Coexisting congenital dysfibrinogenemia with a novel mutation in fibrinogen γ chain (γ322 Phe→Ile, Fibrinogen Beijing) and haemophilia B in a family

Abstract

Both congenital dysfibrinogenemia and haemophilia B (HB) are rare coagulopathies caused by mutations within the fibrinogen and F9 genes respectively. To investigate the pathogenesis of combined dysfibrinogenemia with HB in a family. Coagulation assays, factor IX (FIX) activity (one-stage method), fibrinogen activity (Clauss method), antigen (immunoturbidimetry), fibrinogen polymerization and fibrinolysis velocity were measured. The sequences of fibrinogen genes and F9 were amplified by PCR and analysed by sequencing. The proband, a 16-year-old boy with HB (FIX 2IUdL(-1) ), also had persistently low Clauss fibrinogen level (0.64-0.65gL(-1) ) with normal antigen level (2.23gL(-1) ). The mother had a FIX 45IUdL(-1) and similarly discrepant low Clauss fibrinogen (0.79gL(-1) ) to antigen levels (2.23gL(-1) ). Thrombin time for both were either slightly prolonged or at boundary value. Genetic analysis of the proband and the mother identified similar mutations in the FGG gene (heterozygous c.1042T>A resulting in p.Phe348Ile or γPhe322Ile in the mature protein) and in the F9 gene (c.1243del p.His415Metfs*11 and c.1245T>A p.His415Gln). The father had no fibrinogen or F9 gene mutations. Plasma fibrinogen polymerization was delayed, but fibrinolysis velocity was normal in the proband and his mother. To our knowledge, this is the first report of a family with combined novel dysfibrinogen (Fibrinogen Beijing) and HB with bleeding manifestations.