Application of DNA-based diagnosis to patient care: the example of hemophilia A

DNA-based carrier testing and prenatal diagnosis are rapidly expanding medical applications of recombinant-DNA technology. The ultimate goal of DNA-based diagnosis is the determination of the causative mutation, but, in general, this is possible only for large deletions, insertions, or certain nonsense mutation that, in most diseases, involve only a few percent of affected families. If direct diagnosis of the carrier state or fetal disease state is not feasible, indirect diagnosis can be performed by following the segregation of linked polymorphisms through the family pedigree. For such indirect diagnosis, DNA from multiple family members must be analyzed. Although this procedure is highly accurate in many families, errors can potentially occur because of meiotic recombination, genetic heterogeneity, new mutations, and nonpaternity. In this review, a general introduction to DNA-based diagnosis of mendelian diseases is presented and the methods and strategy are outlined. The use of these techniques for the diagnosis of hemophilia A is then described to illustrate the principles of diagnosis and to highlight some of the complexities encountered. DNA-based diagnosis is in its infancy and has the potential to revolutionize preventive medicine.