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

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.