Submission Details

von Willebrand disease type 2B (VWD2B) was first described as a distinct form of VWD by Rufferi et al., 1980 (PMID: 6767976). Patients often have a variable degree of thrombocytopenia and present with a prolonged bleeding time commonly triggered by trauma, surgery, dental work or delivery. VWD2B is characterized by an enhanced ristocetin-induced platelet aggregation in platelet-rich plasma. The relationship of VWF to autosomal dominant VWD2B was first reported through linkage analysis in 1989 (Ewenstein et al., 1989; unpublished abstract). In April 1991, the first variants were identified in patients by Randi et al. (PMID: 2010538), Cooney et al. (PMID: 1672694), and Ware et al. (PMID: 2011604). At least 43 unique variants have been reported in humans (PMID: 28987708), all of which occur in exon 28 of VWF and consist almost entirely of missense variants (with the exception of one single amino acid duplication). The mechanism for disease is gain of function; vWF functions as an adhesive protein essential for binding platelets (via GPIb/IX) to both subendothelial collagen and to other platelets. VWD2B mutations result in increased von Willebrand factor (VWF) binding to platelet GPIb receptors, causing increased platelet clearance and preferential loss of high molecular weight VWF multimers (reviewed in PMID: 28987708) as well as defective proplatelet formation (PMIDs:16720832 and 27734030). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Thirteen unique variants from 13 probands in 9 publications were curated (PMIDs: 1672694, 1419803, 8123843, 8547152, 9858249, 1373334, 8376405, 2010538, 2011604). Variants in this gene segregated with disease in 16 additional family members (PMIDs: 2010538, 8376405, 1373334, 9858249, 8547152, 8123843). More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence has been reached. Experimentally, this gene-disease relationship is supported by the function of vWF in platelet binding (PMID: 108291), which is consistent with the prolonged bleeding associated with VWD2B. Further support is provided by several mouse systems, including hydrodynamic expression of VWD2B variants in VWF-/- mice (PMIDs: 20371742 and 20200350) and a knock-in mouse model, which recapitulate many features of VWD2B (PMID: 27212476). In summary VWF is definitively associated with autosomal dominant von Willebrand disease type 2B. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Of note, VWF in relation to type 2B VWD has been described as a distinct form of VWD (PMID: 6767976) and is assessed separately from the additional forms of hereditary von Willebrand disease. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms (gain of function in type 2B versus loss of function in types 1, 2A, 2M, 2N, and 3) and phenotypic variability (type 2B has the unique phenotypes of thrombocytopenia, increased platelet volume, and enhanced ristocetin-induced platelet aggregation). Therefore, we have split curations for the disease entities hereditary von Willebrand disease and von Willebrand disease type 2B.