Factor X Deficiency via the F10 Gene

Factor X (FX) deficiency is a severe rare bleeding disorder affecting about 1 in every 1,000,000 individuals. FX deficiency disease severity ranges from mild to severe and is corollary to the degree of FX protein activity impairment. In severe cases, symptoms occur shortly after birth with umbilical cord or central nervous systems bleeding followed by hemarthrosis, muscle hematomas, recurrent epistasis, and gastrointestinal bleeding. Mild cases may only experience bleeding episodes following surgeries, trauma, or childbirth (Menegatti and Peyvandi 2009). Genetic testing can be helpful in distinguishing FX deficiency from other rare bleeding disorders and acquired forms of the disease including systemic amyloid light-chain amyloidosis (Choufani et al. 2001). Patients with FX deficiency can be treated with fresh frozen plasma or prothrombin complex concentrates containing FX to minimize bleeding (Menegatti and Peyvandi 2009).

FX deficiency is primarily inherited in an autosomal recessive manner through pathogenic variants in the F10 gene. Severity of bleeding episodes is correlated to the degree of FX activity with most severe cases having FX activity <1%. Patients heterozygous for a pathogenic variant in the F10 gene have been reported to have mild bleeding phenotypes after surgeries, dental extractions, or child birth and may require replacement therapy (Karimi et al. 2008). There are two types of FX deficiency. In patients with type 1 disease, both FX activity and levels are decreased. In type 2 disease, FX levels are unaffected but activity is decreased (Menegatti and Peyvandi 2009). Missense variants represent about 75% of all causative variants and primarily occur within exon 8. However, missense variants have also been reported throughout the coding region. Small insertions/deletions, gross deletions, nonsense, and splice site variants have also been reported in about 25% of cases (Herrmann et al. 2006; Menegatti and Peyvandi 2009). The F10 gene encodes Factor X protein which is involved in the coagulation cascade. Factor X is the first protein involved in the common pathway and aids in the conversion of prothrombin to thrombin to facilitate fibrin clotting (Karimi et al. 2008).

Rare bleeding disorders (RBD) include inherited deficiencies of coagulation factors fibrinogen, FII, FV, FV + FVIII, FVII, FX, FXI, and FXIII. Factor X deficiency accounts for ~10% of RBD cases. In a series of 102 patients with FX Deficiency, causative variants in the F10 gene were identified in 89% of patients (Herrmann et al. 2006).

Gross deletions ranging from single exon to the entire F10 gene have been reported in patients with FX Deficiency. These pathogenic variants are found in less than 5% of patients with FX deficiency (Menegatti and Peyvandi 2009).

This test provides full coverage of all coding exons of the F10 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).