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Test Code F11NG Hemophilia C, F11 Gene, Next-Generation Sequencing, Varies


Advisory Information


Genetic testing for factor XI deficiency should only be considered after coagulation screening is performed and if factor XI activity is less than 50% of normal (note: reference ranges may vary depending on the locally established reference range).



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. 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)

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

Secondary ID

65164

Useful For

Genetic confirmation of a factor XI deficiency diagnosis with the identification of known or suspected pathogenic alterations in the F11 gene

 

Carrier testing for close family members of an individual with a factor XI deficiency diagnosis

 

This test is not intended for prenatal diagnosis

Testing Algorithm

The clinical workup for factor XI deficiency begins with special coagulation testing for factor XI. See F_11 / Coagulation Factor XI Activity Assay, Plasma.

 

Genetic testing for factor XI deficiency is indicated if:

-Factor XI activity is reduced (less than 50% of normal)

-Acquired causes of factor XI have been excluded

Method Name

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

Reporting Name

F11 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 XI deficiency (FXID) is a bleeding diathesis that is also known as hemophilia C. FXID produces a bleeding disorder that is relatively mild, rarely spontaneous, and associated with certain sites of the body, namely the oral cavity, nasopharynx, and urinary tract. Bleeding frequency and severity are highest when trauma or certain surgical procedures involve tissues in these areas. Menorrhagia and nose bleeds are common.

 

Overall, in the general population, the prevalence of severe FXID is 1 per million. However, FXID is common in certain ethnic groups. In Ashkenazi Jews, severe deficiency is found in 1 in 450 people. Founder mutations are also found among French Basques and French individuals from Nantes. Hereditary FXID is typically inherited in an autosomal recessive manner. However, some rare alterations exert a dominant-negative effect or interfere with the functioning of normal factor XI (FXI), causing an autosomal dominant bleeding disorder.

 

FXID is a result of defects in the concentration or function of coagulation FXI, which is synthesized in the liver and circulates in blood plasma as an inactive zymogen. The role of activated FXI includes sustained activation of factor IX, leading to fibrin formation and clot stability, especially in tissues with high fibrinolytic activity, such as oral cavity, nasopharynx, and urinary tract. A significant deficiency in the amount of functional FXI can cause excessive bleeding in these tissues after trauma or certain surgical procedures.

 

FXID is defined as severe when FXI activity is less than 15% (15 U/dL). It is considered moderate when it is between 15% and 50% (15 to 50 U/dL). However, plasma FXI activity levels to do not correlate well with bleeding phenotype, in part activity levels appear unable to reflect true physiological activity of FXI (eg, p.Ser266Asn is associated with bleeding and defective FXI binding to platelets but is reported not affect aPTT). Some patients with 15% to 50% FXI activity present similarly to severely deficient patients, indicating contributing factors to disease severity, eg, the qualities of the specific alteration(s) underlying the disorder or the co-inheritance of other bleeding disorders. Of note, normal, full-term newborn infants or healthy premature infants may have decreased levels (greater than or equal to 10%) that may not reach adult levels for greater than or equal to 180 days after birth.

 

The F11 gene encodes FXI. Genetic testing for pathogenic alterations in F11 is indicated if FXI activity is below 50% of normal. Patients lacking FXI will also typically have very long activated partial thromboplastin times (aPTT).

 

Acquired FXID appears to be a rare complication of liver disease. Liver disease should be excluded prior to genetic testing.

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. Palla R, Peyvandi F, Shapiro AD: Rare bleeding disorders: diagnosis and treatment. Blood. 2015;125(13):2052-2061

2. Wheeler A, Gailani D: Why factor XI deficiency is a clinical concern. Expert Review of Hematology. 2016;9(7):629-637

3. Bolton-Maggs, P: Factor XI deficiency-resolving the enigma? Hematology Am Soc Hematol Educ Program. 2009;97-105

4. Emsley J, McEwan PA, Gailani D: Structure and function of factor XI. Blood. 2010;115(13):2569-2577

5. Gailani D, Geng Y, Verhamme I, et al: The mechanism underlying activation of factor IX by factor XIa. Thromb Res. 2014;133 Suppl 1:S48-51

6. Berber E: Molecular characterization of FXI deficiency. Clin Appl Thromb Hemost. 2011;17(1):27-32

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
F11NG F11 Gene, Full Gene NGS 94239-1

 

Result ID Test Result Name Result LOINC Value
113060 F11NG Result 50397-9
113054 Alterations Detected 82939-0
113053 Interpretation 69047-9
113055 Additional Information 48767-8
113056 Method 85069-3
113057 Disclaimer 62364-5
113058 Panel Gene List 48018-6
113059 Reviewed By 18771-6