Carrier detection strategy in haemophilia A: the benefits of combined DNA marker analysis and coagulation testing in sporadic haemophilic families

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Abstract
A province wide study of carrier detection methods in haemophilia A is reported. The principal objective of this project was to compare the relative merits of coagulation testing and DNA marker analysis in carrier diagnosis for a large unselected haemophilic population. Factor VIII:C (F.VIII:C) and von Willebrand factor antigen (vWf:Ag) were measured on plasma samples sent to a central laboratory. Coagulation results were analyzed by a logistic regression model of discrimination. Of 91 potential carriers tested, 15% had indeterminate coagulation test carrier probabilities. Two restriction fragment length polymorphisms were analyzed in 123 women (42 obligate carriers and 81 potential carriers). The Bell polymorphism within the F.VIII gene and the locus DXS 52, approximately 5 cM (centimorgan) from F.VIII were used as DNA markers. Of the 81 potential carriers tested with RFLP analysis, a carrier diagnosis was achieved in 52%. Studies with the F.VIII intragenic BgII polymorphism in 23 of these families gave no additional information. Thirty-nine potential carriers remained undiagnosed after DNA marker analysis. Twenty-seven of these women were from families with a sporadic case of haemophilia. In this group of 27 women, 14 were found to have high probability carrier estimates derived from their coagulation tests. Combined coagulation and RFLP data was available in 42 potential carriers. Disagreement between DNA and coagulation carrier diagnoses was found in four instances. In each case, the coagulation data resulted in a carrier probability of indeterminate value. This study emphasizes some of the limitations associated with DNA marker linkage analysis as it pertains to haemophila A carrier detection. Where a previous family history exists and appropriate females are informative for the DNA markers, this type of analysis is very productive. However, large numbers of potential carriers from ''sporadic'' haemophilia families were a factor in this project. With this in mind, an optimal service for haemophilia A carrier diagnosis must continue to offer reliable coagulation test probabilities in addition to DNA marker studies.