Characterization of a novel factor X variant, p.F139L, associated with bleedings in heterozygous and compound heterozygous form

Introduction

Congenital factor X (FX) deficiency is a rare bleeding disorder. Heterozygous patients may experience bleedings like epistaxis or bleeding complications after dental extraction and surgery, whereas homozygous individuals often experience more severe bleedings.

Aim

To characterize a new FX variant found in two unrelated probands with mild to moderate bleeding tendencies.

Methods

Prothrombin time (PT) Quick, APTT, FX activity, FX antigen, thrombin generation and DNA sequencing were performed for probands and their families. F10 variants were explored in programs for in silico predictions and structural analyses, and in vitro expression was used for further characterization.

Results

A novel missense variant (c.415T>C, p.F139L) was found in heterozygous form in proband 1 and in compound heterozygous form in proband 2, in combination with a previously known missense variant (c.424G>A, p.E142K). All individuals carrying the p.F139L variant had borderline/prolonged PT Quick (11.9–15.9 s) and APTT (36–43 s) and reduced thrombin generation. Both FX antigen (30–51 %) and activity (37–63 IU/dL) were reduced, indicating a type I deficiency. Structural analysis indicated that interactions between the EGF-2 and the protease domain of FX could be disrupted in the p.F139L variant, causing destabilization of the protein. The p.E142K variant was predicted to have less impact on FX structure. In vitro expression results further supported plasma findings.

Conclusion

We report a new FX variant, p.F139L, causing a type I FX deficiency associated with mild to moderate bleedings in heterozygous and compound heterozygous form. The variant causes structural changes which likely affect intracellular processing of FX.