Congenital Factor XIII deficiency via the F13A1 Gene

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).

Factor XIII deficiency is inherited in an autosomal recessive manner through mutations in the F13A1 and F13B genes. Heterozygous individuals with mutations in the F13A1 gene have been reported to have milder forms of the disease with symptoms becoming apparent after trauma or surgery. The majority of Factor XIII deficiencies have causative mutations in the F13A1 gene with missense, small insertions/deletions, and splice site alterations being found in >80% of cases (Schroeder and Kohler 2013; www.f13-database.de). Mutations are found throughout the F13A1 gene and presumably alter protein folding and stability (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).

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, F13A1 mutations are found in >80% of cases (Peyvandi et al. 2013). Analytical sensitivity should be high because nearly all mutations reported are detectable by sequencing.

This test provides full coverage of all coding exons of the F13A1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).