Molecular Genetic Analysis in Patients with a Phenotype-Based Putative Diagnosis of Von Willebrand's Disease Type 1

The conclusive diagnosis of von Willebrand's disease (VWD) type 1 represents a challenging task. In addition to repeatedly performed phenotypic assessment, genetic analysis of the VWF gene may help establish the diagnosis. The aim of the present study was to assess the contribution of molecular genetic analysis in confirming the diagnosis in cases of suspected VWD type 1. Twenty-one patients (18 females, 3 males) with bleeding tendency were preliminary classified as likely or possible VWD type 1 based on phenotypic assays (VWF:Ag, VWF:RCoF < 50 % or 51-59 %, respectively) and further investigated by direct sequencing and MLPA analysis of the VWF gene. Ten different heterozygous mutations were identified in eleven patients (52 % confirmation rate). The mutation Y1584C (exon 28) was found in two unrelated patients. Most patients (9 of 11) demonstrated missense mutations in exons 20, 21, 28, 45 and 49. Newly identified mutations were K2566N (exon 45) and a 15 bp insertion predicting L168insX (exon 5). Large deletions and duplications were not detected. The results confirm the varying molecular pathology underlying VWD type 1. Molecular genetic analysis represents a useful approach to conclusively establish the diagnosis of VWD type 1 in approximately 50 % of patients with a phenotype-based preliminary diagnosis.