FGA – Familial Dysfibrinogenemia

Familial dysfibrinogenemia is an autosomal dominant disorder of fibrinogen function caused by heterozygous variants in the FGA gene, encoding the Aα chain of fibrinogen (FGA; familial dysfibrinogenemia). Affected individuals present with discordant functional and antigenic fibrinogen levels and variable thrombotic or bleeding manifestations.

Several unrelated pedigrees (≥6) harbor distinct heterozygous FGA variants that co-segregate with disease in an autosomal dominant manner, with at least 12 probands and 7 additional affected relatives identified. In a Chinese family, the c.103C>A (p.Arg35Ser) variant segregated in three siblings with anemia, hypofibrinogenemia and pulmonary embolism (PMID:29067075), and in a Scandinavian pedigree, Fibrinogen Paris V was detected in five relatives, four of whom experienced cerebral venous thrombosis (PMID:24000886). These data support a strong gene–disease association.

The variant spectrum is dominated by heterozygous missense changes clustered in exon 2 of FGA, with more than 20 unique amino acid substitutions reported, alongside occasional nonsense and frameshift mutations causing truncated Aα chains (PMID:29122299). No clear founder variants have been established, and carrier frequencies are low.

Functional studies show prolonged thrombin and reptilase times, reduced fibrin polymerization with prolonged lag phase and decreased final turbidity, and abnormal fibrin fiber architecture in patient plasma. Recombinant minigene and expression assays of truncating and missense Aα variants demonstrate impaired knob ‘A’ exposure and delayed fibrinopeptide A release, confirming a dominant-negative mechanism disrupting protofibril assembly (PMID:27555433; PMID:20806111).

No studies have refuted the link between FGA heterozygous variants and familial dysfibrinogenemia. Observations are consistent across multiple laboratories and patient populations.

Integration of genetic and experimental evidence yields a strong clinical validity. Genetic testing for FGA variants is recommended in individuals with functional/antigenic fibrinogen discordance to guide management and thromboprophylaxis.

Key Take-home: Heterozygous FGA variants cause autosomal dominant dysfibrinogenemia with thrombotic and hemorrhagic risks, warranting targeted genetic and functional evaluation for personalized care.

References

• Scandinavian journal of clinical and laboratory investigation • 2013 • Dusart Syndrome in a Scandinavian family characterized by arterial and venous thrombosis at young age. PMID:24000886
• Pakistan journal of medical sciences • 2017 • A Chinese family with congenital Dysfibrinogenemia carries a heterozygous missense mutation in FGA: Concerning the genetic abnormality and clinical treatment. PMID:29067075
• Thrombosis research • 2018 • Heterozygous FGA p.Asp473Ter (fibrinogen Nieuwegein) presenting as antepartum cerebral thrombosis. PMID:29122299
• Journal of clinical pathology • 2017 • Dysfibrinogenemia-associated novel heterozygous mutation, Shanghai (FGA c.169_180+2 del), leads to N-terminal truncation of fibrinogen Aα chain and impairs fibrin polymerization PMID:27555433
• Thrombosis and haemostasis • 2010 • Hypodysfibrinogenaemia due to production of mutant fibrinogen alpha-chains lacking fibrinopeptide A and polymerisation knob 'A'. PMID:20806111

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