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

Haematologica. 2008 May;93(5):722-8. doi: 10.3324/haematol.12427. Epub 2008 Apr 2.


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.

MeSH terms

  • Blood Coagulation Factor Inhibitors / metabolism
  • Chromatography, High Pressure Liquid
  • Codon
  • DNA Mutational Analysis
  • Databases, Genetic*
  • Factor VIII / genetics*
  • Genotype
  • Hemophilia A / diagnosis*
  • Hemophilia A / epidemiology
  • Hemophilia A / genetics*
  • Humans
  • Introns
  • Italy
  • Models, Genetic
  • Mutation
  • Phenotype
  • Registries


  • Blood Coagulation Factor Inhibitors
  • Codon
  • Factor VIII