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Congenital afibrinogenemia is a rare autosomal recessive bleeding disorder characterized by complete absence of circulating fibrinogen. FGA encodes the fibrinogen Aα-chain, which assembles with Bβ (FGB) and γ (FGG) chains to form the soluble fibrinogen hexamer. Loss-of-function variants in FGA lead to absent fibrinogen and severe bleeding diathesis. The disease is cataloged as Congenital afibrinogenemia, and FGA is registered as FGA.
Initial genetic evidence arose from a non-consanguineous Swiss kindred with homozygous ~11 kb deletions of FGA in 4 affected males (two brothers and two first cousins) segregating in an autosomal recessive manner (PMID:9916133). A follow-up cohort study of 13 additional unrelated patients identified truncating FGA mutations in 14 of 26 alleles, including the recurrent splice donor variant IVS4+1G>T (c.510+1G>T) (PMID:10891444). Individual case reports have documented homozygous truncating mutations such as c.448C>T (p.Gln150Ter) in a Chinese family (PMID:15795544) and c.1846del (p.Thr616HisfsTer32) in a consanguineous Syrian pedigree (PMID:21245743). To date, over 40 distinct FGA variants—including nonsense, frameshift, splice-site, and initiation codon mutations—have been reported worldwide, with recurrent alleles observed in European and Middle Eastern populations and others being private.
Segregation analyses corroborate autosomal recessive inheritance. In the Swiss kindred, all 4 affected relatives carried biallelic FGA deletions, while heterozygous carriers were asymptomatic (PMID:9916133). In the Chinese family, disease status correlated perfectly with homozygosity for c.448C>T, and heterozygotes showed normal fibrinogen levels (PMID:15795544). The Syrian kindred also demonstrated genotype–phenotype concordance among 12 individuals, reinforcing loss-of-function as the mechanism (PMID:21245743).
Functional assays confirm that FGA null variants impair fibrinogen synthesis and secretion. Minigene splicing studies of IVS4+1G>T revealed activation of cryptic donor sites leading to frameshifts and premature truncation, abolishing Aα-chain secretion (PMID:11238133). Lentiviral transduction of FGA-deficient hepatocytes restored Aα-chain expression and functional fibrinogen secretion in vitro, demonstrating proof-of-principle for gene therapy approaches (PMID:25163824). These experiments underscore a loss-of-function mechanism underpinning congenital afibrinogenemia.
No significant conflicting evidence has been reported; all pathogenic FGA variants result in absent fibrinogen and bleeding. There is no evidence of disease in heterozygotes, and no alternative phenotypes have been convincingly ascribed to FGA biallelic variants.
In conclusion, autosomal recessive FGA loss-of-function variants cause congenital afibrinogenemia through impaired fibrinogen assembly and secretion. Genetic and functional data across multiple families meet ClinGen criteria for a definitive gene–disease association. FGA sequencing is essential in the diagnostic evaluation of patients with undetectable fibrinogen levels, enabling accurate genetic counseling and prenatal diagnosis.
Gene–Disease AssociationDefinitive17 probands (4 in Swiss kindred [PMID:9916133], 13 additional unrelated [PMID:10891444]), segregation in multiple families, and concordant functional data Genetic EvidenceStrongBiallelic FGA variants in 17 probands across multiple populations; reached genetic evidence cap Functional EvidenceModerateIn vitro splicing and secretion assays demonstrate loss-of-function; hepatocyte rescue experiments confirm phenotype |