Factor VII Deficiency via the F7 Gene

Factor VII deficiency is an excessive bleeding disorder with clinical heterogeneity ranging from life-threatening to asymptomatic. Common symptoms include epistaxis, easy bruising, gum bleeding, hematoma, hemarthrosis, gastrointestinal bleeding and menorrhagia. Severe Factor VII deficiency represents ~15% of cases with bleeding starting early in life with intracranial and gastrointestinal hemorrhaging (Mariani and Bernardi 2009). Asymptomatic patients often do not display signs of the disorder until traumatic events or surgery. Late onset/mild form of Factor VII deficiency represents more than half of the cases for disease. Acquired Factor VII deficiency occurs as a result of liver disease and hypovitaminosis K (Giansily-Blaizot et al. 2004). Factor VII deficiency exhibits a poor genotype-phenotype relationship, therefore genetic testing may be helpful in refining inheritance patterns of the disease (Herrmann et al. 2009). Treatments for Factor VII deficiency include fresh frozen plasma, plasma derived FVII, and recombinant FVII (Lapecorella et al. 2008).

Factor VII deficiency is inherited in an autosomal recessive manner through mutations in the F7 gene. Recurrent mutations have been identified in patients with discordant clinical phenotypes suggesting that either environmental or other inherited components modify disease severity. Missense mutations are found in 80% of case of Factor VII deficiency with the majority residing within exon 8 and disrupting the catalytic domain of the protein (Mariani and Bernardi 2009). Splice site, nonsense, small insertion/deletions, and substitution mutations within the promoter region make up the remaining causative variants for disease (Herrmann et al. 2009; Millar et al. 2000; McVey et al. 2001). Gross deletions have been reported in only two cases to date (Herrmann et al. 2009; Giansily-Blaizot et al. 2007). Complete loss of FVII protein is incompatible with life (Rosen et al. 2005). The F7 gene encodes the serine protease FVII, a pro-coagulation factor. Upon vessel injury, FVII binds to tissue factor and initiates the coagulation cascade through activation of secondary coagulation factors including thrombin, FX, FIX, and FXII (Mariani and Bernardi 2009).

Rare bleeding disorders (RBD) comprise inherited deficiencies of coagulation factors fibrinogen, FII, FV, FV + FVIII, FVII, FX, FXI, and FXIII (Peyvandi et al. 2012). Factor VII deficiency is the most common RBD and accounts for ~30% of cases. In 10% of people with Factor VII deficiency, no mutations in the F7 gene were identified (McVey et al. 2001). Analytical sensitivity for detection of F7 mutations is >95% as gross deletions have only been reported in two cases (Herrmann et al. 2009; Giansily-Blaizot et al. 2007).

Clinical sensitivity for deletion/duplication analysis is less than 5%. In a series of 192 patients with Factor VII or X deficiency, three patients had gross deletions spanning exons 1-9 (Rath et al. 2015).

This test provides full coverage of all coding exons of the F7 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).