PB0458 - Candidate gene panel analysis in venous thromboembolism patients with pregnancy or female hormone

Background: Hereditary deficiencies of the natural anticoagulants, antithrombin (AT), protein C (PC), and protein S (PS), increase the risk of venous thromboembolism (VTE). Hereditary thrombophilia is diagnosed by the activity and antigen levels of three anticoagulants, which are influenced by the patient condition such as pregnancy, female hormones, anticoagulants, etc. Therefore, genetic analysis is useful for definitive diagnosis.

Aims: The purpose of this study is to compare the results of a VTE candidate gene panel with clinical and laboratory information to examine the diagnostic accuracy of the panel.

Methods: Nine patients who developed VTE during pregnancy or while taking oral female hormones were enrolled. A VTE candidate gene panel consisting of 29 genes including AT, PC, PS, prothrombin, and FV was constructed using a short read next generation sequencer.

Results: The patients showed decreased anticoagulant levels of one of three natural anticoagulants and were suspected to have hereditary thrombophilia. A total of five pathogenic variants were identified in four of the nine patients using the VTE candidate gene panel. In one patient, a nonsense variant in SERPINC1 (AT) was identified, in the other patients, a missense variant in PROC (PC), and a missense variant in PROS1 (PS) were identified; in the fourth patient, a double heterozygosity of nonsense variant in PROC and missense variant in PROS1 was identified. In five patients whose pathogenic variants were not identified, one was suspected antiphospholipid syndrome, two showed mild decreased PS activity. Although hereditary thrombophilia was strongly suspected based on activity, no variants were identified in two patients.

Conclusion(s): In this study, the identification rate of pathogenic variants in VTE patients was 44% (4/9). Thus, the short-read next generation sequencer employed in this study has the inherent limitation. We identified double heterozygosity in one patient, demonstrating the advantages of candidate gene panel sequencing. Further sequencing improvements are needed.