Congenital Fibrinogen Deficiency via the FGA Gene

Congenital fibrinogen deficiency (CFD) is a rare bleeding disorder, affecting about 1 in a million people, with wide variability in clinical presentation from asymptomatic to life-threatening bleeds. CFDs can be subdivided into type I (afibrinogenemia and hypofibrinogenemia) and type II deficiencies (dysfibrinogenemia and hypo-dysfibrinogenemia). Type I deficiencies are defined by individuals having reduced activity and levels of fibrinogen whereas type II individuals have normal fibrinogen levels but impaired function (Acharya and Dimichele 2008). Afibrinogenemia, the most severe form of CFD, typically presents in the neonatal period with umbilical cord bleeding being the most characteristic of disease. Bleeding tendencies are variable but include life-threatening spontaneous and trauma related bleeds. Patients with hypofibrinogenemia have a milder disease course, as loss of fibrinogen protein is less severe than individuals with afibrinogenemia. Bleeding episodes in these individuals occur later in life and often occur after trauma or surgery. Patients with dysfibrinogenemia are primarily asymptomatic but may experience bleeding after trauma or child birth (de Moerloose et al. 2013). Unlike type I deficiencies, individuals with type II deficiencies have been reported to be at increased risk of thrombosis (Morris et al. 2009). Acquired fibrinogen deficiencies have been found in individuals with liver disease and autoantibodies (Kujovich 2005; Dear et al. 2007). Genetic testing is helpful in differential diagnosis of other rare bleeding disorders, distinguishing inherited and acquired forms, and for diagnosis of asymptomatic hypofibrinogenemia and dysfibrinogenemia patients prior to surgery. Treatment options include fibrinogen concentrates, cryoprecipitate, and fresh frozen plasma (Acharya and Dimichele 2008).

CFD is caused through mutations in the FGA, FGB, or FGG genes. Together these genes encode the hexameric glycoprotein fibrinogen. Onset of afibrinogenemia, hypofibrinogenemia, and dysfibrinogenemia can occur through mutations in any of the three fibrinogen genes. Afibrinogenemia is inherited in an autosomal recessive manner with null mutations accounting for the majority of causative variants. Hypofibrinogenemia and dysfibrinogenemia are inherited in autosomal dominant manners with reduced disease penetrance predominantly due to missense mutations (de Moerloose et al. 2013). Severity of CFD is directly correlative to degree of impaired fibrinogen level and function. Causative mutations for afibrinogenemia and hypofibrinogenemia can overlap with the mutations that cause recessive afibrinogenemia. Thus, asymptomatic individuals with hypofibrinogenemia often are carriers for afibrinogenemia (Acharya and Dimichele 2008). Mutations in the FGA gene account for ~65% of CFD cases. Nonsense mutations are most frequently identified as causative variants in the FGA gene for afibrinogenemia followed by large deletions, frameshift, and splice site alterations (Neerman-Arbez et al. 1999). Missense mutations in the FGA gene are often causative for dysfibrinogenemia (Acharya and Dimichele 2008). Fibrinogen is synthesized in the liver as a disulphide linked hexamer comprised of two heterotrimers each consisting of one alpha, beta and gamma chain. Fibrinogen is catalyzed into fibrin by thrombin to promote blood clot formation through platelet bridging (Acharya and Dimichele 2008).

Rare bleeding disorders (RBD) are comprised of inherited deficiencies of coagulation factors fibrinogen, FII, FV, FV + FVIII, FVII, FX, FXI, and FXIII. CFDs are found ~8% of all RBD cases (Peyvandi et al. 2013). In patients with CFD, causative FGA mutations are found in >65% of cases (Hanss and Biot 2001). Analytical sensitivity is >80% as the majority of causative variants are detectable by sequencing. Large deletions in the FGA gene have been reported for afibrinogenemia (Neerman-Arbez et al. 1999).

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