Novel heterozygous termination variants causing von Willebrand disease type 1

Introduction: Von Willebrand disease (VWD) is the most common inherited bleeding disorder, characterized by quantitative or qualitative deficiencies of von Willebrand factor (VWF). Homozygous termination variants are a typical underlying genetic factor of VWD type 3. In contrast, heterozygous termination variants may result in VWD type 1. However, the diagnosis of milder forms of VWD can be challenging due to the frequently unclear correlation between laboratory assays and clinical manifestations.

Method: For five patients showing clinical signs of VWD type 1, including a mother with her 3-year-old daughter, molecular genetics and laboratory analyses were performed. The complete VWF coding region, exon-intron junctions and specific intronic regions were sequenced using Next Generation Sequencing (NGS). NGS data were analyzed using Emedgene Software (Illumina). Laboratory investigations included Factor VIII activity (FVIII:C), VWF antigen (VWF:Ag), VWF activity (VWF:C), VWF collagen binding (CBA), VWF ristocetin cofactor activity (VWF:RCo), multimeric analysis, PFA-100 closure time, and blood group. In addition, CRP and BMI were assessed as environmental confounders.

Results: Molecular analysis of the VWF gene in the five patients led to the identification of three novel heterozygous termination variants: Exon 11, c.1172_1178del, p.(Thr391AsnfsTer64); Exon 8, c.915del, p.(Ser306ProfsTer151); Exon 35, c.6027del, p.(His2009GlnfsTer14). These variants all based on small deletions causing a shift of the reading frame and subsequently a premature termination codon. The identified deletions in Exon 8 and 11 result in a complete loss of mature VWF whereas the deletion in Exon 35, located within domain D4, causes the loss of the ability to bind to GPIIb/IIa and dimerization of the VWF. All patients showed a quantitative reduction in plasma VWF with a comparable decrease in both VWF:Ag and VWF:C (VWF:RCo). A VWF:RCo/VWF:Ag ratio>0.6, normal VWF-collagen binding as well as normal multimeric pattern were observed.

Conclusion: In the described patients with heterozygous termination variants in the VWF gene, VWD type 1 was confirmed by laboratory analyses. These results underline the potential of NGS for the diagnosis of VWD, particularly for VWD type 1. A semidominant inheritance pattern of VWF variants causing VWD type 3 in homozygous and VWD type 1 in heterozygous form has been a subject of controversy. Based on this study such relationship can be confirmed for heterozygous termination variants.

 

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Conflict of Interest:

No conflict of interest to declare

Publikationsverlauf

Artikel online veröffentlicht:
13. Februar 2025