetica Molecolare e Citogenetica, Centro di Riferimento Regionale per l’Emofilia e le Malattie Emorragiche Congenite, University Hospital of Parma, Parma, Italy;(10) Unita’ di Emostasi e Trombosi, I.R.C.C.S. “Casa Sollievo della Sofferenza”, S. Giovanni Rotondo, Italy |
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| Abstract: | To provide a National database, 1,410 unrelated hemophilia A (HA) patients were investigated using screening methods denaturing high-performance liquid chromatography (DHPLC), conformational-sensitive gel electrophoresis (CSGE)] and/or direct sequencing. F8 gene mutations were identified in 877 (81%), 146 (82%), and 133 (89%) families with severe, moderate, or mild HA, respectively. Among the 382 different mutations detected, 217 (57%) have not previously been reported in the F8 Haemophilia A Mutation, Structure, Test and Resource Site (HAMSTeRS) database. Mutations leading to a null allele accounted for 82, 15%, and less than 1% of severe, moderate, or mild HA, respectively. A missense mutation was identified in 16%, 68%, and 81% of severe, moderate, or mild HA, respectively. They included 105 missense mutations (48%), 41 small deletions (19%), 25 splice site mutations (12%), 24 nonsense mutations (11%), 18 insertions (8%), three large deletions (1%), and one deletion plus insertion. Unreported mutations were distributed throughout the F8 gene, as they affected all F8 exons but exon 20. We report a wide spectrum of mutations collected 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 counseling and medical care of HA families in Italy. |
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| Keywords: | Hemophilia A F8 gene Mutations Phenotype |
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