Clinical and molecular characterisation of 21 patients affected by quantitative fibrinogen deficiency

Abstract

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.

Hepatic fibrinogen storage disease: identification of two novel mutations (p.Asp316Asn, fibrinogen Pisa and p.Gly366Ser, fibrinogen Beograd) impacting on the fibrinogen γ‐module

“…For three of these families, the specific mutation underlying FSD was not disclosed, whereas in all other pedigrees, hypofibrinogenemic mutation carriers showed an extreme variability in the severity of liver injury, ranging from no signs of hepatic disease to severe liver fibrosis or cirrhosis even early in life . This phenotypic heterogeneity has been previously reported not only among patients carrying the mutation in the same gene region, but even in carriers of the same mutation . The families reported here conform to this paradigm, with only the two probands affected by a mild liver disease.…”

Fibrin Formation, Structure and Properties

“…Most congenital defects are rare but have led to important insights into fibrin(ogen) structure-function relationships. Many of these mutations have been described in reviews (Galanakis 1993; Roberts et al 2001; Matsuda and Sugo 2001; de Moerloose and Neerman-Arbez 2009; Asselta et al 2006; de Moerloose et al 2013; Asselta et al 2015; Casini et al 2015). In addition, the website, http://www.geht.org/databaseang/fibrinogen, maintains a database of fibrinogen mutations and their functional consequences.…”

Molecular characterization of 7 patients affected by dys- or hypo-dysfibrinogenemia: Identification of a novel mutation in the fibrinogen Bbeta chain causing a gain of glycosylation

“…Afibrinogenemia is an autosomal recessive disorder characterized by the absence of circulating fibrinogen and caused by homozygosity or compound heterozygosity for mutations in one of the three fibrinogen genes [8][9][10]. In the past considered as a different clinical entity, "true" hypofibrinogenemia is characterized by low fibrinogen levels accompanied by bleeding/ thromboembolic disease, although generally to a milder extent than in afibrinogenemia [9,11].…”

“…In the past considered as a different clinical entity, "true" hypofibrinogenemia is characterized by low fibrinogen levels accompanied by bleeding/ thromboembolic disease, although generally to a milder extent than in afibrinogenemia [9,11]. In most cases, it results from heterozygosity for null or missense mutations, each causing a complete lack or a major decrease of the corresponding chain in circulating hexameric fibrinogen molecules [8][9][10]. As for qualitative defects, congenital dysfibrinogenemia is characterized by normal fibrinogen antigen levels associated with low functional activity [12].…”