FGB – Familial Dysfibrinogenemia

Familial dysfibrinogenemia is an autosomal dominant coagulation disorder caused by heterozygous variants in the fibrinogen Bβ-chain gene (FGB) leading to qualitative defects in fibrin polymerization and fibrinolysis. Clinical validity is strong: over 50 unrelated probands with monoallelic FGB variants have been described, with consistent segregation in multiple families and concordant functional abnormalities (PMID:28211264).

Autosomal dominant inheritance is supported by segregation of the c.901C>T (p.Arg301Cys) variant with thrombotic events in a multigenerational pedigree: eight additional relatives carried the same allele, although most remained asymptomatic (PMID:10911375). Case series and systematic reviews identify 32 distinct FGB missense and frameshift mutations causing dysfibrinogenemia, including the recurrent gammaR275C substitution encoded by c.901C>T (p.Arg301Cys), which is prevalent in thrombotic families (PMID:28211264).

Genetic evidence is strong: more than 27 pathogenic FGB variants have been functionally characterized, and the c.901C>T (p.Arg301Cys) change is repeatedly observed in unrelated probands, fulfilling ClinGen criteria for strong genetic evidence. Functional assays reveal that gammaArg275Cys fibrinogen exhibits markedly impaired thrombin-catalyzed D:D interactions, abnormal clot architecture, and delayed plasmin-mediated lysis (PMID:15009465). These data establish a dominant-negative mechanism in which the mutant Bβ-chain disrupts fibrin assembly and enhances thrombotic risk.

Functional evidence is moderate: in vitro studies of recombinant gamma275C fibrinogen demonstrate disulfide‐mediated aberrant D:D interface formation and profoundly reduced lateral aggregation, consistent with the phenotype observed in patients. Tissue-plasminogen activator–induced fibrinolysis assays confirm increased clot resistance to lysis, linking molecular defects to clinical thrombosis.

Despite strong overall association, incomplete penetrance and phenotypic variability are well recognized. Many heterozygous carriers remain asymptomatic, and co-inherited prothrombotic factors—such as the fibrinogen Bβ ‑455G>A promoter polymorphism—may modulate clinical presentation (PMID:10911375). No studies dispute the FGB–dysfibrinogenemia link, but variable expressivity warrants careful family screening.

Integration of genetic and functional data confirms that FGB variants, particularly c.901C>T (p.Arg301Cys), cause a dysfibrinogenemia with dominant inheritance, variable penetrance, and thrombotic or hemorrhagic manifestations. Additional large cohorts exceed ClinGen scoring caps; however, current evidence supports strong clinical validity and utility in diagnostic decision-making.

Key Take-home: Heterozygous FGB mutations cause autosomal dominant familial dysfibrinogenemia with disrupted fibrin assembly and fibrinolysis, justifying genetic testing in patients with unexplained thrombosis or abnormal fibrinogen functional assays.

References

• Fibrinogen bellingham: a gamma‐chain R275C substitution and a beta‐promoter polymorphism in a thrombotic member of an asymptomatic family. American Journal of Hematology | 2000 PMID:10911375
• Genetics, diagnosis and clinical features of congenital hypodysfibrinogenemia: a systematic literature review and report of a novel mutation. Journal of Thrombosis and Haemostasis | 2017 PMID:28211264
• Recombinant fibrinogen, gamma275Arg→Cys, exhibits formation of disulfide bond with cysteine and severely impaired D:D interactions. Journal of Thrombosis and Haemostasis | 2004 PMID:15009465

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