Novel Pathogenic Genes and Rare Mutations of Congenital Factor V Deficiency: A Case Report

Background: Congenital factor V (FV) deficiency is a rare autosomal recessive bleeding disorder associated with mild to severe bleeding symptoms, with an estimated prevalence of 1/1 000 000 in homozygotes. So far, a total of 56 mutations have been issued, rendering severe or moderately severe FV deficiency; of which, over two-thirds are nonsense mutations (mainly responsible for reducing FV expression), and the rest are missense mutations (which usually impair the secretion of FV).

Case Description: We report a 4-year-old female who was admitted for blood coagulation dysfunction for over a month. More than a month ago, she received oral 1/3 tablets of "Compound Aminopyrine Phenacetin Tablets" because of fever and cough, but difficult-to-control epistaxis occurred about 10 minutes later. Blood tests from other hospitals showed that her prothrombin time (PT) and the activated partial thromboplastin time (APTT) values were 62.1 s and 221.6 s, respectively, and determined the blood coagulation factors II, VII, and X to be 63%, 34%, and 68%, respectively. What's more, multiple administrations of human prothrombin complex and vitamin K1 intravenous infusion did not significantly improve her coagulation function. Results of the lupus anticoagulants (LA) primary screening and confirmation test in our hospital were 159.5 s and 102.0 s, respectively, with a ratio of 1.6; blood coagulation factor II, VII, VIII, IX, X, XI, and XII activity were 87.2%, 57.7%, 60.6%, 50.4%, 76.1%, 61.5%, and 33.3%, respectively, while the FV activity (FV:C) level was quite low (1.6%). In addition, no abnormalities were detected in her thyroid function, anti-streptolysin O (ASO), autoimmune antibody markers, T cell subsets, serum immunoglobulin G4 levels, coagulation FV and its inhibitor levels, and humoral immune combinations. Therefore, we first ruled out the possibility of systemic lupus erythematosus. Furthermore, DNA sequence analysis identified a missense point mutation of the FV gene (NM_000130: exon23: c.C6304T: p.R2102C), a pathogenic site suggested by the ClinVar database. Given the characteristics of heterozygotes, we suspected that there was another mutation site, most likely a compound heterozygous mutation, 2 sites from parents, causing the patient pathogenic(Table 1). Then we examined the above-mentioned gene mutation sites of her parents and sisters, and confirmed her double heterozygote of R2102C missense point mutation and I1740fs frameshift mutation site was indeed from father and mother, respectively(Figure 1).

Conclusion: In summary, this case report sheds light on rare mutations at 3 sites in FV gene. However, the pathogenic R2102C site identified by ClinVar, together with the I1740fs frameshift mutation site, has not been reported in the literature. On one hand, R2102 occurs in the functional structural region of FV gene, predicting the protein function detrimental, thus considered to be a pathogenic site(Figure 2); on the other hand, since frameshift mutations greatly affect gene function, probably also leading to disease in patients. This is extremely rare.

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