VWD shows great variability within and between families. In some kindred the affected
persons show decreased amounts of an apparently normal VIIIR:Ag. In others, abnormal
electrophoretic mobility of VIIIR:Ag has been associated with a defect in the degree
of polymerization. Within kindred, expressivity may be so variable that some transmitters
have normal laboratory findings. Detection of linkage between VWD and a clearly defined
antigenic or biochemical marker might provide the means to make unambiguous diagnoses
and to distinguish between the effects of the multiple genes involved in synthesis
of VIIIR:Ag.
We have examined 4 VWD kindred, using 23 genetic markers. Individuals were classified
for VWD using clinical and laboratory data, pedigree information and 2 statistical
procedures: D I based on 3 measures of F VIII activity, and D II which also included
bleeding time and a subjective index of symptoms. Using D I, a LOD score of 0.66 at
a recombination frequency (θ) of 0.20 was found with GPT (glucose pyruvic transaminase).
Using D II a LOD score of 0.50 at a θ of 0.25 was found. Most of the evidence of a
VWD- GPT linkage was provided by a single kindred. Using D II, evidence suggesting
a second linkage was observed between VWD and GLO (glyoxylase) with a LOD score of
1.03 at a 0 of 0.20, all 4 families contributing.
The LOD scores reported are suggestive of linkage and warrant further study. Since
GLO relates to Chromosome 6 while the chromosomal location of GPT is not known and
since GPT and GLO are unlinked, VWD may be genetically heterogeneous, 2 or more loci
being involved.
Studies to clarify the relationship of VWD to Chromosome 6 are underway using markers
known to be linked to GLO.
