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

Abstract

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, ~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 in FGA (p.Trp52Ter, p.Ser312AlafsTer109 and p.Gly316GlufsTer105), one in FBG (p.Gly430Asp), and two novel mutations in FGB (p.Gly430Arg) and FGG (p.His366ThrfsTer40), while the FGA (p.Arg38Thr) heterozygous mutation was identified in dysfibrinogenemia. MD simulation indicated that the FGA p. 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.

Clotting Factor Deficiencies as an Underlying Cause of Abnormal Uterine Bleeding in Women of Reproductive Age: A Literature Review

“…Fibrinogen (Factor I) is a soluble plasma glycoprotein which is synthesized in the liver and secreted in the plasma. It has a crucial role in the final step of the coagulation cascade and is also implicated in inflammation and wound healing [ 12 , 25 ]. Three genes, the fibrinogen alpha chain ( FGA ), fibrinogen beta chain ( FGB ), and fibrinogen gamma chain ( FGG ) gene, located on chromosome 4q23.5, encode for the three peptide chains which form fibrinogen.…”

Dysfibrinogenemia—Potential Impact of Genotype on Thrombosis or Bleeding

“…Two Italian cases and a Swiss case recently reported by Castaman et al 25 and by Szanto et al 35 were asymptomatic. Moreover, in seven cases with other amino acid substitutions at Arg19, two patients with an Arg19Ser mutation, 15,31,33 one patient with the Arg19Asn mutation, 34 one Iranian patient with the Arg19Thr mutation, 30 and one Chinese patient with Arg19Trp mutation 23 bleeding or bleeding tendency were common clinical symptoms. Two Chinese cases with the Arg19Thr mutation were however asymptomatic.…”

“…Most frequent is the Arg!Gly mutation, which has been identified in 12 studies including the present study 13,[18][19][20][21][24][25][26][27][28][29]32,35,36 (►Tables 1 and 4). The four other mutations encompass Arg!Ser, 15,31,33 Arg!Asn, 34 Arg!Thr, 22,30 and Arg!Trp. 23 The clinical picture associated with the Aα Arg19Gly mutation varies.…”

“…17,18 So far, five different mutations of Aα Arg19 have been reported, including Arg!Gly, Arg!Ser, Arg!Asn, Arg!Thr, and Arg!Trp. 13,[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] Here we review the studies describing mutations affecting fibrinogen knob A, and we present a Danish female patient (the proband), her daughter, and sister with the p. Arg19Gly (Aα Arg19Gly) mutation, together with different combinations of single nucleotide polymorphisms (SNPs) in fibrinogen encoding genes using whole-exome sequencing (WES) in combination with Sanger sequencing. Among individuals with knob A mutations, the proband and her daughter are the first reported carriers of the Aα Arg19Gly mutation combined with one or more SNPs in FGA, FGB, and/or FGG suffering from pulmonary emboli (PE), suggesting that compound genotype may contribute to the thrombogenic phenotype of these patients.…”

Gastrointestinal Bleeding in Congenital Bleeding Disorders

“…The molecular profile of the congenital fibrinogen disorders seen in GIB (14%) shows primarily homozygous mutations. 98 GIB occurs in afibrinogenemia (2%) less frequently than in hypofibrinogenemia (10%) or dysfibrinogenemia (8%). 6 Dysfibrinogenemia, which may have a nonspecific clinical phenotype, can be asymptomatic or may be expressed in hemorrhagic or thrombotic events, singly or together.…”