Coagulation Factor Deficiency Panel

The coagulation factor deficiency panel includes testing for a large group of inherited bleeding disorders including three types of hemophilia (F9), von Willebrand disease (VWD) and rare bleeding disorders (RBD). RBDs include inherited deficiencies in fibrinogen, factor (F) II, FV, FV +FVIII, FVII, FX, FXI, FXII, FXIII, plasminogen activator inhibitor, alpha-s-plasmin inhibitor, and combined factor deficiencies (Othman 2013; Peyvandi et al. 2012). Hemophilia A, B, and VWD disease make up ~95% of bleeding disorders due to coagulation factor deficiencies. RBDs occur in one of 500,000 people and equally affect males and females, unlike Hemophilia A and B which arises in males. Symptoms among the various coagulation factor deficiencies range greatly, yet are often phenotypically similar between the specific disease states (Peyvandi et al. 2013). These disorders are also mirror symptoms of many inherited platelet defect disorders (Watson et al. 2013; Diz-Küçükkaya 2013). Bleeding episodes can range from mild with individuals being asymptomatic until incursion of trauma or surgery to severe with life threatening hemorrhages. The coagulation cascade works concurrently to mitigate bleeding through formation of fibrin clots at sites of injury. Each coagulation factor often has its own biochemical assay to assess its function which means diagnosis, especially of RBDs, may be cumbersome. Genetic testing provides a means to examine multiple coagulation factor genes simultaneously to quickly identify potential causes to disease (Peyvandi et al. 2013).

Hemophilia A and B are inherited through an X-linked recessive manner through pathogenic variants in the F8 and F9 genes respectively and primarily affect males. VWD is inherited in both autosomal dominant and recessive manners through pathogenic variants in the VWF gene. RBDs are all inherited in an autosomal recessive manner with deficiencies in FVII, FXI, or FV accounting for ~80% of cases. RBD genes include FGA, FGB, FGG, F2, F5, F7, F10, F11, F12, F13A1, F13B, MCFD2, LMAN1, SERPINE1, SERPINF2, GGCX, and VKORC1 (Othman 2013; Peyvandi et al. 2012). See individual test descriptions for additional information on the molecular biology of each gene.

Analytical sensitivity should be high because ~95% of pathogenic variants reported are detectable by this method. The exception is the F8 gene which has inversions in ~40% of cases of hemophilia A which are not detected by this method.

For coagulation deficiency genes, large deletions are represent 5% of causative variants in the F10, 2% in F11, 3% in F13A1, 2% in F5, 2% in F7, 6% in F8, 3% in F9, 15% in FGA, and 5% in VWF (Human Gene Mutation Database).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 97.5% coverage of all coding exons of the genes 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 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).