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Fibrinogen Columbus III:  A novel c.963del frameshift mutation in FGG resulting in hypofibrinogenemia and bleeding
Eman Abdelghani1, Jennifer Dawson2, Kristin Zajo1, Michelle Hallam1, Riten Kumar 1
1Division of Pediatric Hematology/Oncology/BMT, Nationwide Children’s Hospital, Department of Pediatrics, The Ohio State University, Columbus, OH, United States/2Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN, United States

Background: Fibrinogen, a 340 kDa glycoprotein, consists of three homologous polypeptide chains (Aɑ, Bß, and 𝛾), encoded by FGA, FGB, and FGG genes, respectively, which are clustered on the long arm of chromosome 4. Congenital fibrinogen disorders are caused by a quantitative deficiency (afibrinogenemia or hypofibrinogenemia) or a qualitative defect (dysfibrinogenemia) in the fibrinogen molecule and are classified according to the amount of functional and antigenic fibrinogen values. Objective: Herein we present an adolescent female with menorrhagia ( in the setting of a family history of significant bleeding) who was found to have hypofibrinogenemia secondary to a novel frameshift mutation in the FGG gene. Methods: Case report  Case presentation: A 14 year old female who was referred to the hematology clinic for a personal history of menorrhagia and a family history of bleeding. In addition to menorrhagia, patient reported recurrent epistaxis and easy bruising. Family history was significant for menorrhagia and post-partum hemorrhage in multiple members on the paternal side. Laboratory evaluation revealed normal CBC, slightly elevated PT at 14.8 (ref range 12.4-14.7) seconds, normal PTT, normal von Willebrand ristocetin cofactor and von Willebrand antigen. Thrombin time was mildly prolonged at 20 (ref range: 14.2-18.9) seconds. Fibrinogen activity was determined via Clauss method using the STA-Fibrinogen kit (Diagnostica Stago, Parsippany, NJ). Fibrinogen antigen was measured via radial immuno-diffusion technique using the BINDARID kit (Binding Site, Birmingham, UK). Patient’s fibrinogen activity was low at 110 (ref range 170-410) mg/dL and her fibrinogen antigen level was proportionately low at 117 (ref range >239) mg/dL.  Sequencing of the FGA, FGB, and FGG genes was pursued. Leukocyte genomic DNA was extracted from EDTA-anticoagulated blood using the ArchivePure DNA purification kit. A combination of Next Generation sequencing and Sanger sequencing was used to cover the full coding region plus 10 base pairs of non-coding DNA flanking each exon.  A previously undescribed heterozygous variant c.963del was identified in the FGG gene. This single nucleotide deletion results in a frameshift for codons downstream of the change.  This largescale change potentially alters the clotting properties of FGG by eliminating critical binding sites, including the chain’s polymerization site, Ca2+-binding site, the γ-γ cross-linking sites, and the platelet and thrombin binding sites at the C-terminal ends of the γA and γ’ isoforms of FGG, respectively.  Previously reported truncations within the C-terminal domain of FGG cause defects in fibrinogen stability, assembly, and hepatocyte secretion into the blood, suggesting similar consequences for the c.963del frameshift mutation.            Conclusion: In summary, we describe a novel frameshift mutation in FGG resulting in autosomal dominant hypofibrinogenemia and a bleeding phenotype. Structural visualization and literature review suggest that the mutation likely impacts stability, assembly, and secretion of fibrinogen from the hepatocytes.