Submission Details

von Willebrand disease (VWD) was first described by Erik von Willebrand in 1926, and is characterized by mucosa-associated bleeding and bleeding after trauma or surgery. There are several (sub)types of VWD that can be classified on the basis of phenotypic characteristics, caused by either quantitative (type 1 and 3) or qualitative (type 2) defects of VWF. The relationship of VWF to autosomal dominant VWD was first determined in 1988 by identification of a gross gene deletion (Ngo et al., 1988; PMID: 3258663) and through linkage analysis (Verweij et al., 1988; PMID: 2895123). In 1989, the first variants were identified in patients by Ginsburg et al. (PMID: 2786201). More than 700 unique variants have been reported in humans (EAHAD Coagulation Factor Variant Databases), consisting of predominantly missense variants as well as nonsense, small deletions or insertions, and splice variants (reviewed in PMID: 28987708). Some patients with type 1 VWD may have heterozygous VWF null alleles, but usually these patients carry heterozygous missense variants. The qualitative VWF defects in type 2 VWD are also mainly caused by missense variants. The severe quantitative VWF deficiency as seen in type 3 VWD is usually caused by genetic defects in the VWF gene leading to homozygous or compound heterozygous VWF null alleles (such autosomal recessive cases have been included in this curation as noted in the scoring explanations). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Twenty-two unique variants from 21 probands in 8 publications were curated (PMIDs: 1415226, 26088471, 8622978, 23496210, 2786201, 8839833, 19566550, 20586924). Variants in this gene segregated with disease in 29 additional family members (PMIDs: 1415226, 8839833, 19566550). 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 adhesion, via collagen and platelet binding (PMIDs: 6809414, 108291), which is consistent with the prolonged bleeding associated with VWD. Alteration of this function has been observed in both patient (PMID: 8435340) and non-patient cells (PMID: 20586924) which exhibit loss of platelet adhesion. Further support is provided by several mouse systems, including a null mouse with extensive bleeding, consistent with type 3 VWD (PMID: 9689113), and hydrodynamic expression of VWD variants in the VWF-/- mice (PMIDs: 22372972, 21346256, PMID: 18487513) which recapitulate many features of types 1 and 2 VWD. In summary VWF is definitively associated with autosomal dominant von Willebrand disease. 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.