Abstract Number: PB0943
Meeting: ISTH 2021 Congress
Theme: Platelet Disorders, von Willebrand Disease and Thrombotic Microangiopathies » VWF and von Willebrand Factor Disorders - Clinical Conditions
Background: Von Willebrand Factor (VWF) is a multimeric protein largely involved in both primary and secondary hemostasis. The diagnosis and classification of von Willebrand Disease (VWD) patients can be challenging. Atypical presentations of VWD might benefit from additional genetic analysis.
Aims: Characterization of a VWD patient with a disproportionately severe bleeding phenotype.
Methods: Routine analysis for VWD was performed. Genetic screening was performed by exome sequencing of hemostasis related genes. VWF mRNA analysis was carried out by RT-PCR and Sanger sequencing.
Results: Routine analysis showed PFA-ADP and PFA EPI >300 seconds, VWF:ACT of 37% with a VWF:AG of 36%. Collagen binding and FVIII-binding were 46% and 28% respectively.
Genetic analysis of the VWF gene disclosed 2 heterozygous variants of unknown significance (VUS): c.2771 G>A (exon 21, p.Arg924.Gln) has a 1-2.5% population prevalence and has been previously described in type 1 and 2N VWD. The other VUS (c.2278 C>A; exon 17) is a novel mutation predicting a major amino acid substitution (p.Arg760Ser) in the D2-domain of VWF. Sequencing of exons 17 and 21 in the patient’s VWF mRNA revealed homozygosity for the mutated allele at both mutation sites, indicating that the two variants are in cis and that the ‘normal’ allele is not expressed at mRNA level. Moreover, an aberrantly spliced mRNA was identified which lacks exon 17, leading to a frameshift and a premature stop codon in exon 18. Structural analysis showed that the Arg760Ser mutation may decrease the affinity of furin to the VWF pro-peptide cleavage site.
Conclusions: The patient carried two VUS on the only VWF allele that was expressed at the mRNA level. The Arg760Ser mutation possibly interferes pro-peptide cleavage by furin. The cause of the silencing of the ‘normal’ allele, the phenotypic impact of the exon 17 variant and the functional impact of the mutations are currently under investigation.
To cite this abstract in AMA style:
van de Berg T, M Todaro A, van Beers J, Wichapong K, Heubel-Moenen F, Castoldi E, Henskens Y, Beckers E. Atypical Presentation of VWD Leading to Discovery of Novel VWF Mutation [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/atypical-presentation-of-vwd-leading-to-discovery-of-novel-vwf-mutation/. Accessed September 22, 2023.« Back to ISTH 2021 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/atypical-presentation-of-vwd-leading-to-discovery-of-novel-vwf-mutation/