A novel pathogenic variant in the fibrinogen gamma chain gene p.Glu275Lys causes congenital hypofibrinogenemia.

Abstract

Congenital hypofibrinogenemia presents not only with bleeding, but also paradoxically with thrombosis. This heterogeneity of clinical phenotype complicates both diagnosis and management. The thrombotic phenotype is thought to arise from alterations in fibrin structure and stability, leading to abnormal clot formation and an increased risk of thrombosis. Coagulation assays, gene analysis, and protein modeling were utilized to elucidate the pathogenic variant. We highlight the pathophysiology of the novel missense variant in the FGG gene (c.823G/A, p.Glu275Lys), which causes mild hypofibrinogenemia and clinically manifests as an ischemic stroke. Protein modeling displays that the amino-acid substitution of glutamine with lysine at position 275 in mentioned missense variant causes local changes in the fibrinogen structure. The structural changes are mainly minor surface alterations and changes in physicochemical properties, which could potentially affect the recruitment of other proteins or lead to abnormal fibrin polymerization. This study provides novel insights into the pathophysiological mechanism, emphasizing the importance of molecular and structural analyses in understanding and managing atypical presentations of fibrinogen disorders.