Identification of genetic variants in the FGB gene associated with congenital hypofibrinogenemia with divergent clinical phenotype

Congenital fibrinogen disorders are rare and clinically heterogeneous conditions that may manifest with both bleeding and thrombotic complications. The relationship between genotype and phenotype remains incompletely understood, particularly in cases involving co-inherited variants with potentially opposing functional effects. We investigated two families with hypofibrinogenemia using coagulation assays, rotational thromboelastometry (ROTEM), genetic analysis, and protein modelling. In the first family, an 18-year-old patient with mild bleeding carried two heterozygous FGB variants: c.794 C > T (p.Pro265Leu) and c.1102T > C (p.Tyr368His), and showed reduced clot firmness on ROTEM, consistent with a quantitative fibrinogen defect. Segregation analysis indicated that p.Pro265Leu was associated with decreased fibrinogen levels, whereas p.Tyr368His was present in an asymptomatic relative. In the second family, an 11-year-old patient and her father carrying p.Tyr368His presented with asymptomatic hypofibrinogenemia and relatively preserved ROTEM parameters, suggesting a limited impact of this variant on fibrin-based clot formation. Protein modelling indicated that p.Tyr368His had the more pronounced predicted structural effect, showing moderate local destabilization in both isolated and assembled models, whereas p.Pro265Leu showed a mild and context-dependent effect that was largely compensated in the trimeric fibrinogen structure. These findings demonstrate that co-inherited fibrinogen variants may exert distinct and potentially opposing effects on clot formation, contributing to variable clinical phenotypes. Integration of genetic data with global functional assays such as ROTEM and with structural modelling provides important insights into variant-specific effects and may improve the interpretation of pathogenicity and support individualized clinical management.