Genetic Characterization of Congenital Fibrinogen Disorders: A Retrospective Analysis of 102 Unrelated Patients in China

Abstract

Congenital fibrinogen disorders (CFDs) result from deficiencies in the fibrinogen-encoding genes FGA, FGB, and FGG, causing either quantitative or qualitative fibrinogen abnormalities. In this study, we conducted an extensive evaluation on clinical, laboratory, and genetic characteristics of 102 CFD patients. Fibrinogen levels were determined by Clauss method and/or prothrombin time (PT)-derived method. Routine coagulation parameters including PT, activated partial thromboplastin time (APTT), and thrombin time (TT) were also assessed. Genetic mutations were detected through either next-generation sequencing or comprehensive whole-exome sequencing. The case series comprised 38 males and 64 females, with a median diagnosis age of 33 years. In patients where laboratory results were available, the function fibrinogen levels tested by Clauss method were decreased, whereas only 51.7% exhibited reduced fibrinogen concentrations by PT-derived method. A total of 55 germline mutations were identified, including 26 novel mutations not previously documented in the literature. Forty-two percent of unrelated patients were carriers of hotspot mutations. The laboratory results and clinical symptoms were highly variable among patients, even within patients harboring the same mutation. However, TT was significantly prolonged in qualitative CFDs compared with quantitative CFDs. All the patients harboring the hotspot mutations showed qualitative deficiency of fibrinogen. We also demonstrated that qualitative CFDs were particularly prone to harboring missense variants, whereas nearly all the null mutations were classified into the quantitative group. This study presents a genetic landscape of CFD patients, and their gene–phenotype relationships. The novel identified genetic variants expand the known genetic spectrum of CFDs.

Keywords

congenital fibrinogen disorders - fibrinogen - coagulation - genetic mutation

Data Availability Statement

The deidentified data will be made available on request to the corresponding author. A data sharing agreement will require a commitment to using the data only for specified research purposes, to securing the data appropriately, and to destroying the data after a nominated period.

Ethical Approval

This study was approved by the Institutional Review Committee of the Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Informed Consent

Informed consent was obtained from individuals included in this study.

^‡ These authors contributed equally to this article.

