Study Of Clinical And Molecular Pathogenesis In Two Patients With Congenital Dysfibrinogenemia

Objective:To analyze the clinical manifestation and laboratory tests of two probands with dysfibrinogenemia who were found from laboratory examination.After the two probands were suspected as congenital dysfibrinogenemia(CD),all exons and exon-intron boundaries of the three fibrinogene genes were analyzed by DNA sequencing to investigate their molecular mechanism,then conducting gengtic diagnosis.Methods:The clinical feature and laboratory tests of two patients with dysfibrinogenemia were analyzed.To exclude inherited hypofibrinogengmia identify and acquired dysfibrinogenemia,the activity and antigen plasma fibrinogen(Fg:C,Fg:Ag)were analyzed by Clauss method and scattering nephelometry method,respectively.All the exons and exon-intro boundaries of the three genes FGA,FGB,FGG were analyzed to identify the genetic mutations.Result:The proband A was A young female,who was about to undergo cesarean section in the obstetrics department of the Second Hospital of Hebei Medical University due to the second term pregnancy.Routine blood coagulation examination showed that the fibrinogen was 1.99g/L(Clauss method,namely Fg:C determination),the thrombin time(TT)was 14.7s,and further examination showed that Fg:Ag was 4.11g/L,and Fg:Ag/Fg:C>2.Prothrombin time(PT),activated partial thrombin time(APTT)and fibrinolytic indexes(D-dimer and fibrin(ogen)degradation products)are in the normal range.Thus,dysfibrinogenemia was clinically diagnosed.There was no previous history of obvious bleeding or spontaneous abortion.The results of gene sequencing indicated that the proband had heterozygous missense mutation at 1433 site of G>A in exon 8 of FGB gene,which resulted in the substitution of arginine at 478 site by lysine(Arg478Lys)of β chain of Fg,resulting in abnormal protein synthesis and thereby affecting the function of fibrinogen.Proband B,also a young woman,was admitted to the fourth hospital of Shijiazhuang due to habitual abortion.The coagulation routine showed that the fibrinogen was 0.52g/L(Clauss method,namely Fg:C determination),TT was 24.2s.Further examination showed that Fg:Ag was 3.55g/L,and Fg:Ag/ Fg:C>2.The PT,APTT and fibrinolysis index(D-dimer and fibrin(ogen)degradation product)were in the normal range.She had a history of two spontaneous abortions with not much bleeding.The results of gene sequencing suggested thata heterozygous G>A change at nucleotide 104 in the exon 2 of FGA gene in the propisituses B,predicting a heterozygous Arg35 His of αchain of Fg,causing abnormal protein synthesis and also affecting the function of fibrinogen.Conclusion:CD in the proband A was caused by heterozygous Arg478 Lys mutation in the β chain of Fg,while in the proband B,CD was caused by heterozygous Arg35 His mutation in the α chain of Fg.