Rare Congenital Fibrinogen Deficiencies

Pattern of Inheritance

Fibrinogen genes FGB, FGA, and FGG are clustered in a region of approximately 50 kb on human chromosome 4(q31),6 and each gene undergoes separate but coordinated transcription and translation to produce nascent Aa, Bβ, and γ polypeptides. The most common fibrinogen defect is found in the FGA gene, irrespective of ethnicity; currently, no genotype-phenotype correlations have been clearly established. Molecular modeling to predict functional consequences of specific mutations is attractive, but many exceptions to model-based prediction efforts exist.

Afibrinogenemia has been shown to follow an autosomal recessive pattern of inheritance with a variable phenotype.8,9 Given the rarity of CFD, recent registries from Italy (http://eu.rbdd.org/; www.rbdd.org), Iran and North America have provided an improved understanding of the clinical spectrum of presentation.12,16,17

Quantitative fibrinogen deficiencies (type I) are usually symptomatic only when inherited on both chromosomal alleles (i.e. autosomal recessive: either homozygous or compound heterozygous) while qualitative fibrinogen deficiencies (type II) are often symptomatic in individuals who carry one abnormal allele (autosomal dominant: heterozygous).

Null mutations of FGA, including large deletions, frameshifts, splice-site mutations and early-truncating nonsense mutations, are the most frequently-identified fibrinogen variants, irrespective of the geographic location of affected individuals.18 In contrast, CFD originating in FGG and FGB include an excess of missense mutations in the C-terminal globular domains.19 Mutation of FGB leading to hypofibrinogenemia is less common, as an intact Bβ-chain is considered to be the rate-limiting factor in the hepatic production and secretion of a functional fibrinogen hexamer.

Knowledge of the types and locations of the various fibrinogen chain mutations has resulted in efficient strategies for mutation detection in new cases. Two common mutations, both in the FGA gene (an 11 kb deletion and a splice site c.510+1G>T mutation), should be screened first in all new kindred before investigating FGB and FGG. A recent report on FGB mutations that impact fibrinogen assembly and secretion processes may provide additional insights into bleeding versus thrombotic phenotypes.20 The cost of gene sequencing is currently decreasing rapidly and should result in the identification of additional novel fibrinogen mutations.  The ongoing characterization of novel genetic defects combined with fibrinogen functional studies will provide a better understanding of the complexity of fibrinogen synthesis. This will lead to deeper insights into the molecular basis for the disease phenotype.

A database is available on the Study Group on Hemostasis and Thrombosis website (http://site.geht.org/base-de-donnees-fibrinogene/),21 which lists the fibrinogen variants identified to date in patients with dysfibrinogenemia, hypofibrinogenemia, and afibrinogenemia. A highly-convincing association between dysfibrinogenemia and thrombosis has been established for several families (Caracas V, Melun, Naples, Paris V, and Vlissingen/Frankfurt IV).22,23