Cosegregation of von Willebrand factor gene polymorphisms and possible germinal mosaicism in type IIB von Willebrand disease.

Recent reports of the mutations resulting in von Willebrand disease (vWD) have indicated that some cases of type IIA vWD are caused by single nucleotide substitutions in the gene encoding von Willebrand factor (vWF). However, the molecular pathogenesis of type IIB vWD remains unresolved and, with the complex posttranslational processing required for fully functional vWF, the mutations responsible for this phenotype may occur at loci other than the vWF gene. This study has used six intragenic vWF polymorphisms to assess the linkage of type IIB vWD to this gene in three families (48 individuals). The results of these studies indicate that there is significant linkage between the vWF gene and the type IIB phenotype (logarithm of the odds ratio of 7.2 at theta = 0), suggesting that the mutations responsible for this disorder frequently occur at this locus. Results from one of these families indicates that the disorder has been transmitted from an unaffected parent to two children who have inherited the same vWF gene as seven unaffected siblings. This finding is suggestive of the presence of germinal mosaicism for the mutation in the father.