Biomedical subjects
Publications and source records attributed to I Peake.
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Carrier detection and prenatal diagnosis in the three commonest bleeding disorders (hemophilia A and B and von Wilebrands disease) can be performed either phenotypically or genotypically. Phenotypic analysis for carrier detection results only in a probabilistic assessment whereas DNA analysis, either by direct defect detection or by DNA polymorphism based gene tracking, can result in an accuracy of effectively 100%. Direct defect detection is the method of choice but can be technically demanding. Polymorphism analysis is much simpler and is now being used in family studies world wide.
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Gel filtration (sepharose 2B CL) patterns of factor VIII coagulant antigen (VIIIC:Ag) and factor VIII related antigen (VIIIR:Ag) were obtained using normal plasma and plasma from patients with von Willebrand's disease. The latter group consisted of five individuals with normal mobility of factor VIIIR:Ag on cross-immunoelectrophoresis (Type I) and five others with abnormal (increased) mobility (Type II). Results showed that the elution of VIIIC:Ag was delayed in those subjects whose ratio of VIIIR:Ag to VIIIC:Ag was reduced. It has previously been reported that VIIIR:Ag exerts a stabilizing influence on the coagulant activity of factor VIII (VIII:C); our data suggests that when VIIIR:Ag is deficient, abnormal (low molecular weight) forms of VIIIC:Ag circulate.
The advent of molecular genetics has had a significant impact on carrier detection and prenatal diagnosis in the haemophilias. Where phenotypic analysis can only identify with varying degrees of probability up to 90% of carriers and can only be used in prenatal diagnosis when fetal blood is obtained (18-20 weeks gestation), genotypic analysis gives a greater than 99% certainty of carrier status (when informative) and allows for prenatal diagnosis at 8-12 weeks utilising DNA obtained by chorionic villus sampling. Furthermore, the introduction of the technique of polymerase chain reaction (PCR) amplification of DNA into genotypic analysis either for the detection of the disease-causing defect itself, or to detect an intragenic informative polymorphism, has significantly increased the ease by which these procedures can be introduced into the laboratory. PCR based family studies in haemophilia will become increasingly available in both developed and developing countries. While in the former detection of the defect itself will become available, particularly for haemophilia B, in other countries simple PCR based DNA polymorphism analysis will become the mainstay of effective, practical haemophilia genetics.