Clinical biochemistry · 2025
Novel and known fibrinogen gene mutations in Chinese pediatric patients with congenital dysfibrinogenemia: genetic and functional characterization.
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Huang Juan, Wang Duocai, Wang Ying, Yang Yongqiang, Peng Dong, Luo Meizhu, Fu Xiaoying
Аннотация
OBJECTIVES: Congenital dysfibrinogenemia (CD) is a rare inherited disorder caused by qualitative abnormalities in fibrinogen, leading to discordance between functional and antigenic fibrinogen levels. Genetic testing plays a pivotal role in confirming diagnosis and elucidating phenotypic heterogeneity. This study aims to emphasize the diagnostic value of combining coagulation assays with genetic testing and underscore the clinical heterogeneity of CD through clinical cases of novel mutations.
DESIGN & METHODS: Five pediatric patients with incidentally identified CD were diagnosed at Shenzhen Children's Hospital. Peripheral blood samples were analyzed for coagulation parameters, including fibrinogen activity (FIB:C) by the Clauss method, fibrinogen derived from the prothrombin time (PT-dF), as well as activated partial thromboplastin time （aPTT）, PT, thrombin time (TT), and thromboelastography (TEG). Sanger sequencing was conducted to assess mutations in FGA, FGB, and FGG genes.
RESULTS: Two unrelated patients harbored a known heterozygous mutation in FGG (c.902G > A; p.Arg301His). Two novel heterozygous mutations were identified: FGA (c.113G > A; p.Arg38Lys) and FGG (c.902G > T; p.Arg301Leu). A homozygous mutation in FGB (c.292G > A; p.Ala98Thr) was detected in another patient; this variant has been reported only twice before in the literature. All patients were asymptomatic. Coagulation testing revealed consistently decreased FIB:C with normal PT-dF, characteristic of CD. TEG analysis showed variable alterations in fibrinogen-related parameters, although no consistent genotype-phenotype correlation was observed.
CONCLUSION: This study expands the genetic and phenotypic spectrum of CD in children, reporting two novel mutations and documenting the first pediatric cases of these variants in a Chinese cohort. Given the potential long-term risks and diagnostic complexity in asymptomatic pediatric patients, individualized surveillance and management strategies are warranted. Further research is needed to evaluate the functional consequences of novel mutations and their implications for pediatric hemostasis.
DESIGN & METHODS: Five pediatric patients with incidentally identified CD were diagnosed at Shenzhen Children's Hospital. Peripheral blood samples were analyzed for coagulation parameters, including fibrinogen activity (FIB:C) by the Clauss method, fibrinogen derived from the prothrombin time (PT-dF), as well as activated partial thromboplastin time （aPTT）, PT, thrombin time (TT), and thromboelastography (TEG). Sanger sequencing was conducted to assess mutations in FGA, FGB, and FGG genes.
RESULTS: Two unrelated patients harbored a known heterozygous mutation in FGG (c.902G > A; p.Arg301His). Two novel heterozygous mutations were identified: FGA (c.113G > A; p.Arg38Lys) and FGG (c.902G > T; p.Arg301Leu). A homozygous mutation in FGB (c.292G > A; p.Ala98Thr) was detected in another patient; this variant has been reported only twice before in the literature. All patients were asymptomatic. Coagulation testing revealed consistently decreased FIB:C with normal PT-dF, characteristic of CD. TEG analysis showed variable alterations in fibrinogen-related parameters, although no consistent genotype-phenotype correlation was observed.
CONCLUSION: This study expands the genetic and phenotypic spectrum of CD in children, reporting two novel mutations and documenting the first pediatric cases of these variants in a Chinese cohort. Given the potential long-term risks and diagnostic complexity in asymptomatic pediatric patients, individualized surveillance and management strategies are warranted. Further research is needed to evaluate the functional consequences of novel mutations and their implications for pediatric hemostasis.