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

The high mutational heterogeneity of Hemophilia A (HA) is a challenge for the provision of genetic services. Objective To elucidate the molecular basis of HA in Italy and to identify the mutation in patients from each affected family to create a confidential national database of mutations for the optimization of genetic services. Patients/Methods The F8 gene was analyzed in 1569 HA patients, belonging to 1392 unrelated families. A total of 1083 (1197 patients) of the families had severe HA, whereas the remaining 309 families (372 patients) had mild/moderate HA. Search for gene mutations was carried out according to standard procedures. Results A F8 gene mutation was identified in 869 (80%) and 277 (90%) families with severe or mild/moderate HA, respectively. In patients with severe HA, in addition to intron inversions, 286 different mutations were recorded, whereas 143 were found in patients with moderate/mild HA. Most point mutations occurred within the exon 14 (30%). However, the rate of mutation involving this large exon was similar to the mean rate (0.6*10-4 vs. 1.0*10-4 in the whole gene). In the whole setting, 251 out of the 579 (43%) point mutations identified were associated with three major motifs. Patients with mutations leading to a null allele developed more frequently inhibitors (22 to 67%) than patients with missense mutations (5%). Conclusions A large spectrum of mutations has been collected. The type of mutation was a strong predictor of inhibitor development. The database will improve genetic counselling in HA patients and their families in Italy.