Abstract Number: PB1199
Meeting: ISTH 2020 Congress
Background: Afibrinogenemia is a rare inherited autosomal recessive trait characterized by bleeding events due to the absolute lack of fibrinogen. To date, genetic defects causing afibrinogenaemia are mostly identified in FGA and FGG, but less frequently in FGB.
Aims: We describe a case of afibrinogenemia with a new mutation in FGB.
Methods: A Pakistan 4-years-old girl and her parents were referred to our Center for a likely diagnosis of congenital fibrinogen deficiency. The proband showed severe bleeding from the umbilical cord after spontaneous delivery and oral mucosa bleeding with melena at the age of 6 months. At the age of 2 years, she showed a post-trauma subdural hematoma. Plasma fibrinogen was functionally assayed by Clauss clotting method and quantitatively evaluated using the Partigen Fibrinogen kit. Amplifications of FGA, FGB, FGG coding regions were subjected to a direct cycle sequencing. In silico analysis of potential splicing mutation was performed by using Human Splicing Finder.
Results: In Pakistan the patien was treated with prophylactic plasma infusion (200 ml once a month). At the age of 4 years, she moved to Italy where the diagnosis of afibrinogenemia was confirmed (undetectable functional and immune-reactive fibrinogen). Therefore, she started prophylaxis with 55 mg/kg of lyophilised human fibrinogen every 4 days to maintain fibrinogen activity higher than 0.5 g/L. Sequencing showed a homozygous mutation in FGB intron 4 (c.718+1G>A). Her parents are first-degree cousins, so far asymptomatic for bleeding events and have fibrinogen within normal ranges. Both carry the c.718+1G>A in heterozygous (Table). In silico analysis revealed that mutation is likely to affect splicing of exon 4.
Conclusions: We report a novel splicing site mutation in FGB. The c.718+1G>A is likely to lead to exon 4 skipping or shortening or inclusion of intronic material, as expected for a null allele variant, with the impair fibrinogen assembly and secretion, resulting in afibrinogenemia.
|Patient reference||Gender||Age (year)||Fibrinogen functional (g/l) Reference range 1.50-4.00 g/l||Fibrinogen antigen (g/l) Reference range 1.82-3.39 g/l||Genotype||Gene region||Nucleotide||Clinical features|
|Proband||Female||4||Undetectable||Undetectable||Homozygous||FGB Intron 4||c.718+1G>A||Umbilical cord bleeding. Oral mucosa bleeding with melena. Post-trauma subdural hematoma.|
|Mother||Female||28||2.46||1.82||Heterozygous||FGB Intron 4||c.718+1G>A||Asymptomatic|
|Father||Male||32||2.50||1.40||Heterozygous||FGB Intron 4||c.718+1G>A||Asymptomatic|
[Table: Genotype-Phenotype relationship]
To cite this abstract in AMA style:Chinni E, Tiscia GL, Favuzzi G, Bruschi B, Coccia P, D'Alba I, Gobbi S, Petroni V, Pierani P, Cappucci F, Fischetti L, Vergura P, Vecchione G, De Laurenzo A, Colaizzo D, Grandone E. Afibrinogenemia: Identification of a New Mutation in FGB [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/afibrinogenemia-identification-of-a-new-mutation-in-fgb/. Accessed January 28, 2022.
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