Genetic mapping and diagnosis of haemophilia A achieved through a BclI polymorphism in the factor VIII gene

Abstract

Haemophilia A is the most common inherited bleeding disorder in man, affecting approximately 1 male in 10,000 (ref. 1). The disease is caused by a deficiency in the gene for factor VIII, a component of the intrinsic coagulation pathway. Due to the broad range of clotting activity in normal and heterozygous females, it is often difficult to confirm the status of women at risk for carrying the disease². A genetic marker in the form of a restriction fragment length polymorphism (RFLP) within or tightly linked to the factor VIII gene would serve as a tag for the haemophilia gene, thus allowing both accurate carrier detection and improved, earlier prenatal diagnosis by chorionic villi sampling^3,4. The recent isolation of the factor VIII gene^5,6 has allowed a search for RFLPs within the gene, and we report here the identification of a common polymorphism within the factor VIII gene, revealed by the restriction enzyme BclI, which can be used diagnostically in about 42% of all families. Although the disease haemophilia A has been mapped to the distal portion of Xq (ref. 7), the BclI RFLP makes possible higher-resolution genetic linkage mapping with respect to other polymorphic markers on this portion of the X chromosome. We have established close linkage of the factor VIII gene to several useful RFLP markers, including the highly informative marker St14 (ref. 8). These markers should also be useful for prenatal diagnosis of haemophilia A and for detection of its carriers.