FGA – Congenital Fibrinogen Deficiency

Congenital fibrinogen deficiency is a rare autosomal recessive bleeding disorder characterized by quantitative defects of the fibrinogen hexamer. The FGA gene encodes the Aα-chain of fibrinogen, and biallelic loss‐of‐function or missense mutations lead to absent or reduced circulating fibrinogen levels, prolonged clotting times and bleeding diathesis.

Genetic studies across multiple cohorts have identified over 200 unrelated affected individuals with FGA mutations: 27 probands from India ([PMID:23560673]) and 166 cases in the PRO-RBDD multicenter database ([PMID:38286442]). Inheritance is autosomal recessive, often in consanguineous families, with no clear gender bias. Variants span frameshifts (≈52%), splice‐site (≈22%), missense (≈19%) and nonsense (≈7%) classes, including recurrent intronic hotspots c.364+2T>G (n=6) and p.Lys185fsTer13 in FGG (n=7) ([PMID:23560673]).

Segregation analysis in multiplex families supports complete cosegregation of biallelic FGA variants with disease, though specific counts of additional affected relatives are not uniformly reported. In the PRO-RBDD cohort, genetic data were available for 91 cases, revealing 41 distinct FGA alleles and reaching the ClinGen genetic evidence cap ([PMID:38286442]).

Functional assessment of the common splice donor mutation IVS4+1G>T demonstrates activation of cryptic splice sites, resulting in null transcripts and loss of Aα‐chain expression in COS‐7 models ([PMID:11238133]). Expression of c.1215del (p.Asn406ThrfsTer15) showed severely reduced fibrinogen assembly and secretion, confirming haploinsufficiency as the mechanism of pathogenicity ([PMID:17531448]). Rescue experiments with wild‐type constructs restore normal fibrin polymerization rates.

No studies have convincingly refuted the FGA–congenital fibrinogen deficiency association. The evidence meets criteria for a definitive ClinGen gene–disease relationship, with robust genetic and experimental concordance over two decades.

Key Take-home: Biallelic FGA mutations cause autosomal recessive congenital fibrinogen deficiency, identifiable by genetic testing and amenable to replacement therapy.

References

• Haemophilia • 2013 • Molecular basis of quantitative fibrinogen disorders in 27 patients from India. PMID:23560673
• Blood advances • 2024 • Congenital fibrinogen disorders: a retrospective clinical and genetic analysis of the Prospective Rare Bleeding Disorders Database. PMID:38286442
• Blood • 2001 • Activation of multiple cryptic donor splice sites by the common congenital afibrinogenemia mutation, FGA IVS4 + 1 G-->T. PMID:11238133
• Biochimica et biophysica acta • 2007 • Molecular characterization of the first missense mutation in the fibrinogen Aalpha-chain gene identified in a compound heterozygous afibrinogenemic patient. PMID:17531448

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