Molecular and clinical profile of congenital fibrinogen disorders in Iran, identification of two novel mutations

Introduction: Congenital fibrinogen disorders (CFDs) comprise the quantitative and qualitative fibrinogen molecule abnormalities that are caused by fibrinogen gene mutations. The objective of this cohort research was to study the molecular and clinical profiles of patients with CFDs. Materials and methods: Genomic DNA Sanger sequencing of 14 Iranian patients was performed to determine CFDs-causing mutations. The disorders were diagnosed by routine and specific (fibrinogen antigen and functional assay) coagulation tests, and clinical data were obtained from medical records. Molecular dynamics (MD) simulations were performed to investigate the effect of missense mutation on the protein structure. Results: Thirteen out of 14 patients had afibrinogenemia while the remaining patient had dysfibrinogenemia. Umbilical cord bleeding was the most common clinical presentation (n: 9, similar to 70%) which led to the diagnosis of afibrinogenemia, while menorrhagia led to the diagnosis of dysfibrinogenemia. Six homozygous mutations were identified in afibrinogenemia: three previously described variants inFGA(p.Trp52Ter, p.Ser312AlafsTer109 and p.Gly316GlufsTer105), one inFBG(p.Gly430Asp), and two novel mutations inFGB(p.Gly430Arg) andFGG(p.His366ThrfsTer40), while theFGA(p.Arg38Thr) heterozygous mutation was identified in dysfibrinogenemia. MD simulation indicated that theFGAp. Arg38Thr mutation probably interferes with polymerization of fibrin monomers. Conclusions: In Iran, with its high rate of consanguinity, autosomal recessive afibrinogenemia with severe clinical presentations is relatively common due to heterogeneous molecular defects.