Forms

Congenital Factor XIII Deficiency via the F13B Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
Order Kits
TEST METHODS

Sequencing

Test Code TestIndividual Gene PriceCPT Code Copy CPT Codes
2912 F13B$970.00 81479 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity

Rare bleeding disorders (RBD) comprise of inherited deficiencies of coagulation factors fibrinogen, FII, FV, FV + FVIII, FVII, FX, FXI, and FXIII. Factor XIII deficiencies are found ~5% of all RBD cases. In patients with Factor XIII deficiency, F13B mutations are found in >20% of cases (Peyvandi et al. 2013). Analytical sensitivity should be high because all mutations reported are detectable by sequencing.

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Deletion/Duplication Testing via aCGH

Test Code TestIndividual Gene PriceCPT Code Copy CPT Codes
600 F13B$690.00 81479 Add to Order
Pricing Comment

# of Genes Ordered

Total Price

1

$690

2

$730

3

$770

4-10

$840

11-30

$1,290

31-100

$1,670

Over 100

Call for quote

Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Features

Factor XIII deficiency is a rare bleeding disorder that is typically severe. The first and most characteristic symptom seen in about 80% of patients is umbilical cord bleeding following birth. Other frequent symptoms include superficial bruising, subcutaneous hematomas, spontaneous abortions in early pregnancy and joint bleeds leading to hemarthrosis (Schroeder and Kohler 2013). Intracranial hemorrhage appears in one in four patients and is a leading cause of death. Unlike other rare bleeding disorders, mucosal tract bleeding is a common symptom and seen in over a third of affected individuals. This is due to the dual role of Factor XIII in crosslinking fibrin chains to promote clotting and crosslinking fibronectin and collagen to enhance gut wound healing. Factor XIII deficiency is also acquired through development of autoantibodies against FXIII protein (Hayashi et al. 2012; Sugiyama et al. 2013). Genetic testing may aid in differential diagnosis of acquired and congenital forms of the deficiency. Affected patients with congenital factor XIII deficiency may be treated with fresh frozen plasma, recombinant FXIII or plasma derived FXIII concentrates to mitigate symptoms (Nugent 2006; Inbal et al. 2012). These therapies fail to alleviate disease in acquired Factor XIII deficiency and require immunosuppressive drugs for treatment. Diagnosis of Factor XIII deficiency is often difficult because deficiency cannot be detected by routine global coagulation assays (Bolton-Maggs et al. 2012) and because FXIII laboratory assays must be carefully timed with blood sampling (Perez et al. 2011; Karimi et al. 2009).

Genetics

Factor XIII deficiency is inherited in an autosomal recessive manner through mutations in the F13A1 and F13B genes. Mutations in the F13B gene are causative in ~20% cases of Factor XIII deficiencies with missense, small insertions/deletions, and splice site alterations being documented (Schroeder and Kohler 2013; www.f13-database.de). To date, large deletions and duplications have not been reported. Mutations are found throughout the F13B gene and presumably alter protein folding and stability (Ivaskevicius et al. 2010; Biswas et al. 2011). The FXIII protein is a heterotetramer consisting of two A and two B subunits (FXIII A2B2). This tetramer functions as a transglutaminase with the A subunit containing the catalytic domain and the B subunit being the carrier protein. In plasma, FXIII activation is essential for fibrin polymerization and stabilizing clots during the hemostatic process (Muszbek et al. 2011).

Testing Strategy

This test involves bidirectional Sanger sequencing using genomic DNA of all coding exons of the F13B gene plus ~20 bp of flanking non-coding DNA on each side. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.

Indications for Test

Candidates typically have moderate to severe bleeding episodes with umbilical cord bleeding often being the first symptom of disease. Ideal candidates have decreased FXIII functional activity assay.

Gene

Official Gene Symbol OMIM ID
F13B 134580
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Factor XIII, B Subunit, Deficiency Of 613235

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Biswas A, Ivaskevicius V, Seitz R, Thomas A, Oldenburg J. 2011. An update of the mutation profile of Factor 13 A and B genes. Blood Rev. 25: 193–204. PubMed ID: 21640452
  • Bolton-Maggs PHB, Favaloro EJ, Hillarp A, Jennings I, Kohler HP. 2012. Difficulties and pitfalls in the laboratory diagnosis of bleeding disorders. Haemophilia 18 Suppl 4: 66–72. PubMed ID: 22726086
  • Factor XIII Registry Database
  • Hayashi T, Kadohira Y, Morishita E, Asakura H, Souri M, Ichinose A. 2012. A case of acquired FXIII deficiency with severe bleeding symptoms. Haemophilia 18: 618–620. PubMed ID: 22356719
  • Inbal A, Oldenburg J, Carcao M, Rosholm A, Tehranchi R, Nugent D. 2012. Recombinant factor XIII: a safe and novel treatment for congenital factor XIII deficiency. Blood 119: 5111–5117. PubMed ID: 22451421
  • Ivaskevicius V, Biswas A, Loreth R, Schroeder V, Ohlenforst S, Rott H, Krause M, Kohler H-P, Scharrer I, Oldenburg J. 2010. Mutations affecting disulphide bonds contribute to a fairly common prevalence of F13B gene defects: results of a genetic study in 14 families with factor XIII B deficiency. Haemophilia 16: 675–682. PubMed ID: 20331752
  • Karimi M, Bereczky Z, Cohan N, Muszbek L. 2009. Factor XIII Deficiency. Semin. Thromb. Hemost. 35: 426–438. PubMed ID: 19598071
  • Muszbek L, Bereczky Z, Bagoly Z, Komáromi I, Katona É. 2011. Factor XIII: a coagulation factor with multiple plasmatic and cellular functions. Physiol. Rev. 91: 931–972. PubMed ID: 21742792
  • Nugent DJ. 2006. Prophylaxis in rare coagulation disorders -- factor XIII deficiency. Thromb. Res. 118 Suppl 1: S23–28. PubMed ID: 16616323
  • Perez DL, Diamond EL, Castro CM, Diaz A, Buonanno F, Nogueira RG, Sheth K. 2011. Factor XIII deficiency related recurrent spontaneous intracerebral hemorrhage: a case and literature review. Clin Neurol Neurosurg 113: 142–145. PubMed ID: 20950938
  • Peyvandi F. et al. 2013. Blood. 122: 3423-31. PubMed ID: 24124085
  • Schroeder V, Kohler HP. 2013. Factor XIII deficiency: an update. Semin. Thromb. Hemost. 39: 632–641. PubMed ID: 23929307
  • Sugiyama H, Uesugi H, Suzuki S, Tanaka K, Souri M, Ichinose A. 2013. Aggressive fatal case of autoimmune hemorrhaphilia resulting from anti-Factor XIII antibodies. Blood Coagul. Fibrinolysis 24: 85–89. PubMed ID: 23183237
Order Kits
TEST METHODS

Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (http://www.hgvs.org).  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing Via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

Order Kits

Ordering Options


myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
REQUISITION FORM
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

SPECIMEN TYPES
WHOLE BLOOD

(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.

DNA

(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.

CELL CULTURE

(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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