Congenital Fibrinogen Deficiency via the FGG 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 most characteristic. 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 in individuals with afibrinogenemia. Bleeding episodes in these individuals occur later in life often 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 an autosomal dominant manner with reduced disease penetrance predominantly due to missense mutations (de Moerloose et al. 2013). Severity of CFD is correlated with fibrinogen level and function. Asymptomatic individuals with hypofibrinogenemia often are carriers for afibrinogenemia (Acharya and Dimichele 2008). Mutations in the FGG gene account for ~30% of CFD cases with missense mutations being most prevalent and affecting assembly, secretion, and/or stability of the hexameric fibrinogen (Matsuda and Sugo 2002; Hanss and Biot 2001; Vu et al. 2007; Neerman-Arbez and de Moerloose 2007). About 70% of causative FGG mutations are associated with hypofibrinogenemia and dysfibrinogenemia instead of afibrinogenemia. Only one large deletion has been associated with the FGG gene (Human Gene Mutation Database). Fibrinogen is synthesized in the liver as a disulphide linked hexamer comprised of two heterotrimers consisting of one alpha, beta, and gamma chain. Fibrinogen is converted 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 comprise ~8% of all RBD cases (Peyvandi et al. 2013). In patients with CFD, causative FGG mutations are found in ~30% of cases (Hanss and Biot 2001). Analytical sensitivity is >95% as the great majority of causative variants are detectable by sequencing. Only one large deletion has been reported (Human Gene Mutation Database).

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