Fibrinogen is a plasma
glycoprotein mainly synthesised by hepatocytes and circulating as a 340-kDa hexamer consisting of two sets of three different
polypeptide chains (Aα, Bβ, and γ, encoded by the FGA, FGB, and FGG gene, respectively).
Congenital afibrinogenaemia and hypofibrinogenaemia are rare
bleeding disorders characterised by abnormally low levels of functional and immunoreactive
fibrinogen in plasma, associated with haemorrhagic manifestations of variable severity. While afibrinogenaemia is caused by mutations in the homozygous or compound heterozygous state in one of the three
fibrinogen genes, hypofibrinogenaemia is generally due to heterozygous mutations, and is usually characterised by a milder phenotype. The mutational spectrum of these quantitative
fibrinogen disorders includes large deletions, point mutations causing
premature termination codons, and missense mutations often affecting
fibrinogen assembly and/or secretion. Here we report the clinical and molecular characterisation of 13 unrelated afibrinogenaemic and eight hypofibrinogenaemic patients, leading to the identification of 17 different mutations (10 hitherto unknown). All the newly-identified missense and splicing mutations werein vitro expressed to verify their pathogenic role. Our data increase the number of mutations causing quantitative
fibrinogen deficiencies by about 7 %. The high number of private mutations identified in the analysed probands indicates that the full mutational screening of the three
fibrinogen genes is still required for molecular diagnosis.