Carrier detection in the hemophilias

Abstract The subject of carrier detection in the hemophilias has received new impetus in the past several years. Treatment complications arising from clotting factor concentrates have become more evident and earlier prenatal diagnosis and new genetic markers for the clotting factor genes have focused interest on this area. Until now, carrier diagnosis has relied upon standard pedigree analysis and clotting factor assays. The results obtained using these methods are probabilistic, and the coagulation tests are unavoidably influenced by the effects of random X chromosome inactivation and the inherent variability of the methods involved. With the cloning and characterization of both factor IX and factor VIII genes, has come the capability of using gene analysis to diagnose the carrier state. This usually involves the detection of restriction fragment length polymorphisms (RFLPs) and their use as linked markers for the defective clotting factor gene. In hemophilia A, the combined use of three intragenic RFLPs and two closely linked, highly polymorphic extragenic markers will make carrier information available to approximately 90% of kindred. In hemophilia B, phenotypic analysis has been complicated by the more heterogeneous expression of the gene defect. To date, five intragenic and one closely linked RFLP have been reported, as well as two protein polymorphisms detectable by monoclonal antibody immunoassays. With the combined use of these genetic markers it is likely that accurate carrier assignment will be available to more than 80% of hemophilia B families.