Mutations Accounting for Congenital Fibrinogen Disorders: An Update

Abstract

Fibrinogen is a complex protein that plays a key role in the blood clotting process. It is a hexamer composed of two copies of three distinct chains: Aα, Bβ, and γ encoded by three genes, FGA, FGB, and FGG, clustered on the long arm of chromosome 4. Congenital fibrinogen disorders (CFDs) are divided into qualitative deficiencies (dysfibrinogenemia, hypodysfibrinogenemia) in which the mutant fibrinogen molecule is present in the circulation and quantitative deficiencies (afibrinogenemia, hypofibrinogenemia) with no mutant molecule present in the bloodstream. Phenotypic manifestations are variable, patients may be asymptomatic, or suffer from bleeding or thrombosis. Causative mutations can occur in any of the three fibrinogen genes and can affect one or both alleles. Given the large number of studies reporting on novel causative mutations for CFDs since the review on the same topic published in 2016, we performed an extensive search of the literature and list here 120 additional mutations described in both quantitative and qualitative disorders. The visualization of causative single nucleotide variations placed on the coding sequences of FGA, FGB, and FGG reveals important structure function insight for several domains of the fibrinogen molecule.

Congenital fibrinogen disorders: Strengthening genotype–phenotype correlations through novel genetic diagnostic tools

“…Frequencies of these mutations vary between 43.8% and 94% of patients in published case series of patients with dysfibrinogenaemia, 37,43 with the GEHT HFD reporting frequencies of approximately 80%–90% for both sites 33,51 (Figure 3). These findings are concordant with those reported in an update of mutations found in CFDs recently published by Richard et al 58 …”

“…both sites 33,51 (Figure 3). These findings are concordant with those reported in an update of mutations found in CFDs recently published by Richard et al 58 The two most frequently mutated hotspots occur at FGA p.Arg35 (Arg16 when describing the mature protein post-signal peptide cleavage) and FGG p.Arg301 (Arg275) (Figure 3). The amino acid change at these positions is to either Cys or His at both sites.…”

Diagnosis and classification of hereditary fibrinogen disorders

“…HFDs result from monoallelic or biallelic mutations in FGA, FGB and FGG genes in chromosome 4 23 . Besides the confirmation of the diagnosis, genotype may help for familial screening, prenatal testing, and prediction of the clinical phenotype.…”

Physiological correction of hereditary mild hypofibrinogenemia during pregnancy

“…Severe and moderate hypofibrinogenemia (functional fibrinogen below 1 g/L) are often associated with a bleeding phenotype, while mild hypofibrinogenemia (fibrinogen higher than 1 g/L) is usually asymptomatic except after trauma or surgery 2 . Hypofibrinogenemia is very often caused by heterozygosity for a fibrinogen gene mutation, which in homozygosity or compound heterozygosity would cause afibrinogenemia 3 . The exact prevalence of hereditary hypofibrinogenemia is not known, but it is probably underestimated 4 …”