PB0227 - Symptomatic Factor X Deficiency in a Single Family with a Genetic Mutation Previously Reported as of Uncertain Significance

Background: Hereditary Factor X (FX) deficiency is a rare (1:1,000,000), autosomal recessive, bleeding disorder caused by alteration in F10 gene of which over 180 variants are reported to date. Phenotype depends on FX activity level ranging from mild (6-10%) to severe ( < 1%). Genotyping may offer an understanding about clinical prognosis. Same locus variants of the F10 gene with different amino acid substitutions are reported to cause mild to severe disease; however, c.1351A>C missense mutation, previously reported in one individual with FX deficiency, has been classified as a variant of uncertain significance (VUS).

Aims: To report a family affected with FX deficiency due to a previously described VUS [F10 (c.1351A>C, p.Ile451Leu)].

Methods: Case series, retrospective chart review with IRB exemption.

Results: We report a Hispanic, non-consanguineous, family with FX deficiency. The proband is a 6-year-old female with congenital heart disease post corrective surgeries who presented with epistaxis and hematemesis associated with prolonged PT/PTT and low FX level (51%); other coagulation factors were normal. Genetic testing showed a heterozygous mutation in F10 gene (c.1351A>C, p.Ile451Leu). Family history revealed menorrhagia in the mother and a 12-year-old sister both of whom tested positive for the same mutation, with FX levels 59% and 54% respectively; her symptomatic sister was started on tranexamic acid during menses improving flow and duration of bleeding. The proband, yet pre-menarchal, is managed with aminocaproic acid as needed for occasional epistaxis. Another 15-year-old asymptomatic sister tested negative for F10 gene mutation with normal FX levels.

All symptomatic family members have mild FX deficiency with the same heterozygous mutation of the F10 gene, whereas the asymptomatic member neither carries the mutation nor has FX deficiency (see table 1).

Conclusion(s): Heterozygous carriers of the F10 gene variant (c.1351A>C, p.Ile451Leu) may exhibit bleeding symptoms and FX deficiency; our case series supports the potential clinical significance of this variant.