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Congenital fibrinogen deficiency (CFD) is an autosomal recessive bleeding disorder with a prevalence of approximately 1:1 000 000, caused by defects in the fibrinogen Aα (FGA), Bβ (FGB), and γ (FGG) chain genes. The FGG–encoded γ‐chain is critical for hexamer assembly and fibrin polymerization, and pathogenic variants lead to quantitative deficiencies of circulating fibrinogen (PMID:23560673).
In a cohort of 27 unrelated Indian patients with prolonged clotting times and low fibrinogen levels, screening of FGA, FGB, and FGG identified 14 distinct mutations: frameshifts (51.9%), splice-site (22.2%), missense (18.5%), and nonsense (7.4%) variants. Seven FGG frameshifts—including p.Ser81fs*5, p.Lys185fs*13, and p.Asp278_279fs*17—were novel and collectively accounted for quantitative deficiency in seven individuals (PMID:23560673).
The Prospective Rare Bleeding Disorders Database (PRO-RBDD) captured 166 CFD cases across 16 countries, with genetic analysis in 91 patients revealing 41 distinct FGA, FGB, and FGG variants. Within dysfibrinogenemia, hotspot FGG variants p.Arg301Cys and p.Arg301His together comprised 51% of alleles. Obstetric complications, including miscarriage, were prevalent in dysfibrinogenemic women (PMID:38286442).
Segregation analysis of a Chinese pedigree with a novel FGG IVS9+1delG splice-donor mutation showed co-segregation in three additional female relatives (mother, sister, daughter), all exhibiting decreased fibrinogen activity but normal antigen levels (PMID:25551304). A separate intron 1 +5G>A mutation in a Pakistani family demonstrated homozygosity, aberrant mRNA splicing, and absence of secreted γ-chain in expression assays (PMID:11001902).
The spectrum of FGG variation in quantitative CFD includes recurrent and founder alleles. In the Indian cohort, p.Lys185fs*13 was observed in seven probands, suggesting targeted screening in this population. PRO-RBDD further documented 41 variants across phenotypes, with biallelic loss-of-function and hypomorphic alleles contributing to disease severity.
Functional studies of FGG mutations confirm a loss-of-function mechanism. The γ337Asn→Lys substitution impairs monomer polymerization in vitro (PMID:8400260). Splicing mutations (c.78+5G>A) lead to retention of intron 1 and premature termination, as shown in HeLa cell assays (PMID:11001902). Frameshift variants such as c.147del (p.Cys49Trpfs*14) undergo nonsense-mediated mRNA decay, resulting in marked reduction of γ-chain synthesis in CHO cells (PMID:24011387).
Integration of genetic and experimental data establishes a Strong gene–disease association between FGG and congenital fibrinogen deficiency, with autosomal recessive inheritance, robust segregation in families, and concordant in vitro functional assays. This evidence supports molecular diagnosis and guides targeted genetic screening, particularly in populations with recurrent founder mutations.
Key Take-home: FGG loss-of-function variants cause autosomal recessive congenital fibrinogen deficiency; genetic testing of FGG should be prioritized in AR bleeding phenotypes to inform diagnosis and management.
Gene–Disease AssociationStrongOver 100 unrelated probands including 27 in Indian series (PMID:23560673) and 91 in PRO-RBDD cohort (PMID:38286442), concordant functional data Genetic EvidenceStrong118 probands with biallelic or heterozygous FGG variants across multiple cohorts, AR inheritance, segregation in families Functional EvidenceModerateIn vitro studies demonstrate loss of γ-chain function via defective polymerization, aberrant splicing, and NMD |