Congenital hypofibrinogenemia associated with novel homozygous fibrinogen A alpha and heterozygous B beta chain mutations

摘要

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 A alpha 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 B beta 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 A alpha chain may be associated with mild fibrinogen deficiency. (C) 2015 Elsevier Ltd. All rights reserved.