FGG – Thrombophilia

FGG encodes the fibrinogen γ chain, a critical component of the fibrinogen hexamer involved in clot formation. Heterozygous truncating variants in FGG have been reported in individuals with hypodysfibrinogenemia and thrombotic phenotypes, supporting a causal link to thrombophilia. A 54-year-old man carrying a novel frameshift deletion, c.637del (p.Ser213LeufsTer16), presented with multiple unprovoked venous thromboemboli and deep vein thrombosis following myocardial infarction; functional analyses showed reduced clottable fibrinogen levels and altered γ–γ and α–α chain cross-linking ((PMID:26540127)). Computational molecular dynamics of another γ-chain variant, c.1067A>T (p.Asp356Val), predicted local unfolding in the C-terminal module, potentially disrupting D-D interactions essential for fibrin polymerization ((PMID:27677677)).

A large prospective cohort of 1,717 IVF patients carrying common thrombophilic SNPs, including variants in FGG, showed no significant impact on IVF outcomes, indicating that common polymorphisms do not confer appreciable thrombosis risk in this setting ((PMID:26545911)). Nevertheless, rare FGG loss-of-function alleles appear to predispose to thrombophilia via hypodysfibrinogenemia and altered fibrin network architecture.

Key Take-home: Rare truncating and structurally disruptive FGG variants cause hypodysfibrinogenemia with a prothrombotic phenotype, warranting consideration in genetic thrombophilia work-ups.

References

• Hamostaseologie • 2015 • A novel fibrinogen γ chain frameshift deletion (c.637delT) in a patient with hypodysfibrinogenemia associated with thrombosis PMID:26540127
• Journal of biomolecular structure & dynamics • 2017 • Molecular dynamics-based analyses of the structural instability and secondary structure of the fibrinogen γ chain protein with the D356V mutation PMID:27677677
• Journal of assisted reproduction and genetics • 2016 • Multiple thrombophilic single nucleotide polymorphisms lack a significant effect on outcomes in fresh IVF cycles: an analysis of 1717 patients. PMID:26545911

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