Test Id : GNF13

The clinical workup for factor FXIII deficiency (FXIIID) should begin with special coagulation testing for factor XIII activity.

A standard testing algorithm for FXIIID has been developed by the Scientific and Standardization Committee of the International Society for Thrombosis and Haemostasis.(1)

Genetic testing for FXIIID is indicated if:

-The clot solubility test, a screening test for possible factor XIII deficiency, is abnormal or FXIII antigen or activity is decreased

-Acquired causes of FXIIID have been excluded (eg, leukemia, liver disease, Henoch-Schonlein purpura, inflammatory bowel diseases, disseminated intravascular coagulation, pulmonary embolism, stroke, and sepsis, exposure to valproate)

Note: Factor XIII may occur spontaneously in older adults.

For prenatal specimens only:

-If amniotic fluid (nonconfluent cultured cells) is received, amniotic fluid culture/genetic test will be added at an additional charge.

-If chorionic villus specimen (nonconfluent cultured cells) is received, fibroblast culture for genetic test will be added at an additional charge.

For any prenatal specimen that is received, maternal cell contamination testing will be performed at an additional charge.

Special coagulation testing for factor XIII (FXIII) activity should be performed prior to any genetic testing. For assessment of FXIII activity, order ALBLD / Bleeding Diathesis Profile, Limited, Plasma, which includes the factor XIII screening assay.

Genetic testing should only be considered if clinical and family history, initial coagulation screens, or initial activity tests indicate a diagnosis of FXIII deficiency (see Testing Algorithm).

If genetic testing for hereditary bleeding disorders using a larger panel is desired, both a 6-gene focused bleeding panel and a 25-gene comprehensive bleeding panel are available. For more information see GNBLF / Bleeding Disorders, Focused Gene Panel, Next-Generation Sequencing, Varies or GNBLC / Bleeding Disorders, Comprehensive Gene Panel, Next-Generation Sequencing, Varies.

Testing for the F13A1 and F13B genes as part of a customized panel is available. For more information see CGPH/ Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies.

Targeted testing for familial variants (also called site-specific or known mutations testing) is available for the F13A1 and F13B genes. See FMTT / Familial Variant, Targeted Testing, Varies. To obtain more information about this testing option, call 800-533-1710.

All prenatal specimens must be accompanied by a maternal blood specimen; order MATCC / Maternal Cell Contamination, Molecular Analysis, Varies on the maternal specimen as this must be a different order number than the prenatal specimen.

Specimen preferred to arrive within 96 hours of collection.

Rare Coagulation Disorder Patient Information is required. 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.

Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. For instructions for testing patients who have received a bone marrow transplant, call 800-533-1710.

Submit only 1 of the following specimens:

Specimen Type: Whole blood

Container/Tube:

Preferred: Lavender top (EDTA)

Acceptable: Yellow top (ACD)

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send whole blood specimen in original tube. Do not aliquot.

Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated

Prenatal Specimens

Due to its complexity, consultation with the laboratory is required for all prenatal testing; call 800-533-1710 to speak to a genetic counselor. 

Specimen Type: Amniotic fluid

Container/Tube: Amniotic fluid container

Specimen Volume: 20 mL

Specimen Stability Information: Refrigerated (preferred)/Ambient

Additional information:

1. A separate culture charge will be assessed under CULAF / Culture for Genetic Testing, Amniotic Fluid.

2. All prenatal specimens must be accompanied by a maternal blood specimen; order MATCC / Maternal Cell Contamination, Molecular Analysis, Varies on the maternal specimen.

Specimen Type: Chorionic villi

Container/Tube: 15-mL tube containing 15 mL of transport media

Specimen Volume: 20 mg

Specimen Stability Information: Refrigerated

Additional Information:

1. A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing.

2. All prenatal specimens must be accompanied by a maternal blood specimen; order MATCC / Maternal Cell Contamination, Molecular Analysis, Varies on the maternal specimen.

Acceptable:

Specimen Type: Confluent cultured cells

Container/Tube: T-25 flask

Specimen Volume: 2 Flasks

Collection Instructions: Submit confluent cultured cells from another laboratory.

Specimen Stability Information: Ambient (preferred)/Refrigerated

Additional Information:

All prenatal specimens must be accompanied by a maternal blood specimen; order MATCC / Maternal Cell Contamination, Molecular Analysis, Varies on the maternal specimen.

