von Willebrand Disease Types 1, 2, and 3 via the VWF Gene

von Willebrand Disease (VWD) is one of the most common inherited bleeding disorders worldwide with a prevalence of ~1% of the normal population (Werner et al. 1993) . VWD is caused by defective or deficient von Willebrand Factor (VWF) (Ginsburg et al. 1985). VWF is a large, multimeric glycoprotein that is released into the blood from endothelial cells and platelets and plays a key role in hemostasis through binding with the platelet GP1Bα receptors (See Bernard Soulier Syndrome) and by transporting factor VIII to sites of vascular damage (Goodeve 2010). Symptoms of VWD are present from birth, but may become more severe with hemostatic challenge and with increasing age. There are three main types of VWD and several subtypes (Sadler et al. 2006):

Type 1 VWD--accounts for ~70% of cases. Mutations are identified in ~65% of cases. Autosomal dominant inheritance with mild mucocutaneous bleeding and quantitative deficiency of VWF.
Type 2 VWD--accounts for ~25% of cases. Characterized by qualitatively defective VWF and is divided into four subgroups based upon the defective function of VWF:
Type 2A-- mainly autosomal dominant, some recessive inheritance with mild to moderate mucocutaneous bleeding due to reduced platelet interactions.
Type 2B-- autosomal dominant inheritance with mild to moderate mucocutaneous bleeding and potential thrombocytopenia; type 2B is associated with enhanced platelet interactions.
Type 2M-- autosomal dominant inheritance with mild to moderate mucocutaneous bleeding due to reduced platelet interactions.
Type 2N-- autosomal recessive inheritance, mimics mild hemophilia A and is characterized by excessive bleeding with hemostatic challenge (e.g. surgery); type 2N is associated with impaired binding of VWF to factor VIII.
Type 3 VWD-- accounts for ~5% of cases. Mutations are identified in up to 90% of cases. Autosomal recessive inheritance with severe mucocutaneous and musculoskeletal bleeding due to nearly complete quantitative deficiency of VWF.

See also Goodeve and James 2011. 

VWD is inherited in either an autosomal dominant or recessive manner (see Clinical Features). Causative mutations are primarily missense or nonsense mutations located throughout the VWF gene, but found in particularly high numbers in select exons including exons 18-21 and 25-28. Approximately 50% of mutations in type 1 VWD are found between exons 18 and 28, and most mutations found with types 2A, 2B, and 2M are located in exon 28. Type 2N is associated with a high frequency of mutations in exons 18-20, and in type 3 VWD, mutations are abundant throughout the VWF gene but are commonly found in exon 28 (Goodeve 2010). We note that mutations in GP1BA result in a phenotype similar to VWD type 2B called platelet-type VWD.

See Clinical Features for discussion of clinical sensitivity by type.

Large multi-exon and whole gene deletions make up approximately 5% of reported causative variants for the VWF gene (Yadegari et al. 2011; Goodeve 2010).

This test provides full coverage of all coding exons of the VWF gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).