Genetic heterogeneity in patients with von Willebrand disease type I: a regional study from Northeast Germany

M. Steiner, D. Jenzen, R. Toenges, D. Friday, B. Krammer-Steiner (Rostock, Germany)

Laboratory tests
Date: 17.02.2017,
Time: 17:15 - 18:15

Objective: The most prevalent inherited bleeding disorder von Willebrand disease (vWD) type I is characterized by pathogenic variants throughout the entire molecule and missense gene mutations account for the majority of cases. Approximately half of the known point mutations are located in the central region of von Willebrand factor (vWF) encoded by exons 18-28. The present study was undertaken to investigate if a targeted and/or stepwise sequencing approach can be employed to identify mutations in vWD type I patients in a regional setting.

Methods: Thirty-two patients of Northeast German origin (29 females, 3 males) with bleeding tendency classified as VWD type I based on phenotypic assays (VWF:Ag, VWF:RCoF) were further investigated by direct sequencing and MLPA analysis of the VWF gene.

Results: Twenty patients (63 %) demonstrated gene mutations located in exons 18-28. Interestingly, recurrent mutations included Pro812Argfs*31 in exon 18 (n=5), Arg924Gln in exon 21 (n=7), and Tyr1584Cys in exon 28 (n=4). Therefore, in this regional cohort, mutation testing for the three most common vWD type I mutation would identify the pathogenic variant in half of all patients. Based on these findings, a validation study using a three-step genetic testing approach consisting of initial analysis of the most common three mutations, followed by sequencing of exons 18, 21, and 28 and by full sequencing of the remaining coding region of the gene should be performed.

Conclusion: Results of this regional study confirm the genetic heterogeneity of vWD type I. Analysing molecular genetic data of a given geographic/ethnic population may identify a mutational spectrum which may point to a targeted and/or stepwise genetic approach in the molecular diagnostic workup of vWD type I.