Congenital<unk>  is inherited as an autosomal dominant disorder caused by at least 32 different types of single mutations. Ten of these mutations are in the fibrinogen alpha chain gene (also termed the FGA gene), 5 in the fibrinogen beta chain gene (also termed the FGB gene), and 17 in the fibrinogen gamma chain gene (also termed the FGG gen). The mutations are mainly missense mutations with nonsense and Frameshift mutations each occurring in 12.5% of cases. The causes of two fibrinogen abnormalities that characterize<unk> , i.e. circulation at reduced levels of fibrinogen at least some of which is dysfunctional, reflect different molecular mechanisms: # A heterozygous mutation in one of the two copies of either the FGA, FGB, or FGG gene leads to production of a fibrinogen that is both dysfunctional and poorly secreted into the blood stream, e.g. fibrinogen Vlissingen, fibrinogen Philadelphia, and fibrinogen Freiburg. # A homozygous mutation in both copies of one of the cited genes leads to production of a fibrinogen that is both dysfunctional and poorly secreted into the blood stream, e.g. fibrinogen Otago, fibrinogen Marburg, and fibrinogen Sfax. # Two different mutations (see Compound heterozygosity) occur in each of the two copies of one of the cited genes, with one mutation coding for reduced formation of a functionally normal circulating fibrinogen and the second mutation coding for the circulation of a dysfunctional fibrinogen, e.g. fibrinogen Leipzig. # Two different mutations occur in one copy of the cited genes, with one mutation causing hypofibrinogenemia and the other mutation coding for a dysfunctional fibrinogen, e.g. fibrinogen Keokuk. The following Table adds further information on the just cited examples of<unk> s. The Table gives: a) each mutated protein's trivial name; b) the gene mutated (i.e. FGA, FGB, or FGG), its mutation site (i.e. numbered nucleotide in the cloned gene), and name of the nucleotides (i.e. C, T, A, G) at these sites before>after the mutation; c) the name of the altered fibrinogen peptide (Aα, Bβ, or λ) and the amino acids (using standard abbreviations) occurring before-after the mutation at the numbered amino acid(s) sites in the circulating mutated fibrinogen; d) the pathophysiology for the mutated fibrinogen's misfunction(s); and e) the clinical consequence(s) of the mutation. Unless noted as a deletion (del) or frame shift (fs), all mutations are missense or nonsense mutations. A nonsense mutation causing a premature stop codon and thereby a shorten polypeptide chain is notated by an X (PSC) after the altered amino acid codon. Trivial name Gene: mutation Polypeptide chain: mutation Pathophysiology Clinical disorder fibrinogen Otago FGA: c.858_859incC Aα: Arg268Gln followed by fs impaired secretion; defective polymerization post-surgical and post-partum bleeding, recurrent miscarriages fibrinogen Marburg FGA: c.1438A>T Aα: Lys461X (PSC) defective polymerization post-partum bleeding, recurrent venous thrombosis fibrinogen Keokuk FGA: c.510 +1 G>T; FGA c.1039C>T (PSC) Aα: splice mutation; Aα: Gln321X (PSC) impaired fibrinogen assembly, poor fibrin clot lysis, defective polymerization recurrent venous and arterial thromboses fibrinogen Sfax FGB: c.679T>C Bβ: Cys197Arg defective aggregation of fibrin post-surgical and postpartum bleeding, metrorrhagia during pregnancy fibrinogen Vlissingen FGG: c.1033_1038del γ: delAsn319-Asp-320 impaired secretion, defective calcium binding, defective polymerization venous thrombosis fibrinogen Philadelphia FGG: c.1210T>C γ: Ser378Pro impaired assembly of intracelllar fibrinogen, defective polymerization post-surgical, postpartum, and post-trauma bleeding fibrinogen Freiburg FGG: c.103C>T γ: Arg16Cys impaired assembly of intracelllar fibrinogen, defective polymerization recurrent venous and arterial thromboses fibrinogen Leipzig II FGG: c.323C>G and FGG c.1129G>A γ: Ala108Gly and λ: Gly377Ser impaired assembly of intracelllar fibrinogen, defective polymerization recurrent venous and arterial thromboses
Hypodysfibrinogenemia
Dysfibrinogenemia
Hypoprothrombinemia
COAT platelet defect
Factor VII deficiency
Congenital afibrinogenemia
Factor XII deficiency
Factor XIII deficiency