Publication History

Received: 30 July 2025

Accepted: 21 October 2025

Article published online:
26 November 2025

• References

• 1 Casini A, Moerloose P, Neerman-Arbez M. One hundred years of congenital fibrinogen disorders. Semin Thromb Hemost 2022; 48 (08) 880-888
• 2 Casini A, Moerloose P, Neerman-Arbez M. Clinical, laboratory, and molecular aspects of congenital fibrinogen disorders. Semin Thromb Hemost 2025; 51 (02) 103-110
• 3 Dobson DA, Fish RJ, de Vries PS, Morrison AC, Neerman-Arbez M, Wolberg AS. Regulation of fibrinogen synthesis. Thromb Res 2024; 242: 109134
• 4 Wolberg AS. Fibrinogen and fibrin: synthesis, structure, and function in health and disease. J Thromb Haemost 2023; 21 (11) 3005-3015
• 5 Mohsenian S, Palla R, Menegatti M. et al. Congenital fibrinogen disorders: a retrospective clinical and genetic analysis of the prospective rare bleeding disorders database. Blood Adv 2024; 8 (06) 1392-1404
• 6 Casini A, Undas A, Palla R, Thachil J, de Moerloose P. Subcommittee on Factor XIII and Fibrinogen. Diagnosis and classification of congenital fibrinogen disorders: communication from the SSC of the ISTH. J Thromb Haemost 2018; 16 (09) 1887-1890
• 7 Verhovsek M, Moffat KA, Hayward CP. Laboratory testing for fibrinogen abnormalities. Am J Hematol 2008; 83 (12) 928-931
• 8 Landrum MJ, Lee JM, Benson M. et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res 2018; 46 (D1): D1062-D1067
• 9 Neerman-Arbez M, de Moerloose P, Casini A. Laboratory and genetic investigation of mutations accounting for congenital fibrinogen disorders. Semin Thromb Hemost 2016; 42 (04) 356-365
• 10 Li Y, Ding B, Wang X, Ding Q. Congenital (hypo-)dysfibrinogenemia and bleeding: a systematic literature review. Thromb Res 2022; 217: 36-47
• 11 Rodeghiero F, Tosetto A, Abshire T. et al; ISTH/SSC joint VWF and Perinatal/Pediatric Hemostasis Subcommittees Working Group. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost 2010; 8 (09) 2063-2065
• 12 Luo M, Xiang L, Yan J. et al. Fibrinogen Clauss and prothrombin time derived method ratio can differentiate dysfibrinogenemia from hypofibrinogenemia and hyperfibrinogenemia. Thromb Res 2020; 194: 197-199
• 13 Ioannidis NM, Rothstein JH, Pejaver V. et al. REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet 2016; 99 (04) 877-885
• 14 Jaganathan K, Kyriazopoulou Panagiotopoulou S, McRae JF. et al. Predicting splicing from primary sequence with deep learning. Cell 2019; 176 (03) 535-548.e24
• 15 Pejaver V, Byrne AB, Feng BJ. et al; ClinGen Sequence Variant Interpretation Working Group. Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for PP3/BP4 criteria. Am J Hum Genet 2022; 109 (12) 2163-2177
• 16 Richards S, Aziz N, Bale S. et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424
• 17 Biesecker LG, Byrne AB, Harrison SM. et al; ClinGen Sequence Variant Interpretation Working Group. ClinGen guidance for use of the PP1/BS4 co-segregation and PP4 phenotype specificity criteria for sequence variant pathogenicity classification. Am J Hum Genet 2024; 111 (01) 24-38
• 18 Casini A, Blondon M, Lebreton A. et al. Natural history of patients with congenital dysfibrinogenemia. Blood 2015; 125 (03) 553-561
• 19 Winter WE, Flax SD, Harris NS. Coagulation testing in the core laboratory. Lab Med 2017; 48 (04) 295-313
• 20 van den Besselaar AMHP, van Rijn CJJ, Cobbaert CM. et al. Fibrinogen determination according to Clauss: commutability assessment of International and commercial standards and quality control samples. Clin Chem Lab Med 2017; 55 (11) 1761-1769
• 21 Mackie I, Casini A, Pieters M, Pruthi R, Reilly-Stitt C, Suzuki A. International Council for Standardisation in Haematology recommendations on fibrinogen assays, thrombin clotting time and related tests in the investigation of bleeding disorders. Int J Lab Hematol 2024; 46 (01) 20-32
• 22 Xiang L, Luo M, Yan J. et al. Combined use of Clauss and prothrombin time-derived methods for determining fibrinogen concentrations: screening for congenital dysfibrinogenemia. J Clin Lab Anal 2018; 32 (04) e22322
• 23 Miesbach W, Schenk J, Alesci S, Lindhoff-Last E. Comparison of the fibrinogen Clauss assay and the fibrinogen PT derived method in patients with dysfibrinogenemia. Thromb Res 2010; 126 (06) e428-e433
• 24 Krammer B, Anders O, Nagel HR, Burstein C, Steiner M. Screening of dysfibrinogenaemia using the fibrinogen function versus antigen concentration ratio. Thromb Res 1994; 76 (06) 577-579
• 25 Flood VH, Nagaswami C, Chernysh IN, Al-Mondhiry HA, Weisel JW, Farrell DH. Incorporation of fibrin molecules containing fibrinopeptide A alters clot ultrastructure and decreases permeability. Br J Haematol 2007; 138 (01) 117-124
• 26 Ramanan R, McFadyen JD, Perkins AC, Tran HA. Congenital fibrinogen disorders: strengthening genotype-phenotype correlations through novel genetic diagnostic tools. Br J Haematol 2023; 203 (03) 355-368
• 27 Li Y, Meng Z, Qing W, Yi P. Pathogenic mechanisms in congenital afibrinogenemia: a systematic review of genetic variants. Haemophilia 2025; 31 (03) 353-364
• 28 Cai Y, Lu H, Lin W. et al. Clinical and genetic characterization of 51 patients with congenital fibrinogen disorders from China. Thromb Haemost 2025; 125 (10) 972-984
• 29 Wan Y, Li T, Zhang W. et al. Mutations in inherited fibrinogen disorders correlated with clinical features in the Chinese population. J Thromb Thrombolysis 2021; 51 (04) 1127-1131
• 30 Wypasek E, Klukowska A, Zdziarska J. et al. Genetic and clinical characterization of congenital fibrinogen disorders in Polish patients: identification of three novel fibrinogen gamma chain mutations. Thromb Res 2019; 182: 133-140
• 31 Shen MC, Wang JD, Tsai W. et al. Clinical features and genetic defect in six index patients with congenital fibrinogen disorders: three novel mutations with one common mutation in Taiwan's population. Haemophilia 2021; 27 (06) 1022-1027
• 32 Casini A, Blondon M, Tintillier V. et al. Mutational epidemiology of congenital fibrinogen disorders. Thromb Haemost 2018; 118 (11) 1867-1874
• 33 Côté HC, Lord ST, Pratt KP. Gamma-chain dysfibrinogenemias: molecular structure-function relationships of naturally occurring mutations in the gamma chain of human fibrinogen. Blood 1998; 92 (07) 2195-2212
• 34 Casini A, Neerman-Arbez M, Ariëns RA, de Moerloose P. Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management. J Thromb Haemost 2015; 13 (06) 909-919