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Von Willebrand Disease, Genetic Testing

Von Willebrand disease (VWD) is a genetic bleeding disorder affecting blood clotting ability. It is the most common inherited bleeding disorder and is caused by a deficiency or dysfunction of von Willebrand factor (VWF), a protein that plays a crucial role in blood clotting. von Willebrand`s disease is the most common inherited bleeding disorder and affects one in every 1.000 people. 

Von Willebrand disease genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).

The key features and aspects of von Willebrand disease include:

  • Genetic Basis: Von Willebrand disease is usually inherited in an autosomal dominant manner, meaning that an affected individual has a 50% chance of passing the condition on to their offspring. There are three main types of von Willebrand disease: Type 1, Type 2, and Type 3, each with different levels of severity.
  • Role of Von Willebrand Factor (VWF): Von Willebrand factor has two main functions in blood clotting. It helps platelets stick together and adhere to the site of a blood vessel injury, and it carries and stabilizes clotting factor VIII. Deficient or dysfunctional von Willebrand factor leads to difficulties in forming stable blood clots.
  • Clinical Presentation: The symptoms of von Willebrand disease can vary widely. Common signs and symptoms include easy bruising, prolonged bleeding from minor cuts, nosebleeds, heavy or prolonged menstrual periods, and, in severe cases, spontaneous joint or muscle bleeding.
  • Diagnosis: Diagnosis involves a combination of clinical evaluation, family history, bleeding history assessment, and laboratory tests to measure VWF levels and function. Genetic testing may also be performed to identify specific mutations.
  • Treatment: Treatment of von Willebrand disease depends on the type and severity of the condition. Mild cases may not require treatment, while more severe cases may involve medications such as desmopressin or von Willebrand factor replacement products. Antifibrinolytic drugs may also be used to prevent blood clot breakdown.
  • Management and Lifestyle Considerations: Individuals with von Willebrand disease may need to take precautions to prevent bleeding episodes, such as avoiding certain medications and activities that increase the risk of injury. Regular medical follow-ups are essential for monitoring and adjusting treatment plans.
  • Genetic Counseling: Individuals diagnosed with von Willebrand disease may consider genetic counseling, especially if they are planning to have children, to understand the inheritance pattern and potential risks.

Types of von Willebrand Disease

  • Type 1 is the mildest form, characterized by a quantitative deficiency of von Willebrand factor.
  • Type 2: This type is characterized by qualitative defects in the von Willebrand factor. It is further divided into four subtypes (2A, 2B, 2M, and 2N), each with specific abnormalities in von Willebrand function.
  • Type 3 is the most severe form, involving a near-complete absence of von Willebrand factor. It is associated with a higher risk of bleeding.

Individuals with von Willebrand disease must work closely with a healthcare team, including hematologists and other specialists, to manage the condition effectively and improve their quality of life.

More Information

Von Willebrand's disease is mainly caused by mutations in the VWF gene that affect protein levels or function. Hundreds of mutations have been identified in VWF that can produce various effects on the protein.

The most frequent VWF gene mutation in Europe is p.Arg854Gln, R854Q, or c.2561G>A, where 1% of the population carries one copy of c.2561G>A. This variant is associated with von Willebrand disease type 2N and follows an autosomal recessive mode of inheritance. The mutation affects the binding of vWF to coagulation factor VIII, making it sometimes difficult to distinguish between von Willebrand disease type 2N and mild hemophilia A.

Another variant associated with type 2N von Willebrand disease is c.2446C>T, p.Arg816Trp, or R816W, which has been observed in homozygosis and compound heterozygosis (one copy of the mutation combined with a different mutation in the same gene).

The nonsense mutation c.7390C>T, p.Arg2464Cys, or R2464C, is characteristic of patients with the von Willebrand disease type 1 form and follows an autosomal recessive inheritance pattern. It has also been observed in compound heterozygosis. It is important to note that approximately half of the families with VWD1 have incomplete penetrance (only some individuals with a mutation show symptoms).

The variant c.4135C>T, p.Arg1379Cys, or R1379C has been found in patients with von Willebrand disease type 2B. This variant can produce circulating aggregates of VWF and platelets that are removed from the circulation, reducing the number of platelets in the blood (thrombocytopenia). Another mutation associated with type 2B von Willebrand disease is c.3946G>A, p.Val1316Met, or V1316M, patients with this variant show, among other things, increased bleeding, reduced platelet aggregation and macrothrombocytopenia (decreased platelet count and significantly increased platelet size or "giant platelets").

The p.Arg2535Ter, R2535*, or c.7603C>T is a loss-of-function variant in the VWF gene that produces a truncated protein. It is associated with the severe form of von Willebrand disease type 3.

Von Willebrand disease genetic testing analyzes the 6 most frequent pathogenic mutations of the VWF gene.

The technique used for genetic testing analyzes only the gene's specific mutations, which are the most important and frequent in the literature. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested that cannot be identified with this method. Different analysis techniques can be used for these cases, such as next-generation sequencing (NGS).

Additional information
Results Time4 - 5 Weeks
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