A novel fibrinogen variant in a Chinese pedigree with congenital dysfibrinogenemia caused by FGA P. Arg38Thr mutation

Abstract

Rationale:Congenital dysfibrinogenemia (CD) is characterized by altered functional properties of the fibrinogen; people who suffer from CD often have a low activity of fibrinogen and the mutation in the genomic DNA.Patient concerns:A 6-year-old child was examined with a low activity of fibrinogen measured by Von Clauss method and PT-derived method which indicated a normal level of fibrinogen; this abnormality was also detected in her mother. The genomic DNA of all the family members was extracted, and all exons of 3 fibrinogen genes which encode fibrinogen alpha chain (FGA), fibrinogen beta chain (FGB), and fibrinogen gamma chain (FGG) were amplified by polymerase chain reaction (PCR), in addition, sanger sequencing, homologous sequence alignment and bioinformatics software were performed for the further analysis.Diagnoses:CD in this pedigree is associated with c.113G>C in the exon 2 of FGA which caused Arg38Thr mutation.Outcomes:The child and her mother showed a low plasma concentration of fibrinogen measured by Von Clauss method, whereas a normal result measured by PT-derived method; finally, c.113G>C in the exon 2 of FGA was detected in the pedigree which caused Arg38Thr mutation and it is the first report on a pedigree with CD caused by AαArg38Thr.Lessons:This case gives us the lesson that not all patients with CD showed typical symptoms and laboratory test results; the result of fibrinogen concentration and antigen which is tested by Von Clauss method and immunoturbidimetric assay is various according to the condition of each CD patient.

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

“…Our results demonstrated that Arg38Thr missense mutation results in dysfibrinogenemia via impaired knob‐hole interaction and consequently weak and unstable clot formation. This mutation was recently reported for the first time in a 6‐year‐old Chinese child; however, this patient was asymptomatic 26 …”

“…This mutation was recently reported for the first time in a 6-year-old Chinese child; however, this patient was asymptomatic. 26 In this study, we report a new missense mutation in FGB exon 8 (c.1288 G>C) that results in an amino acid substitution of Gly to Arg at residue 430 (p.Gly430Arg). This amino acid substitution was identified in the C-terminal globular portion of the fibrinogen Bb chain in a highly conserved region.…”

Dysfibrinogenemia—Potential Impact of Genotype on Thrombosis or Bleeding

“…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.…”

“…Two Chinese cases with the Arg19Thr mutation were however asymptomatic. 22 It is important to note that for the Aα Arg19Gly mutation, the few clinical manifestations reported as thrombosis (►Table 4) were either TIA (n ¼ 2), 28,32 "uncertain ischemic lesion" identified by magnetic resonance scanning of the brain (n ¼ 1), 20 retinal thrombosis with cardiovascular risk factors (n ¼ 1), 24 or occurrence of "phlebothrombosis" and bleeding after trauma (n ¼ 1). 26 None of the publications reported a specific clinical manifestation of PE for this mutation as presented in our cases.…”

“…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.…”