A case of congenital prothrombin deficiency with two concurrent mutations in the prothrombin gene

Abstract

Congenital prothrombin deficiency is an extremely rare, autosomal recessive bleeding disorder with a prevalence of 1 in 2 million individuals. Here, we report a case of congenital prothrombin deficiency with two concurrent mutations in the prothrombin gene (F2), affecting the heavy B chain. The patient presented with a history of multiple bleeding events in his youth that are mostly trauma associated, with a family history of prothrombin deficiency. Laboratory analysis showed a prolonged activated partial thromboplastin time and a prothrombin activity level of 5%. Genetic analysis of the F2 gene identified two heterozygous variants; one is a previously reported pathogenic deletion (c.1814_1815del; p.His605Argfs*13), and the other is a novel missense variant (c.1147C>T; p.Arg383Trp). In silico analysis predicted that p.Arg383Trp is likely to be disease causing, as it affects one of the anion-binding exosites-I of the B chain. This case highlights the significance of molecular findings in confirming the diagnosis of patients with congenital prothrombin deficiency.

Keywords: bleeding disorder; dysprothrombinemia; hypoprothrombinemia; prothrombin deficiency; prothrombin mutation.

FIGURE 1

Family pedigree

FIGURE 2

Structure of prothrombin protein and effect of variants on protein. (A) This figure shows the domain architecture of the prothrombin protein with location of the two variants (identified in our patient) in the B‐chain region of the protein. (B) Amino acid sequence of the B chain with highlighted (blue and green) exosite‐I and II positions and pink boxes highlighting the exosite‐I/II positions affected by these two variants