title: Exome Sequencing and Clot Lysis Experiments Demonstrate the R458C Mutation of the Alpha Chain of Fibrinogen to be Associated with Impaired Fibrinolysis in a Family with Thrombophilia.
abstract: We report the study of a familial rare disease with recurrent venous thromboembolic events that remained undiagnosed for many years using standard coagulation and hemostasis techniques.
  
  
  
  Exome sequencing was performed in three familial cases with venous thromboembolic disease and one familial control using NimbleGen exome array. Clot lysis experiments were performed to analyze the reasons of the altered fibrinolytic activity caused by the mutation found.
  
  
  
  We found a mutation that consists of a R458C substitution on the fibrinogen alpha chain (FGA) gene confirmed in 13 new familial subjects that causes a rare subtype of dysfibrinogenemia characterized by venous thromboembolic events. The mutation was already reported to be associated with a fibrinogen variant called fibrinogen Bordeaux. Clot-lysis experiments showed a decreased and slower fibrinolytic activity in carriers of this mutation as compared to normal subjects, thus demonstrating an impaired fibrinolysis of fibrinogen Bordeaux.
  
  
  
  The exome sequencing and clot-lysis experiments might be powerful tools to diagnose idiopathic thrombophilias after an unsuccessful set of biochemical laboratory tests. Fibrinogen Bordeaux is associated with impaired fibrinolysis in this family with idiopathic thrombophilia.
authors.affiliation: Stroke pharmacogenomics and genetics laboratory, Fundació Docencia i Recerca MutuaTerrassa, Hospital Mutua de Terrassa.
authors.forename: Israel
authors.initials: I
authors.lastname: Fernández-Cadenas
authors.forename: Anna
authors.initials: A
authors.lastname: Penalba
authors.forename: Cristina
authors.initials: C
authors.lastname: Boada
authors.forename: Caty
authors.initials: C
authors.lastname: Carrerra
authors.forename: Santiago Rodriguez
authors.initials: SR
authors.lastname: Bueno
authors.forename: Adoración
authors.initials: A
authors.lastname: Quiroga
authors.forename: Jasone
authors.initials: J
authors.lastname: Monasterio
authors.forename: Pilar
authors.initials: P
authors.lastname: Delgado
authors.forename: Eduardo
authors.initials: E
authors.lastname: Anglés-Cano
authors.forename: Joan
authors.initials: J
authors.lastname: Montaner
mesh_terms: D001777:Blood Coagulation; D001780:Blood Coagulation Tests; D059472:Exome; D005192:Family Health; D005260:Female; D005337:Fibrin / Q000235:genetics; D005340:Fibrinogen / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D017422:Sequence Analysis, DNA; D013917:Thrombin / Q000235:genetics; D019851:Thrombophilia / Q000235:genetics*; D013927:Thrombosis / Q000235:genetics; D054556:Venous Thromboembolism / Q000235:genetics*
chemical_list: D005337:Fibrin; D005340:Fibrinogen; D013917:Thrombin