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Test ID F822B Hemophilia A F8 Gene, Intron 22 Inversion Known Mutation, Whole Blood

Useful For

First-tier molecular testing for males affected with severe hemophilia A, when a familial intron 22 inversion has been previously identified.

 

Determining hemophilia A carrier status for at-risk females, ie, individuals with a family history of severe hemophilia A due to F8 intron 22 inversion

Reflex Tests

Test ID Reporting Name Available Separately Always Performed
MATCC Maternal Cell Contamination, B Yes No

Testing Algorithm

Maternal cell contamination testing will be performed for all cord blood specimens. A maternal whole blood sample is required to perform this test.

 

The following algorithms are available in Special Instructions:

-Hemophilia Carrier Testing Algorithm

-Hemophilia Testing Algorithm

Reporting Name

HA F8 Intron 22 Inversion KM, B

Specimen Type

Whole blood


Specimen Required


Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.

Container/Tube: 

Preferred: Lavender top (EDTA) or yellow top (ACD)

Acceptable: Sodium citrate

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube.

Additional Information: Each molecular coagulation test requested must have its own tube.


Specimen Minimum Volume

1 mL blood

Specimen Stability Information

Specimen Type Temperature Time
Whole blood Ambient (preferred) 7 days
  Frozen  7 days
  Refrigerated  7 days

Clinical Information

Hemophilia A (HA) is caused by a deficiency of clotting factor VIII (FVIII). HA is an X-linked recessive bleeding disorder that affects approximately 1 in 5,000 males. Males are typically affected with bleeding symptoms, whereas carrier females generally do not have bleeding symptoms but are at risk of having affected sons. Rarely, approximately 10% of carrier females have FVIII activity levels below 35% and are at risk for bleeding.

 

Bleeding, the most common clinical symptom in individuals with HA, correlates with FVIII activity levels. FVIII activity levels of <1% are associated with severe disease, 1% to 5% activity with moderate disease, and 5% to 40% with mild disease. In males with severe deficiency, spontaneous bleeding may occur. In individuals with mild HA, bleeding may occur only after surgery or trauma.

 

FVIII is encoded by the factor VIII (F8) gene. Approximately 98% of patients with a diagnosis of HA are found to have a mutation in F8 (ie, intron 1 and 22 inversions, point mutations, insertions, and deletions). The intron 22 inversion mutations account for approximately 45% of mutations associated with severe HA. These inversions are typically not identified in patients with mild or moderate HA.

 

Intron 22 inversion known mutation analysis is only recommended for individuals when an intron 22 inversion has already been identified in the family.

 

If a familial mutation has not been identified in a severely affected HA patient the F8 gene intron 1 and 22 inversion analysis (F8INV / Hemophilia A F8 Gene, Intron 1 and 22 Inversion Mutation Analysis, Whole Blood) should be ordered.

 

If the intron 22 inversion analysis is negative, the tested individual has not inherited the familial mutation.

 

It is recommended that the F8 mutation be confirmed in the affected male or obligate carrier female prior to testing at-risk individuals. Affected males are identified by FVIII activity (F8A / Coagulation Factor VIII Activity Assay, Plasma) and clinical evaluation, while obligate carrier females are identified by family history assessment. If the intron inversion assays do not detect an inversion in these individuals, additional analysis (ie, F8 sequencing) may be able to identify the familial mutation. Of note, not all females with an affected son are germline carriers of a F8 mutation, as de novo mutations in F8 do occur. Approximately 20% of mothers of isolated cases do not have an identifiable germline F8 mutation. Importantly, there is a small risk for recurrence even when the familial F8 mutation is not identified in the mother of the affected patient due to the possibility of germline mosaicism.

Reference Values

Not applicable

Interpretation

An interpretive report will be provided.

Clinical Reference

1. Antonarakis SE, Rossiter JP, Young M, et al: Factor VIII gene inversions in severe hemophilia A: results of an international consortium study. Blood 1995;86(6):2206-2212

2. Rossiter JP, Young M, Kimberland ML, et al: Factor VIII gene inversions causing severe hemophilia A originate almost exclusively in male germ cells. Hum Mol Genet 1994;3(7):1035-1039

3. Castaldo G, D'Argenio V, Nardiello P, et al: Haemophilia A: molecular insights. Clin Chem Lab Med 2007;45(4):450-461

4. Oldenburg J, Rost S, El-Maarri O, et al: De novo factor VIII gene intron 22 inversion in a female carrier presents as a somatic mosaicism. Blood 2000;96(8):2905-2906

5. Pruthi RK: Hemophilia: A Practical Approach to Genetic Testing. Mayo Clin Proc 2005;80:1485-1499

Day(s) and Time(s) Performed

Monday through Friday

Analytic Time

14 days

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

81403

LOINC Code Information

Test ID Test Order Name Order LOINC Value
F822B HA F8 Intron 22 Inversion KM, B In Process

 

Result ID Test Result Name Result LOINC Value
35139 HA F8 Int22 KM Reason for Referral 42349-1
35007 HA F8 Intron 22 Inversion KM, B In Process
35008 F822B Interpretation 69047-9
35009 HA F8 Int22 KM Reviewed By 18771-6

Method Name

Inverse Shifting-Polymerase Chain Reaction (IS-PCR)

Forms

1. Hemophilia A Patient Information (T712) in Special Instructions

2. New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (T576) is available in Special Instructions.

3. If not ordering electronically, complete, print, and send a Coagulation Test Request Form (T753) with the specimen (http://www.mayomedicallaboratories.com/it-mmfiles/coagulation-test-request-form.pdf)