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Abstract In order to determine the phenotypic variability within families transmitting classic von Willebrand's disease (vWd), a single cross-sectional examination was made of two large seven-generation vWd kindred living in the Carolinas. A total of 181 subjects were examined at least once. Fifty-eight were classified as “affected,” 24 in the smaller kindred of 418 persons and 34 (2 of whom were homozygous) in the larger kindred of 750 persons. Detailed histories were taken, and bleeding time (BT), coagulant factor VIII (VIII:C), factorVlll-related antigen (VIIIR:Ag), and Willebrand factor (VIIIR:WF) were determined on all subjects. Affected persons were present in several generations in each kindred, and the affected state (defined as having a value outside the normal range in one or more of the four tests in the direction expected in vWd) was transmitted by both sexes to both sexes. Segregational analysis showed the pattern of inheritance to be consistent with an autosomal dominant mode, and both kindred appeared to be transmitting classic vWd. The abnormal gene was found to have a highly variable expression, 11 of the 16 possible combinations of normal or abnormal results for BT, VIILC, VIIIR:Ag, and VIIIRiWF being observed among the affected persons. Penetrance of the abnormal gene was incomplete, 11 of the 26 presumably heterozygous transmitters having all F-VIII-related activities within the normal range. Two years after the initial study, a subsample of one kindred was reexamined twice, 5 mo apart. The phenotype of the affected state was found to be highly stable over time; 77% of those restudied were assigned the same classification as originally. Among the 5 of 22 who were phenotypically reclassified on second or third test, no changes in genotypic designation were required, since their genotypes could be correctly determined from genetic data.
Miller et al. (Sun,) studied this question.