Recent evidence has demonstrated that these modifier genes influence VWF gene expression. For example, CLEC4M has been shown to affect VWF plasma clearance by means of binding and internalizing the blood glycoprotein. Other studies have also indicated that the modifier gene may play a role in factor VIII (FVIII) clearance, independent of VWF, thereby highlighting the potential utility of CLEC4M beyond diagnosis. These findings suggest CLEC4M genotypes may inform optimization of treatment for patients with VWD and other blood disorders.

Dr Flood told Hematology Advisor, “I suspect that much of the low VWF phenotype [is] due to some of these modifier [genes], but [I’m] not sure how clinically useful [this is] once [a] diagnosis of low VWF is made.”

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She continued, “[Current] treatment does not depend on what combination of genes caused [the disorder], but [this] is the state of our knowledge now, and this may change in the future.”

At present, genome-wide association studies are still detecting other modifier genes that could have an effect on VWF levels. In the future, a more nuanced understanding of the function of modifier genes will be essential to fully characterizing these genes’ role in the pathogenesis of VWD.

Our Current State

Many barriers impede the use of genetic testing to diagnosis type 1 VWD. As a result, this diagnosis is currently established on the basis of VWF levels and presenting symptoms. Although useful from a research perspective, gene sequencing provides little value from a clinical perspective at this time. In contrast, sequencing may be clinically useful for identifying specific variants in type 2 VWD. Ultimately, further studies are needed to fully understand the role of modifier genes in VWD and in the optimization of future therapies.

Reference

1. Flood VH, Garcia J, Haberichter SL. The role of genetics in the pathogenesis and diagnosis of type 1 von Willebrand disease. Curr Opin Hematol. 2019;26:331-335. doi:10.1097/MOH.0000000000000524