Molecular analysis of simple and complex genetic variants in a cohort of patients with hemophilia A :mechanisms and diagnostic implications

摘要

Haemophilia A (HA) is caused by widespread mutations in the factor VIII gene. Although genetic alterations responsible for HA can now be identified in a vast majority of patients, molecular diagnostic remains challenging in some patients. This thesis addresses important issues in the diagnostic and molecular mechanisms of some frequent or rare genetic alterations associated with HA. It demonstrates the value of computational and molecular approaches for predicting the causality of unreported missense mutations. It also shows that the overrepresentation of specific missense mutations in mild HA can be explained by a founder effect rather than by an independent occurrence. Also, it highlights how complex genetic rearrangements such as tandem inversion duplication within intron 1 and exons 1-22 duplications involving intron 22 homologous repeats (int22h) can be detected and their occurrence best explained. Finally, it demonstrates for the first time the existence of wild-type human genotype harbouring five int22h copies identified in the rare intron22 inversion type 3 of the factor VIII gene.