Two novel VWF gene mutations associated with von Willebrand Disease type 1

Background

Von Willebrand disease (VWD) is the most frequent hereditary bleeding disorder in man. Its prevalence is about 1 %. The von Willebrand gene consists of 52 exons and spans about 180 kb of the genome. Several genetic variants have been identified causing quantitative deficiencies (type 1 and type 3) and qualitative deficiencies (type 2). Nevertheless, new genetic variants are constantly being found. We describe two variants whose causal relationship to VWD type 1 has not yet been established.

Methods

In 2 patients with mild bleeding history, von Willebrand factor antigen (VWF Ag), ristocetin cofactor activity, and the activity of factor VIIIc were measured on STA R Max3, Stago, France. Multimer analysis was performed using SDS-agarose gel electrophoresis (Hydrasys 2, Sebia, France). In vitro bleeding times were measured using the platelet function analyzer PFA-200 (Siemens, Germany). VWF gene was analyzed via next generation sequencing (MiSeq, Illumina). The characterization of variants was performed with in silico evaluation tools, including varSEAK Online.

Results

A 45-year-old woman presented with VWF Ag of 0.57 U/ml, RistoCoF of 0.42 U/ml, F VIIIc of 1.08 U/ml and bleeding times of 250 and 163 s. VWF gene sequencing identified a heterozygous variant in exon 45 (c.7666delG; p.Val2556SerfsTer8), resulting in the deletion of G at the 7666th position in the coding sequence, that causes a frameshift and a premature stop codon. A 32-year-old woman presented with VWF Ag of 0.46 U/ml, RistoCoF of 0.35 U/ml, F VIIIc of 1.01 U/ml and bleeding times of 255 and 212 s. VWF gene sequencing identified a heterozygous deletion of 6 bp at the junction between intron 41 and exon 42 (c.7082-3_7084delCAGCCT) likely leading to aberrant splicing and subsequently to a non-functional VWF antigen.

Conclusion

Genetic analysis of the VWF gene is useful in addition to in vitro analysis by laboratory experiments and common diagnostic tests, multimer analysis, phenotypic studies of patients and co-segregation analysis within families to classify the type of VWD.

Offenlegung Interessenkonflikt:

There are no conflicts of interest.