A novel Mutation p.Thr308Asn in the Snout-like Region of the Fibrinogen Bβ Chain: Analysis of the Pathogenic Mechanism of Hereditary Hypofibrinogenemia.

ABSTRACT:

BACKGROUND

Fibrinogen, encoded by FGA, FGB, and FGG, is essential for blood coagulation. Mutations in these genes cause congenital fibrinogen disorders, leading to bleeding and thrombotic complications. The Bβ chain is the rate-limiting component in fibrinogen production, and its C-terminal region is essential for assembly and secretion. However, the pathogenic mechanism of missense mutations in the FGB gene remains to be fully elucidated.

ABSTRACT:

OBJECTIVE

This study aimed to analyze the genotype and phenotype of a pedigree with hereditary hypofibrinogenemia and to preliminarily elucidate the potential pathogenic mechanism.

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METHODS

Fibrinogen levels were measured using the Clauss and PT-derived methods. DNA sequence analysis was performed to identify the mutation. Conservation and protein structural modeling analyses were performed using online bioinformatics tools. The pathogenicity of the variant was assessed according to the ACMG/AMP guidelines.

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RESULTS

The fibrinogen level of the proband was 0.74 g/L. Thromboelastography (TEG) showed that the proband's clot kinetics time (K time) was 4.4 min (prolonged), thrombus generation angle (α angle) was 42.6° (decreased), and clotting index (CI) was -4.8 (decreased). Genetic analysis revealed a heterozygous c.923C > A (p.Thr308Asn) mutation in FGB gene. Bioinformatics and modeling analysis suggested that the missense mutation may have a deleterious effect on fibrinogen. The variant was classified as likely pathogenic based on the ACMG/AMP guidelines.

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CONCLUSION

The c.923C > A(p.Thr308Asn) mutation in exon 6 of the FGB gene may be responsible for the reduced fibrinogen level observed in this pedigree. To our knowledge, this point mutation is reported for the first time.