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Test Catalog

Test ID: F13NG    
F13A1 and F13B Genes, Next-Generation Sequencing, Varies

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

Detecting the pathogenic alterations within the F13A1 and F13B genes to delineate the underlying molecular defect in a patient with a laboratory diagnosis of factor XIII deficiency

 

Genetic confirmation of hereditary factor XIII deficiency with the identification of an alteration in either the F13A1 or F13B gene known or suspected to cause the condition

 

Testing for close family members of an individual with a factor XIII deficiency diagnosis

 

This test is not useful for prenatal 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 F13A1 and F13B genes to delineate the underlying molecular defect in a patient with a laboratory diagnosis of factor XIII deficiency.

 

The gene targets for this test are:

Gene name (transcript): F13A1 (GRCh37 [hg19] NM_000129)

Chromosomal location: 6p24-p25

 

Gene name (transcript): F13B (GRCh37 [hg19] NM_001994)

Chromosomal location: 1q31-q32.1

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

A standard testing algorithm for factor 13 deficiency (FXIIID) has been developed by the Scientific and Standardization Committee of the International Society for Thrombosis and Haemostasis (ISTH).(1)

 

Genetic testing for factor XIII deficiency is indicated if:

-Factor XIII activity (FXIII) is reduced on a qualitative functional FXIII activity test

-Acquired causes of factor XIII deficiency have been excluded

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

Factor FXIII deficiency (FXIIID) is a bleeding diathesis of variable severity. The prevalence of factor FXIII deficiency is currently estimated to be 1 in 2 million but the exact prevalence is unknown. The disorder is inherited in an autosomal recessive manner.

 

Factor XIII is a transglutaminase cross-linking enzyme critical to fibrin clot stabilization. It serves to crosslink alpha and gamma fibrin chains, leading to greater clot strength and resistance to fibrinolysis. Deficiency in FXIII leads to defective crosslinking of fibrin and the formation of a weak, unstable clot. Clots may form properly but break down 24 to 48 hours later, leading to abnormal bleeding. Factor XIII is formed from two subunits: catalytic protein FXIII-A, encoded by the F13A1 gene and synthesized by megakaryocytes and certain white blood cells in bone marrow; and stabilizing protein FXIII-B, encoded by the F13B gene and synthesized in the liver. Together, two FXIII-A subunits and two FXIII-B subunits circulate in plasma as heterotetramer.

 

Patients with FXIII caused by alteration in F13A1 (i.e., FXIII-A deficiency) typically have a severe bleeding tendency. Onset of life-threatening symptoms is early and may present as umbilical cord and central nervous system (CNS) bleeding. 80% to 90% of patients have umbilical bleeding in neonatal period. 40% to 60% of patients have spontaneous intracranial haemorrhage within first two decades of life, making early diagnosis critical. In women, miscarriage, menorrhagia, and intraperitoneal bleeding are common without prophylaxis. Delayed wound healing is sometimes seen. Subjects with heterozygous alterations may be at risk for bleeding complications following surgery, dental extraction, or trauma. Patients with FXIII caused by alterations in F13B (FXIII-B deficiency) typically have a relatively milder bleeding tendency relative to individuals with FXIII-A deficiency.

 

The unpredictable nature of symptoms in FXIII deficiency, its apparent rarity, and limitations in the development of laboratory tests for its detection, especially when activity levels are very low, have made genotype-phenotype correlation difficult (2). Additionally, any correlation may be impractical given the high risk of intracranial bleeding among all affected patients and the recommendation of a general prophylactic strategy at the time of diagnosis (2). However, in general, individuals with virtually undetectable functional activity typically have a severe bleeding tendency. FXIII levels between 1 and 4 IU/dL produce moderate to severe bleeding episodes. It is difficult to predict bleeding pattern in patients with alterations that cause activity level to be greater than 5% (3). Heterozygotes (i.e., individuals with only one pathogenic alteration in either F13A1 or F13B) have 50% to 70% factor activity and are typically asymptomatic, although serious bleeding episodes have been reported (4).

 

Causes of acquired (non-genetic) factor XIII deficiency that should be excluded prior to genetic testing include several medical conditions, such as major surgery, leukemia, liver disease, Henoch-Schonlein purpura (HSP), pulmonary embolism, stroke, inflammatory bowel diseases, sepsis, and disseminated intravascular coagulation. In these acquired FXIII-deficient states, FXIIIA levels drop into the 30% to 70% range. Valproate induces a decrease in FXIII level. FXIII antibodies may develop spontaneously in patients long treated with drugs such as isoniazid, penicillin, phenytoin, practolol, and amiodarone. Development of antibodies are also reported in some cases of severe FXIII deficiency, monoclonal gammopathy of undetermined significance, rheumatoid arthritis, and systemic lupus erythematosus. Factor XIII may also develop spontaneously in elderly patients.

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 mutation, therefore, does not eliminate the possibility of factor XIII deficiency. 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 polymorphisms may be present that could lead to false-negative or false-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 and 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.

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

1. Kohler HP, Ichinose A, Seitz R, et al.: Diagnosis and classification of factor XIII deficiencies. J Thromb Haemost. 2011;9(7):1404-6

2. Karimi M, Bereczky, Cohan N, et al.: Factor XIII deficiency. Semin Thromb Hemost. 2009;35(4):426-38

3. de Moerloose P, Schved JF, Nugent D: Rare coagulation disorders: fibrinogen, factor VII and factor XIII. Haemophilia. 2016;22(suppl 5):61-5

4. Dorgalaleh A, Rashidpanah J: Blood coagulation factor XIII and factor XIII deficiency. Blood Rev. 2016;30(6):461-75

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