Abstract
Background: Congenital fibrinogen deficiency (CFD) is a rare inherited bleeding disorder characterized by reduced fibrinogen levels or activity, resulting from pathogenic variants in FGA, FGB, or FGG genes. Clinical manifestations are highly variable, ranging from asymptomatic presentations to bleeding complications, thrombotic events, or miscarriage. Over half of patients are diagnosed incidentally following identification of prolonged routine coagulation tests such as prothrombin time (PT) and activated partial thromboplastin time (APTT). Recent advances in molecular and genetic technologies have significantly enhanced diagnostic capabilities and informed clinical management strategies for CFD. This study performs genetic analysis in suspected CFD patients and investigate their genotype-phenotype correlations.
Methods: We conducted targeted next-generation sequencing(NGS) of fibrinogen genes (FGA, FGB, FGG) in 41 clinically suspected CFD patients. Detected variants were classified according to ACMG (American College of Medical Genetics and Genomics) guidelines. Relevant laboratory parameters, including fibrinogen level (FIB), thrombin time (TT), PT and APTT were documented. Correlations among clinical manifestations, laboratory findings, and genotypes were analyzed.
Results:
Genetic analysis of 41 probands with suspected CFD identified 41 variants within the fibrinogen genes(FGA/FGB/FGG), comprising 22 distinct mutations. Variant distribution by gene was as follows: FGA (17, 41.5%), FGB (4, 9.8%), and FGG (20, 48.9%). The mutational spectrum included 32 missense, 5 nonsense, 2 frameshift, and 2 splice-site mutations. Recurrent hotspot mutations were identified in FGA Arg35 (14/17 FGA-mutated cases) and FGG Arg301 (8/20 FGG-mutated cases). Ten novel variants were identified, 7 of which were classified as pathogenic or likely pathogenic (P/LP) according to ACMG guidelines. These included 2 FGA variants (p.Arg38Met and p.Trp248Ter) and 5 FGG variants (p.Cys45Ter, p.Val434Serfs32, p.His427Thrfs39, p.Gly392Val and p.Trp395Ter). Additionally, 3 FGG variants (p.Asp181Glu, p.Trp402Leu and c.667-12A>G) were classified as Variants of Uncertain Significance (VUS). Genotype- phenotype analysis revealed that probands harboring the FGA Arg35 or FGG Arg301 hotspot variants exhibited significantly lower fibrinogen levels (p=0.0039), prolonged PT (p=0.005), and TT (p=0.0127) versus with other mutations. Patients with FGA mutations additionally showed reduced fibrinogen levels relative to those with FGG mutations (p=0.0372). No significant difference in age at diagnosis was observed among the different genotype groups.
Conclusion: This study establishes NGS as a rapid, cost-effective and accurate diagnostic tool for CFD while significantly expanding the documented genetic spectrum of FGA, FGB, and FGG mutations. Furthermore, we demonstrate differential phenotypic effects based on the affected gene and variant type, offering critical guidance for clinical management and genetic counseling.
