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Test Code F12NG F12 Gene, Next-Generation Sequencing, Varies


Advisory Information


Genetic testing for factor XII deficiency typically has little clinical utility. Caution in ordering is advised.

 

For hereditary angioedema type III, genetic testing should only be considered when there is a documented family history of angioedema that does not respond to chronic, high-dose antihistamine therapy, normal complement studies, normal C1 inhibitor level and function, and no exposure to medications that could cause angioedema, such as angiotensin-converting enzyme (ACE) inhibitors or nonsteroidal anti-inflammatory drugs.



Shipping Instructions


Ambient and refrigerated specimens must arrive within 7 days (168 hours of draw), and frozen specimens must arrive within 14 days (336 hours of draw).

Collect and package specimen as close to shipping time as possible.



Necessary Information


Rare Coagulation Disorder Patient Information is required, see Special Instructions. Testing may proceed without the patient information, however, the information aids in providing a more thorough interpretation. Ordering providers are strongly encouraged to fill out the form and send with the specimen.



Specimen Required


Submit only 1 of the following specimens:

 

Specimen Type: Peripheral blood

Container/Tube:

Preferred: Lavender top (EDTA)

Acceptable: Yellow top (ACD) or green top (sodium citrate)

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube.

Specimen Stability: Ambient (preferred)/Refrigerated/Frozen

 

Specimen Type: Extracted DNA

Container/Tube: 1.5- to 2-mL tube

Specimen Volume: Entire specimen

Collection Instructions:

1. Label specimen as extracted DNA and source of specimen.

2. Provide indication of volume and concentration of the DNA.

Specimen Stability: Frozen (preferred)/Refrigerated/Ambient


Forms

1. Rare Coagulation Disorder Patient Information (T824) is required, see Special Instructions. Fax the completed form to 507-284-1759.

2. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available in Special Instructions:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

3. If not ordering electronically, complete, print, and send a Coagulation Test Request (T753) with the specimen.

Secondary ID

64865

Useful For

Genetic confirmation of hereditary angioedema (HAE) type III with the identification of an alteration in the F12 gene known or suspected to cause the condition

 

Testing for close family members of an individual with an HAE type III diagnosis

 

Genetic confirmation of factor XII deficiency with the identification of an alteration in the F12 known or suspected to cause the condition

 

This test is not intended for prenatal diagnosis

Testing Algorithm

Factor XII deficiency:

Special coagulation testing for factor XII (F_12 / Coagulation Factor XII Activity Assay, Plasma) should be performed prior to any genetic testing.

 

Genetic testing for factor XII deficiency may be considered if:

-Factor XII activity is reduced (less than 55% of normal)

-Acquired causes of factor XII have been excluded

 

Hereditary angioedema type III (FXII-HAE):

An international consortium has established a testing and diagnostic algorithm for the identification of hereditary angioedema (HAE) type III.(1)

Method Name

Custom Sequence Capture and Targeted Next-Generation Sequencing (NGS) Followed by Polymerase Chain Reaction (PCR) and Sanger Sequencing When Appropriate

Reporting Name

F12 Gene, Full Gene NGS

Specimen Type

Varies

Specimen Minimum Volume

Blood: 1 mL
Extracted DNA: 100 mcL at 50 ng/mcL concentration

Specimen Stability Information

Specimen Type Temperature Time Special Container
Varies Ambient (preferred) 7 days
  Frozen  14 days
  Refrigerated  7 days

Reject Due To

Gross hemolysis OK
Gross lipemia OK

Clinical Information

Factor XII (FXII) is a serine protease capable of activating factor VII and factor IX to their active forms but does not appear to significantly contribute to hemostasis. Rather, factor XII activity appears directed more toward inflammatory response through activation of the kallikrein-kinin system (KKS). Pathogenic alterations in the F12 gene, which encodes FXII, can cause one of two different phenotypes. Alterations in F12 that reduce the amount of plasma FXII or disrupt its functional activity result in FXII deficiency. Alterations in F12 that disrupt glycosylation or lead to increased contact-mediated autoactivation of zymogen FXII are associated with hereditary angioedema (HAE) type III with normal C1 inhibitor (C1INH).

