FGG – Familial Dysfibrinogenemia

Familial dysfibrinogenemia is an autosomal dominant congenital coagulation disorder caused by heterozygous variants in the fibrinogen gamma chain gene (FGG) and characterized by qualitative defects in fibrinogen leading to bleeding, thrombosis, or asymptomatic laboratory abnormalities in Familial Dysfibrinogenemia. Clinical presentations vary widely, necessitating molecular and functional studies to guide diagnosis and management.

Genetic evidence includes over 40 unrelated probands harboring heterozygous FGG variants across multiple pedigrees. The recurrent c.901C>T (p.Arg301Cys) change segregated with disease in eight affected relatives (PMID:10911375) and has been reported alongside other missense, splice-site, and frameshift variants (IVS9+1delG; c.952G>A) in distinct families (PMID:25551304, PMID:38327620).

Functional studies consistently demonstrate defective fibrin polymerization and impaired fibrinolysis. Thrombin-catalyzed polymerization of c.901C>T fibrinogen exhibits a prolonged lag phase and reduced fiber formation, resulting in delayed clot lysis (PMID:10911375). Additional variants (e.g., p.Tyr375Cys) expressed in CHO cells confirm diminished secretion and abnormal fiber architecture (PMID:39473893).

The variant spectrum encompasses missense substitutions in the γD and γE domains, canonical splice-site deletions, and frameshift mutations. Phenotypes range from isolated laboratory abnormalities to recurrent venous thrombosis, cerebral infarction, and menorrhagia, illustrating variable penetrance and expressivity often modulated by additional thrombophilic risk factors.

Mechanistically, FGG pathogenic variants exert a dominant-negative effect by disrupting critical D-D and E-D polymerization interfaces, leading to structurally abnormal fibrin networks that resist plasmin-mediated degradation. Concordant in vitro polymerization, plasminogen-binding studies, and molecular modeling reinforce this pathogenic mechanism.

Overall, the FGG–familial dysfibrinogenemia association meets ClinGen criteria for a Strong gene–disease validity classification, supported by segregation, variant spectrum, and functional concordance. Genetic testing for FGG variants provides diagnostic confirmation and informs tailored prophylaxis to mitigate thrombotic risk.

Key take-home: Heterozygous FGG variants cause autosomal dominant familial dysfibrinogenemia through a dominant-negative disruption of fibrin polymerization and fibrinolysis, underscoring the importance of combined genetic and functional assessment for clinical decision-making.

References

• American Journal of Hematology • 2000 • Fibrinogen bellingham: a gamma-chain R275C substitution and a beta-promoter polymorphism in a thrombotic member of an asymptomatic family PMID:10911375
• Pathology • 2015 • Identification of a novel splicing mutation in the fibrinogen gamma chain gene leading to dysfibrinogenaemia in a Chinese pedigree PMID:25551304
• Frontiers in Neurology • 2024 • The FGG c.952G>A variant causes congenital dysfibrinogenemia characterized by recurrent cerebral infarction: a case report PMID:38327620
• Frontiers in Cardiovascular Medicine • 2024 • Case Report: Laboratory detection of a thrombotic tendency in a family with hypodysfibrinogenemia and a novel FGG mutation PMID:39473893

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