Genetics of Classic von Willebrand's Disease. II. Optimal Assignment of the Heterozygous Genotype (Diagnosis)

In classic von Willebrand’s disease (vWd). assignment of the heterozygous genotype for genetic studies and diagnosis for clinical purposes (which are not exactly the same) are formidable problems. We have pointed out in the first report in this series that almost 50% of the members of two large kindred who transmitted this disease. and were therefore heterozygous. were scored as normal by the usual tests of hemostasis. This report describes how this large proportion can be significantly reduced by application of discriminant analysis. Using linear discriminants in three variables-coagulation factor VIII (VIll:C), factor-VIll-related antigen (VIIIR:Ag). and the ristocetin cofactor related to factor VIII (VIIIR:WF)-we were able to classify as heterozygous more than 80% of the transmitters in the two large kindred. It was of particular interest that the four parents of two related vWd homozygotes could be scored as heterozygous by discriminant analysis even though all their laboratory tests were within the normal ranges. T HE FIRST REPORT in this series’ documented the wide phenotypic variation among the members of two large families transmitting classic von Willebrand’s disease (vWd) when bleeding time (BT), factor VIII coagulant activity (VI I I:C), factor-VI I I-related antigen (VI I IR:Ag), and ristocetin-related platelet aggregation or Willebrand factor (VIIIR:WF) were tested. Specifically, 1 1 of the 16 phenotypes possible when the results of the four tests are considered simultaneously as binary variables were observed in the two families. It was also pointed out that only58% of a group of 26 transmitters, presumably heterozygous, could be so identified by these tests. Assigning the heterozygous vWd genotype to a particular individual in genetic studies or for clinical purposes is difficult. This report will evaluate most of the methods currently used for this purpose, including each of the factor-Vill-related activities and certain ratios between these activities. We have also applied linear discriminant analysis using three variables (VIII:C, VIIIR:Ag, and VIIIR:WF) and have found it to be superior to all other procedures