The molecular basis of hemophilia A: genotype-phenotype relationships and inhibitor development

The molecular basis of hemophilia A has been extensively studied over the last two decades, and this analysis of the factor VIII (FVIII) gene has rendered it one of the most studied of all human genes. A wide range of different mutation types has been identified that includes the novel intrachromosomal inversions involving regions in introns 1 and 22 of the FVIII gene as well as many mutation types found in other genetic diseases, including large and small deletions and insertions, and point mutations resulting in nonsense, missense, and splice site mutations. Inhibitory antibodies that develop in a proportion of patients with hemophilia A following replacement therapy are now known to correlate with FVIII mutation type and location. This correlation is demonstrated, and a potential algorithm for predicting inhibitor development in newly diagnosed patients is presented. Many patients with mild hemophilia A have a discrepancy between the levels of FVIII:C determined by the one-stage and two-stage assays. The molecular basis of the discrepancy is explored. This article thus highlights both the molecular basis of hemophilia and some of the additional information that can be gained from determination of the mutation responsible for hemophilia in affected patients.