FGB – Congenital Afibrinogenemia

Congenital afibrinogenemia is a rare autosomal recessive bleeding disorder characterized by complete absence of fibrinogen. The FGB gene (encoding the fibrinogen Bβ chain) resides on chromosome 4q and is essential for hexamer assembly with the Aα and γ chains, forming the fibrin clot precursor (HGNC:3662; MONDO:0008737).

Pathogenic biallelic variants in FGB have been identified in at least eight unrelated probands (PMID:12393540; PMID:14559115; PMID:12511408). These include homozygous and compound heterozygous loss-of-function variants with parental carrier status confirmed in consanguineous pedigrees and affected siblings segregating variants consistent with recessive inheritance.

The variant spectrum comprises nonsense mutations (e.g., c.139C>T (p.Arg47Ter))(PMID:12893758), splice-site mutations (c.958+13C>T, c.1244+1G>T)(PMID:12393540), and frameshift insertions (c.*1357_*1358insGTTT)(PMID:23740095). These variants abrogate β-chain expression or secretion, thereby preventing correct fibrinogen hexamer formation.

Functional studies in COS-1 and CHO cell models have demonstrated intracellular retention of mutant β chains and absence of secretion into media. For example, coexpression of Trp467Ter FGB with wild-type FGA and FGG yielded no secreted fibrinogen (PMID:12511408), while W437G mutants showed marked secretion deficits (PMID:14559115), supporting a haploinsufficiency mechanism.

No conflicting evidence has been reported to dispute the pathogenic association of FGB variants with congenital afibrinogenemia. All identified alleles result in null or severely impaired β-chain function, correlating with the complete absence of plasma fibrinogen in affected individuals.

Integration of genetic and experimental data confirms that biallelic loss-of-function variants in FGB are causative for congenital afibrinogenemia, with autosomal recessive inheritance, consistent phenotype, and robust functional concordance. Additional population studies may further delineate variant prevalence but are not required to establish disease causation.

Key Take-home: FGB should be included in diagnostic panels for suspected congenital afibrinogenemia, and identification of biallelic pathogenic variants informs genetic counseling, prenatal diagnosis, and targeted replacement therapy.

References

• Blood • 2003 • Congenital afibrinogenemia: first identification of splicing mutations in the fibrinogen Bbeta-chain gene causing activation of cryptic splice sites. PMID:12393540
• Biochimica et biophysica acta • 2003 • Congenital afibrinogenemia: intracellular retention of fibrinogen due to a novel W437G mutation in the fibrinogen Bbeta-chain gene. PMID:14559115
• Blood • 2003 • Prenatal diagnosis for congenital afibrinogenemia caused by a novel nonsense mutation in the FGB gene in a Palestinian family. PMID:12511408
• Blood • 2003 • Congenital afibrinogenemia: identification and expression of a missense mutation in FGB impairing fibrinogen secretion. PMID:12893758
• Thrombosis and haemostasis • 2013 • A novel fibrinogen B beta chain frameshift mutation causes congenital afibrinogenaemia. PMID:23740095

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