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Test Catalog

Test ID: VWFNG    
von Willebrand Disease, VWF Gene, Next-Generation Sequencing, Varies

Useful For Suggests clinical disorders or settings where the test may be helpful

Genetic confirmation of hereditary von Willebrand disease with the identification of alterations in the VWF gene known or suspected to cause the condition

 

Testing for close family members of an individual with a von Willebrand disease diagnosis

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

This test detects pathogenic alterations within the VWF gene to delineate the underlying molecular defect in a patient with a laboratory diagnosis of von Willebrand disease (VWD), a bleeding disorder of variable severity.

 

The gene target for this test includes the following:

Gene name (transcript): VWF (GRCh37 (hg19) NM_000552)

Chromosomal location: 12p13.31

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

A clinical and laboratory testing algorithm for von Willebrand disease (VWD) has been developed by the National Heart, Lung, and Blood Institute of the National Institutes of Health that is freely available at https://www.nhlbi.nih.gov/health-pro/guidelines/current/von-willebrand-guidelines.

 

The laboratory workup for VWD is complex and requires initial coagulation screening (including a CBC, platelet count, partial thromboplastin time (PTT), prothrombin time (PT), and fibrinogen or thrombin time) should be performed prior to any consideration of genetic testing. Genetic testing should not be performed until a definitive diagnosis of VWD has been made.

 

Prenatal genetic testing is not performed without the prior identification of familial VWF alterations.

 

For any cord blood or prenatal specimen that is received, maternal cell contamination studies will be added. A maternal whole blood sample is required to perform this test.

 

If amniotic fluid is received, amniotic fluid culture will be added and charged separately. If chorionic villus specimen is received, fibroblast culture will be added and charged separately.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

von Willebrand disease (VWD) is a bleeding diathesis that usually involves mucous membranes and skin sites. It is typically of mild to moderate severity, although life-threatening bleeding in the central nervous system or gastrointestinal (GI) tract can occur. The most common presenting symptoms in individuals affected by VWD include epistaxis, menorrhagia, bleeding after dental extraction, postoperative bleeding, ecchymoses, bleeding from minor cuts or abrasions, gingival bleeding, and hemarthrosis.(1)

 

VWD affects up to 1% of the general population. While VWD occurs with equal frequency among men and women, symptoms in women are more obvious because of increased bleeding during menstrual periods, pregnancy, and after childbirth.

 

VWD is a result of defects in the concentration, structure, or function of von Willebrand factor (VWF), leading to decreased factor VIII (FVIII) in circulation and/or impaired platelet adhesion and aggregation at the site of vascular injury. The VWF gene encodes for VWF, a protein that protects blood clotting FVIII from degradation in circulation and promotes platelet adhesion and aggregation at the site of vascular injury. In circulation, VWF assembles into linear strings called multimers, the size of which is biologically important, larger multimers being more reactive than smaller multimers.

 

In general, bleeding risk is typically proportional to severity of VWF deficiency or the degree to which it impairs VWF function. However, bleeding risk is highly variable in von Willebrand due to the complexity of the protein structure and function and the great heterogeneity in alteration types that cause this disease. Further, because VWD is an autosomal gene, biallelic combinations of different sequence variants also contribute to phenotypic variability.

 

VWD is classified into 3 types:

Type 1- Partial quantitative deficiency of VWF

Type 2- Qualitative VWF defects including

-Type 2A-Decreased VWF-dependent platelet adhesion and a selective deficiency of high-molecular-weight VWF multimers,

-Type 2B-Increased affinity for platelet glycoprotein Ib

-Type 2M-Decreased VWF-dependent platelet adhesion without a selective deficiency of high-molecular-weight VWF multimers

-Type 2N-Markedly decreased binding affinity for factor VIII

Type 3- Virtually complete deficiency of VWF

 

VWD type 1 and type 2B are inherited in an autosomal dominant manner. VWD type 2A and 2M have been observed to be inherited in both autosomal dominant or autosomal recessive manners. VWD type 2N and 3 are inherited in an autosomal recessive manner.

 

Causes of acquired (nongenetic) VWD that should be excluded prior to genetic testing include:

1) Autoimmune clearance of inhibition of VWF, typically in association with lymphoproliferative diseases, monoclonal gammopathies, systemic lupus erythematosus, and some cancers

2) Increased shear-induced proteolysis of VWF, which can occur with cardiovascular lesions or with pulmonary hypertension

3) Increased binding of VWF to platelets and other cell surfaces, associated with myeloproliferative disorders

4) Nonimmune-related hypothyroidism

5) Use of valproic acid, ciprofloxacin, griseofulvin, hydroxyethyl starch, and other drugs.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

An interpretive report will be provided.

 

Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics and Genomics (ACMG) recommendations as a guideline. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

 

Consultations with the Mayo Clinic Special Coagulation Clinic, Molecular Hematopathology Laboratory, or Thrombophilia Center are available for DNA diagnosis cases. This may be especially helpful in complex cases or in situations where the diagnosis is atypical or uncertain.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Clinical:

Some individuals may have a mutation that is not identified by the methods performed. The absence of a variant, therefore, does not eliminate the possibility of von Willebrand disease (VWD). This assay does not distinguish between germline and somatic alterations, particularly with variant allele frequencies (VAF) significantly lower than 50%. Test results should be interpreted in context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.

 

Technical Limitations:

Next-generation sequencing (NGS) may not detect all types of genetic variants. Additionally, rare alterations may be present that could lead to false negative or positive results. Therefore test results should be interpreted in the context of activity and antigen measurements, clinical findings, family history, and other laboratory data. If results do not match clinical findings, consider alternative methods for analyzing these genes, such as Sanger sequencing or large deletion/duplication analysis. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.

 

If multiple alterations are identified, NGS is not able to distinguish between alterations that are found in the same allele ("in cis") and alterations found on different alleles ("in trans"). This limitation may complicate diagnosis or classification and has implications for inheritance and genetic counseling. To resolve these cases, molecular results must be correlated with clinical history, activity and antigen measurements, and family studies.

 

Unless reported or predicted to cause disease, alterations found deep in the intron or alterations that do not result in an amino acid substitution are not reported. These and common polymorphisms identified for this patient are available upon request.

 

Reclassification of Variants Policy:

At this time, it is not standard practice for the laboratory to systematically review likely pathogenic variants or variants of uncertain significance that are detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time.

 

Contact the laboratory if additional information is required regarding the transcript and/or human genome assembly used for the analysis of this patient's results.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Nichols WL, Hultin MB, James AH, et al: von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia. 2008;14(2):171-232

2. Goodeve AC: The genetic basis of von Willebrand disease. Blood Rev 2010;24(3):123-134

3. Springer TA: von Willebrand factor, Jedi knight of the bloodstream. Blood 2014;124(9):1412-1425

Special Instructions Library of PDFs including pertinent information and forms related to the test