• Informed Consent for Genetic Testing
• Informed Consent for Genetic Testing (Spanish)
• Rare Coagulation Disorder Patient Information

1. Rare Coagulation Disorder Patient Information (T824) is required

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:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing (Spanish) (T826)

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

Blood: 1 mL; Amniotic fluid: 10 mL; Other specimen types: See Specimen Required

Evaluating factor XIII deficiency (FXIIID) in patients with a personal or family history suggestive of FXIIID

Confirming an FXIIID diagnosis with the identification of known or suspected disease-causing alterations in the F13A1 or F13B genes

Determining the disease-causing alterations within the F13A1 or F13B genes to delineate the underlying molecular defect in a patient with a laboratory diagnosis of FXIIID

Identifying the causative alterations for genetic counseling purposes

Prognosis and risk assessment based on the genotype-phenotype correlations

Carrier testing for close family members of an individual with a diagnosis of FXIIID

This test utilizes next-generation sequencing to detect single nucleotide and copy number variants in the F13A1 and F13B genes associated with factor XIII deficiency (FXIIID), a rare bleeding disorder. See Method Description for additional details.

Identification of a disease-causing variant may assist with diagnosis, prognosis, clinical management, recurrence risk assessment, familial screening, and genetic counseling for FXIIID.

The clinical workup for factor FXIII deficiency (FXIIID) should begin with special coagulation testing for factor XIII activity.

A standard testing algorithm for FXIIID has been developed by the Scientific and Standardization Committee of the International Society for Thrombosis and Haemostasis.(1)

Genetic testing for FXIIID is indicated if:

-The clot solubility test, a screening test for possible factor XIII deficiency, is abnormal or FXIII antigen or activity is decreased

-Acquired causes of FXIIID have been excluded (eg, leukemia, liver disease, Henoch-Schonlein purpura, inflammatory bowel diseases, disseminated intravascular coagulation, pulmonary embolism, stroke, and sepsis, exposure to valproate)

Note: Factor XIII may occur spontaneously in older adults.

For prenatal specimens only:

-If amniotic fluid (nonconfluent cultured cells) is received, amniotic fluid culture/genetic test will be added at an additional charge.

-If chorionic villus specimen (nonconfluent cultured cells) is received, fibroblast culture for genetic test will be added at an additional charge.

For any prenatal specimen that is received, maternal cell contamination testing will be performed at an additional charge.

Factor XIII deficiency (FXIIID) is a rare hereditary bleeding disorder associated with germline variants in the F13A1 and F13B genes. It is inherited in an autosomal recessive manner with variable expressivity; both male and female patients may be affected. The estimated prevalence is 1 in 2 million individuals.(2-4)

FXIIID caused by homozygous or compound heterozygous variants in F13A1 (FXIII-A deficiency) typically presents as a severe bleeding tendency. Onset of life-threatening symptoms often occurs early with umbilical cord and central nervous system bleeding. Additional symptoms include easy bruising, intramuscular and subcutaneous hematomas, oral mucosal bleeding, epistaxis, perioperative bleeding, and impaired wound healing. Among the rare bleeding disorders, FXIIID appears uniquely associated with pregnancy loss. Affected women have an increased risk of miscarriage, postpartum hemorrhage, menorrhagia, and intraperitoneal bleeding.(2- 7)

Individuals with FXIIID caused by homozygous or compound heterozygous variants in F13B (FXIII-B deficiency) tend to have a milder bleeding tendency, although a severe phenotype can occur.(1,2)

Accurate correlation between genotype and phenotype in FXIIID has proven challenging due to the unpredictable nature and variability of disease symptoms, its rarity, and the limitation of some laboratory assays. Routine coagulation tests are often normal.(2,3,5)

Several causes of acquired (nongenetic) FXIIID should be excluded prior to genetic testing, including leukemia, liver disease, Henoch-Schonlein purpura, inflammatory bowel diseases, disseminated intravascular coagulation, pulmonary embolism, stroke, sepsis, and exposure to valproate. FXIIID also may occur spontaneously in older adults.(1-3)

The United Kingdom Haemophilia Centre Doctors' Organization provides guidelines regarding diagnosis and management for individuals with inherited bleeding disorders, including FXIIID.(8)

An interpretive report will be provided.

All detected variants are evaluated according to American College of Medical Genetics and Genomics recommendations.(9) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Clinical Correlations:

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.

If testing was performed because of a clinically significant family history, it is often useful to first test an affected family member. Detection of a reportable variant in an affected family member would allow for more informative testing of at-risk individuals.

To discuss the availability of additional testing options or for assistance in the interpretation of these results, contact the Mayo Clinic Laboratories genetic counselors at 800-533-1710.

Technical Limitations:

Next-generation sequencing may not detect all types of genomic variants. In rare cases, false-negative or false-positive results may occur. The depth of coverage may be variable for some target regions; assay performance below the minimum acceptable criteria or for failed regions will be noted. Given these limitations, negative results do not rule out the diagnosis of a genetic disorder. If a specific clinical disorder is suspected, evaluation by alternative methods can be considered.

There may be regions of genes that cannot be effectively evaluated by sequencing or deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC) content, and repetitive sequences. Confirmation of select reportable variants will be performed by alternate methodologies based on internal laboratory criteria.

