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Congenital afibrinogenemia (MONDO:0008737) is a rare autosomal recessive bleeding disorder resulting from complete loss of functional fibrinogen. The fibrinogen gamma chain gene (FGG) encodes the γ chain of the fibrinogen hexamer and pathogenic variants disrupt assembly or secretion, leading to plasma levels below detection. Early work focused on FGA and FGB, but the first FGG causative variant was reported in 2000, establishing FGG as a definitive disease gene (PMID:11001902). Since then, multiple independent FGG null alleles have been described, consolidating its role in congenital afibrinogenemia.
The inheritance pattern of FGG-related afibrinogenemia is autosomal recessive. Over 20 unrelated probands with biallelic FGG loss-of-function variants have been reported (PMID:11001902, PMID:12695755). Homozygous or compound heterozygous variants include splice-site, nonsense, and frameshift changes that result in premature truncation and absent fibrinogen. Carriers display approximately half-normal fibrinogen levels without bleeding. This AR transmission has been confirmed in diverse consanguineous and non-consanguineous families.
Segregation analysis in multiple pedigrees demonstrates clear cosegregation of FGG pathogenic alleles with disease. In a large consanguineous Turkish kindred, a homozygous 403 bp duplication at the exon 8–intron 8 junction was found in 10 affected individuals, with obligate carrier parents (PMID:34196169). Similar segregation has been observed in Dutch and Pakistani families harboring splice-site and deletion variants (PMID:12695755). These data satisfy strong segregation evidence under ClinGen guidelines.
The variant spectrum in FGG includes at least 40 distinct alleles. The first reported pathogenic change was the intronic c.78+5G>A variant leading to retention of intron 1 and truncation of the γ chain (PMID:11001902). Additional null alleles encompass c.307+5G>A, c.637del, and multiple nonsense and frameshift mutations throughout the gene. No recurrent founder alleles have been noted outside region-specific hotspots. Both small insertions/deletions and point mutations yield truncated γ chains that fail to form mature fibrinogen.
Functional studies confirm loss-of-function as the pathogenic mechanism. In vitro minigene splicing assays for c.78+5G>A demonstrate exclusive retention of intron 1 with premature stop codon generation (PMID:11001902). Transient expression of FGG constructs bearing splice-junction or nonsense mutations in cell lines yields unstable, truncated γ chains and absent secretion (PMID:15284111). Similar assays with exon 8 duplications produce aberrant transcripts and premature truncations (PMID:34196169). These concordant results align with undetectable fibrinogen in patient plasma.
In summary, FGG (HGNC:3694) biallelic loss-of-function variants definitively cause congenital afibrinogenemia (MONDO:0008737) via autosomal recessive inheritance and impaired γ-chain production. The weight of genetic and functional data meets ClinGen criteria for a Definitive gene–disease association. Genetic testing of FGG should be included in diagnostic panels for bleeding diatheses with undetectable fibrinogen. Early molecular diagnosis enables carrier detection, family counseling, and targeted replacement therapy. Key takeaway: FGG loss-of-function variants are clinically validated markers for congenital afibrinogenemia.
Gene–Disease AssociationDefinitiveOver 20 unrelated probands, segregation in multiple consanguineous pedigrees, concordant functional data Genetic EvidenceStrong20 probands with biallelic FGG null variants and segregation in ≥3 families ([PMID:11001902], [PMID:12695755]) Functional EvidenceModerateIn vitro splicing and expression assays demonstrate aberrant mRNA and truncated γ chains leading to loss of secretion ([PMID:11001902], [PMID:15284111]) |