Genetic analysis of two Chinese pedigrees affected with Hereditary hypofibrinemia due to missense variants / 中华医学遗传学杂志

OBJECTIVE@#To retrospectively analyze the clinical phenotypes and genetic variants in two Chinese pedigrees affected with Hereditary hypofibrinemia (IFD) and explore their molecular pathogenesis.@*METHODS@#Two probands and their pedigree members were admitted to the First Affiliated Hospital of Wenzhou Medical University on March 30, 2021 and May 27, 2021, respectively. Clinical phenotypes of the probands were collected, and blood clotting indexes of the probands and their pedigree members were determined. Variants of the FGA, FGB and FGG genes were analyzed by Sanger sequencing, and candidate variants were verified by sequence comparison. Bioinformatic software was used to analyze the conservation of the amino acids and pathogenicity of the proteins. Alteration in protein structure and intermolecular force before and after the variant was analyzed by simulating the protein model.@*RESULTS@#Proband 1, a 18-year-old male, had significantly low plasma fibrinogen activity (Fg:C) and plasma fibrinogen antigen (Fg:Ag), respectively at 0.80 g/L and 1.00 g/L. Proband 2, a 43-year-old male, had slightly low Fg:C and Fg:Ag at 1.35 g/L and 1.30 g/L, respectively. The Fg:C and Fg:Ag of proband 1's father, proband 2's father and son were also below the normal level. Genetic testing showed that proband 1 had harbored a heterozygous missense variant of c.688T>G (p.Phe230Val) in exon 7 of the FGG gene, which was inherited from his father. Proband 2, his father and son all had harbored a heterozygous variant of c.2516A>C (p.Asn839Thr) in exon 6 of the FGA gene. Homology analysis showed that the Phe230 and Asn839 residues were highly conserved among homologous species. Bioinformatic analysis predicted that both p.Phe230Val and p.Asn839Thr were pathogenic variants.@*CONCLUSION@#Analysis of protein simulation model showed that the p.Asn839Thr variant has changed the hydrogen bo`nd between the amino acids, thus affecting the stability of the protein structure. The heterozygous missense variants of p.Phe230Val and p.Asn839Thr probably underlay the IFD in the two pedigrees.

Congenital Fibrinogen Deficiency Caused by Novel FGG Gene Mutation / 中国实验血液学杂志

OBJECTIVE@#To detect and analyze coagulation related indexes and genotypes of a patient with congenital fibrinogen deficiency and his family members, and to investigate the possible molecular pathogenesis.@*METHODS@#Four peripheral blood samples (proband and 3 family members) were collected and the prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (Fg), D-Dimer and eight coagulation factor indicators were detected. All exons and flanking sequences of the FGA, FGB, and FGG genes encoding the three peptide chains of fibrinogen were sequenced and analyzed by bioinformatics.@*RESULTS@#Among the eight coagulation factors of the proband and the elder sister, F Ⅴ and F Ⅷ were slightly higher, TT was significantly prolonged, and Fg was significantly reduced. Sequencing results showed that c.901C>T heterozygous mutation existed in the FGG gene. Bioinformatics analysis showed that the mutation changed the original protein structure and reduced the number of hydrogen bonds.@*CONCLUSION@#The fibrinogen gamma chain c.901C>T heterozygous mutation is the main cause of congenital fibrinogen deficiency in this family. This mutation is reported for the first time at home and abroad.

A case of inherited afibrinogenemia caused by an IVS7-12A>G splice mutation of FGG gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a Chinese pedigree affected with inherited afibrinogenemia.@*METHODS@#For the proband and his family members, prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), Fibrin(ogen) degradation products (FDPs), D-dimer (D-D), plasminogen activity (PLG:A) and the TT mixed experiment with protamine sulfate were determined with a STAGO-R automatic coagulation analyzer. The activity and antigen of fibrinogen (Fg) in plasma were measured with the Clauss method and immunonephelometry method, respectively. All exons and flanking regions of the fibrinogen genes (FGA, FGB and FGG) were amplified by PCR and directly sequenced. Human Splicing Finder software was used to predict and score the change of splicing site caused by the mutation.@*RESULTS@#The proband showed normal FDPs and D-D but significantly prolonged TT, PT and APTT. The activity and antigen of fibrinogen in plasma were significantly decreased (G (g.4147A>G) mutations of the FGG gene, for which his parents and young sister were heterozygous. As predicted by Human Splicing Finder and Mutation Taster software, the variant may generate a new splicing site which can extend the sequence of exon 7 by 11 bp, with alteration of the coding sequence. PROVEAN suggested the variant to be deleterious.@*CONCLUSION@#The afibrinogenemia of the proband may be attributed to the FGG IVS7-12A>G variant, which was unreported previously.

Afibrinogenemia Congénita. Reporte de un Caso

La afibrinogenemia congénita, descrita en 1920, es un raro transtorno hemorrágico de carácter autosómico recesivo. Estos pacientes a pesar de tener una sangre totalmente incouguable, no suelen presentar graves hemorragias o hemertrosis espontaneas, pero los traumatismos o las intervenciones quirurgicas pueden ir seguidas de graves hmorragias. En el siguiente articulo se presenta el caso de una paciente de 2 meses de edad que se hospitalizo en el servicio de pediatria del Hospital de la Victoria en Santafé de Bogotá (Colombia) y que cumplio con los criterios clinicos y paraclinicos para dicha entidad

Congenital afibrinogenaemia.

A case of congenital afibrinogenaemia in a young female child is described. She had haemorrhagic tendency since birth in the form of markedly prolonged umbilical bleeding and easy bruising afterwards. Two of her brothers had bleeding tendencies, one died shortly after birth due to uncontrollable umbilical bleeding and other died at the age of 12 years from internal haemorrhage. The family study indicates the mode of inheritance to be probably autosomal recessive. The principal laboratory findings are complete non-coagulability of blood, grossly abnormal coagulation tests, zero ESR value, failure to detect fibrinogen by heat coagulation or chemical precipitation tests and biuret reaction and correction of thrombin time after fibrinogen infusion.