Hemophilia a patients with undetectable mutations: Current knowledge and future directions

Classical hemophilia A (HA) is characterized by absence or decrease in factor VIII activity. F8 is an essential cofactor of F9 to activate F10. Most known genetic mutations that lead to HA phenotype can be traced to the F8 gene itself. However, in some cases, mutations in chaperon proteins, such as LMNA1 and MCFD2, cause a decrease in secretion of both F5 and F8 resulting in a combined F5/F8 deficiency. Moreover, mutations in the domain of von Willebrand factor (VWF) that interact with F8 cause a HA-like syndrome known as type 2N (Normandy) von Willebrand disease (VWD-2N). Still, in a minority of HA cases, no mutations could be attributed to any of the genes known to be involved in the F8 pathway. In this article we will give an overview of these cases and outline future efforts needed to identify the molecular defects in such patients.