Congenital hypofibrinogenemia associated with novel homozygous fibrinogen Aα and heterozygous Bβ chain mutations

- Mild deficiency of fibrinogen rarely causes a bleeding tendency
- Heterozygous point mutations in one of the three fibrinogen genes are responsible
- A novel homozygous null mutation in Aalfa fibrinogen produces hypofibrinogenemia
- A novel heterozygous BBeta chain mutation was identified in a patient with stroke

We report the molecular characterisation of two novel cases of inherited hypofibrinogenemia. After sequencing all coding regions and intron-exon boundaries of the three fibrinogen genes (FGA, FGB, and FGG), two different novel mutations were found, one homozygous and one heterozygous. The first patient, with a mild bleeding history and mild discrepancy between functional and immunological fibrinogen, showed a novel homozygous nonsense mutation in exon 5 of FGA (p.Trp373*, p.Trp354* according to the mature protein) caused by a G > A transition at nucleotide position 1,119. The resulting truncation in the Aα chain is likely to reduce the efficiency of fibrinogen assembly and secretion. The second patient, referred after ischemic stroke (functional fibrinogen 77 mg/dL), had a novel heterozygous splicing mutation in intron 5 of FGB (IVS5 + 2 T > A or c.832 + 2 T > A), which we demonstrated to cause either exon 5 skipping or the inclusion of 75 bp belonging to intron 5. Neither splicing defect alters the reading frame: one results in a 38-residue deletion and the other in a 25-residue insertion in the D domain of fibrinogen Bβ chain. This report confirms that genetically determined partial deficiencies of fibrinogen with levels greater than 50 mg/dL are rarely associated with significant bleeding symptoms and that homozygous null mutations removing a significant portion of the Aα chain may be associated with mild fibrinogen deficiency.