Related Experiment Video
Updated: Apr 16, 2026
Analysis of β-Amyloid-induced Abnormalities on Fibrin Clot Structure by Spectroscopy and Scanning Electron Microscopy
Published on: November 30, 2018
Identification and Pathogenicity Analysis of a Novel Fibrinogen Bβ Chain p.Gly293Val Variant Causing
Xiao Li Cheng1, Lin Zhu1, Yi Juan Xin1
1Department of Clinical Laboratory Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
Background:
Hypofibrinogenemia is a rare bleeding disorder characterized by excessive bleeding, impaired wound healing, and elevated perioperative risk. It most commonly results from pathogenic variants in the FGB gene. This study aimed to analyze the clinical phenotypes and genetic variants in a family with hypofibrinogenemia and explore its molecular pathogenic mechanisms.
Methods:
Fibrinogen (Fg) activity (Fg:C) was measured using the Clauss method and the prothrombin time (PT)-derived method, and Fg antigen (Fg:Ag) levels were determined by enzyme-linked immunosorbent assay (ELISA). Fg polymerization capacity was evaluated via a thrombin-induced Fg polymerization assay, and Fg levels and function were assessed using thromboelastography. Sanger sequencing was performed to screen for variants in all exons and flanking regions of the FGA, FGB, and FGG genes. Multiple in silico tools, including ClustalX-2.1-win, MutationTaster, PolyPhen-2, PROVEAN, I-Mutant 2.0 and Swiss-Pdb Viewer, were used to assess the conservation of the variation sites and their impact on protein structure and function. The pathogenicity of the variation sites was evaluated according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines for the interpretation of sequence variants.
Results:
The proband and affected members exhibited prolonged thrombin time (TT), reduced Fg:C and Fg:Ag levels, and a hypocoagulable thromboelastography profile. Notably, Fg polymerization kinetics remained preserved, consistent with hypofibrinogenemia rather than dysfibrinogenemia. Genetic analysis identified a heterozygous missense variant FGB c.878G>T (p.Gly293Val) segregating with the phenotype. This variant was absent from population databases, located at a highly conserved residue, and predicted to be deleterious by multiple in silico tools. Protein structural modeling indicated local conformational disturbance. The variant was classified as likely pathogenic following the 2015 ACMG/Association for Molecular Pathology (AMP) standard guidelines.
Conclusions:
The FGB p.Gly293Val variant may cause a significant decrease in Fg:C and Fg:Ag by disrupting the structure and function of the Fg protein.
Insights
A rare bleeding disorder, hypofibrinogenemia, was linked to a novel FGB gene variant (p.Gly293Val). This genetic mutation significantly reduces fibrinogen levels and function, impacting coagulation.
Area of Science:
- Hematology
- Genetics
- Molecular Biology
Background:
- Hypofibrinogenemia is a rare bleeding disorder with symptoms including excessive bleeding and impaired wound healing.
- Pathogenic variants in the FGB gene are the most common cause of hypofibrinogenemia.
- This study investigates a family with hypofibrinogenemia to understand its genetic basis and molecular mechanisms.
Purpose of the Study:
- To analyze the clinical phenotypes and genetic variants in a family affected by hypofibrinogenemia.
- To explore the molecular pathogenic mechanisms underlying hypofibrinogenemia.
- To identify and characterize novel genetic variants associated with the disorder.
Main Methods:
- Fibrinogen (Fg) activity (Fg:C) and antigen (Fg:Ag) levels were measured using Clauss and ELISA methods.
- Fg polymerization, thromboelastography, and Sanger sequencing of FGA, FGB, and FGG genes were performed.
- In silico tools and ACMG guidelines were used to assess variant pathogenicity and impact on protein structure.
Main Results:
- Affected individuals showed prolonged thrombin time, reduced Fg:C and Fg:Ag, and hypocoagulable thromboelastography.
- A heterozygous missense variant, FGB c.878G>T (p.Gly293Val), was identified and segregated with the phenotype.
- The FGB p.Gly293Val variant was predicted to be deleterious, located at a conserved residue, and classified as likely pathogenic.
Conclusions:
- The identified FGB p.Gly293Val variant is likely pathogenic and causes hypofibrinogenemia.
- This variant may significantly decrease Fg:C and Fg:Ag by disrupting Fg protein structure and function.
- Understanding the molecular mechanisms is crucial for managing hypofibrinogenemia.
Related Concept Videos
01:16Clot Retraction and Fibrinolysis
01:30Anticoagulant Drugs: Low-Molecular-Weight Heparins
01:20Extrinsic and Intrinsic Pathways of Hemostasis
The Extrinsic Pathway
The extrinsic pathway of coagulation is typically initiated by tissue damage that exposes blood to tissue factor (TF), a protein released by the damaged tissue cells outside the blood vessels—this interaction with TF triggers biochemical reactions involving specific clotting factors. The key player here is Factor VII, which...