Identification and Pathogenicity Analysis of a Novel Fibrinogen Bβ Chain p.Gly293Val Variant Causing...

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.