This test is validated to detect 95% of deletions up to 75 base pairs (bp) and insertions up to 47 bp. Deletions-insertions (delins) of 40 or more bp, including mobile element insertions, may be less reliably detected than smaller delins.

Deletion/Duplication Analysis:

This analysis targets single and multi-exon deletions/duplications; however, in some instances, single exon resolution cannot be achieved due to isolated reduction in sequence coverage or inherent genomic complexity. Balanced structural rearrangements (such as translocations and inversions) may not be detected.

This test is not designed to detect low levels of mosaicism or to differentiate between somatic and germline variants. If there is a possibility that any detected variant is somatic, additional testing may be necessary to clarify the significance of results.

For detailed information regarding gene specific performance and technical limitations, see Method Description or contact a laboratory genetic counselor.

If the patient has had an allogeneic hematopoietic stem cell transplant or a recent blood transfusion, results may be inaccurate due to the presence of donor DNA. Call Mayo Clinic Laboratories for instructions for testing patients who have received a bone marrow transplant.

Reclassification of Variants:

Currently, it is not standard practice for the laboratory to systematically review previously classified variants on a regular basis. The laboratory encourages healthcare providers to contact the laboratory at any time to learn how the classification of a particular variant may have changed over time. Due to broadening genetic knowledge, it is possible that the laboratory may discover new information of relevance to the patient. Should that occur, the laboratory may issue an amended report.

Variant Evaluation:

Evaluation and categorization of variants are performed using published American College of Medical Genetics and Genomics and the Association for Molecular Pathology recommendations as a guideline.(9) Other gene-specific guidelines may also be considered. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. Variants classified as benign or likely benign are not reported.

Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and periodic updates to these tools may cause predictions to change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.

Rarely, incidental or secondary findings may implicate another predisposition or presence of active disease. These findings will be carefully reviewed to determine whether they will be reported.

1. Kohler HP, Ichinose A, Seitz R, et al: Diagnosis and classification of factor XIII deficiencies. J Thromb Haemost. 2011 Jul;9(7):1404-1406

2. Karimi M, Bereczky Z, Cohan N, Muszbek L: Factor XIII deficiency. Semin Thromb Hemost. 2009 Jun;35(4):426-438

3. Dorgalaleh A, Rashidpanah J: Blood coagulation factor XIII and factor XIII deficiency. Blood Rev. 2016 Nov;30(6):461-475

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

5. de Moerloose P, Schved JF, Nugent D: Rare coagulation disorders: fibrinogen, factor VII and factor XIII. Haemophilia. 2016 Jul;22 Suppl 5:61-65

6. Pelcovits A, Schiffman F, Niroula R: Factor XIII deficiency: a review of clinical presentation and management. Hematol Oncol Clin North Am. 2021 Dec;35(6):1171-1180

7. Sharief LAT, Kadir RA: Congenital factor XIII deficiency in women: a systematic review of literature. Haemophilia. 2013 Nov;19(6):e349-e357

8. Mumford AD, Ackroyd S, Alikhan R, et al: Guideline for the diagnosis and management of the rare coagulation disorders: a United Kingdom Haemophilia Centre Doctors' Organization guideline on behalf of the British Committee for Standards in Haematology. Br J Haematol. 2014 Nov;167(3):304-326

9. Richards S, Aziz N, Bale S, et al; ACMG Laboratory Quality Assurance Committee: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-424

Next-generation sequencing (NGS) and/or Sanger sequencing are performed to test for the presence of variants in coding regions and intron/exon boundaries of the F13A1 and F13B genes, as well as some other regions that have known disease-causing variants. The human genome reference GRCh37/hg19 build was used for sequence read alignment. At least 99% of the bases are covered at a read depth over 30X. Sensitivity is estimated at above 99% for single nucleotide variants, above 94% for deletions-insertions (delins) less than 40 base pairs (bp), above 95% for deletions up to 75 bp, and insertions up to 47 bp. NGS and/or a polymerase chain reaction-based quantitative method is performed to test for the presence of deletions and duplications in the F13A1 and F13B genes.

There may be regions of genes that cannot be effectively evaluated by sequencing or deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC) content, and repetitive sequences.(Unpublished Mayo method)

The reference transcript for F13A1 is NM_ 000129.4 and F13B is NM_001994.2. Reference transcript numbers may be updated due to transcript re-versioning. Always refer to the final patient report for gene transcript information referenced at the time of testing. Confirmation of select reportable variants may be performed by alternate methodologies based on internal laboratory criteria.

Varies

• Authorized users can sign in to Test Prices for detailed fee information.
• Clients without access to Test Prices can contact Customer Service 24 hours a day, seven days a week.
• Prospective clients should contact their account representative. For assistance, contact Customer Service.

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

81479

88233-Tissue culture, skin, solid tissue biopsy (if appropriate)

88240-Cryopreservation (if appropriate)

88235-Amniotic fluid culture (if appropriate)

81265-Maternal cell contamination (if appropriate)