 

A deficiency of FXII does not cause excessive bleeding tendency or abnormal bleeding even during trauma or surgery despite prolonged partial thromboplastin time (aPTT). Some with severe deficiency experience thrombosis, but a causal connection remains unproven. Individuals with FXII deficiency are generally entirely asymptomatic, making disease state classifications unnecessary. FXII deficiency is inherited in an autosomal recessive manner. Genetic testing for FXII deficiency is generally unnecessary but may be considered if prolonged activated partial thromboplastin time (aPTT) and reduced FXII activity is documented and acquired causes of low FXII are excluded. Causes of acquired (non-genetic) FXII deficiency that should be excluded prior to genetic testing include liver disease, nephrotic syndrome, and chronic granulocytic leukemia. A study of 300 healthy blood donors found that 2.3% had FXII deficiency.(2) Actual prevalence of the condition is unknown. Of note, normal, full-term newborn infants or healthy premature infants may have decreased levels (≥15%-20%) that may not reach adult levels for greater than or equal to 180 days after birth.

 

Defects in F12 that increase contact-mediated FXII autoactivation and lead to excess generation of proinflammatory peptide hormone bradykinin cause hereditary angioedema (HAE) type III with normal C1 inhibitor (C1INH). HAE type III is characterized by recurrent skin swelling, abdominal pain attacks, and upper airway obstruction. Symptoms occur almost exclusively in women because estrogen exposure appears to exacerbate the condition and attacks are precipitated or worsened by high estrogen levels. However, not all females who carry FXII alterations are symptomatic, thus HAE type III is considered an autosomal dominant disorder with incomplete penetrance. Alterations in F12 are found in 20 to 30% of patient with HAE type III. Genetic testing for HAE type III may be indicated when there is a documented family history of angioedema that does not respond to chronic, high-dose antihistamine therapy, normal complement studies, normal C1INH level and function, and no exposure to medications that could cause angioedema, angiotensin-converting enzyme (ACE) inhibitors or nonsteroidal anti-inflammatory drugs. Of note, acquired causes of angioedema, such as B cell lymphoproliferative, the presence of autoantibodies to C1 inhibitors, and the use of renin-angiotensin-aldosterone (RAAS) blockers, should be considered and excluded prior to genetic testing of F12 for HAE type III.

Reference Values

An interpretive report will be provided

Interpretation

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.

Clinical Reference

1. Bowen T, Cicardi M, Farkas H, et al: 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol. 2010;6(1):24

2. Halbmayer WM, Haushofer A, Schon R, et al: The prevalence of moderate and severe FXII (Hageman factor) deficiency among the normal population: evaluation of the incidence of FXII deficiency among 300 healthy blood donors. Thromb Haemost. 1994;71(1):68-72

3. Schmaier AH: The contact activation and kallikrein/kinin systems: pathophysiologic and physiologic actitivies. J Thromb Haemost. 2016;14(1):28-39

4. Banerji, A: The burden of illness in patients with hereditary angioedema. Ann Allergy Asthma Immunol. 2013;111(5):329-336

5. Björkqvist J, de Maat S, Lewandrowski U, et al.: Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III. J Clin Invest. 2015;125(8):3132-3146

Day(s) and Time(s) Performed

Performed weekly, Varies

Analytic Time

21 days

Performing Laboratory

Mayo Clinic Laboratories in Rochester

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration.

CPT Code Information

81479

LOINC Code Information

Test ID Test Order Name Order LOINC Value
F12NG F12 Gene, Full Gene NGS In Process

 

Result ID Test Result Name Result LOINC Value
113068 F12NG Result 50397-9
113062 Alterations Detected 82939-0
113061 Interpretation 69047-9
113063 Additional Information 48767-8
113064 Method 85069-3
113065 Disclaimer 62364-5
113066 Panel Gene List 58902-8
113067 Reviewed By 18771-6