Rapid identification of a pathogenic variant of PROS1 in a thrombophilic family by whole exome sequencing

Abstract Rationale: Venous thrombosis remains a significant problem in modern days. Genetic factors contribute to a subset of patients with venous thrombosis. It is sometimes challenging to identify the underlying culprit in thrombophilic individuals based on traditional laboratory testing and Sanger sequencing. Patient concerns: A thrombophilic family presented with multiple venous thrombosis was examined. Diagnoses: Molecular genetic analysis revealed a pathogenic missense variant of the PROS1 gene. Based on this finding and clinical manifestations, a final diagnosis of protein S deficiency was made. Interventions: Whole exome sequencing (WES) of the proband was performed to identify disease-causing variants. Subsequently, Sanger sequencing was performed to validate the variant in the affected members. Outcomes: Using WES, we rapidly identified a proven pathogenic missense variant (c.1543C > T, p.Arg515Cys) in the sex hormone-binding globulin domain of PROS1, which was confirmed by Sanger sequencing. The decreased level and activity of protein S caused by the variant explained the phenotypes of the family. Patients received rivaroxaban as a long-term anticoagulation therapy and achieved a good prognosis. Lessons: Our study suggests WES as a rapid search strategy to identify the genetic factors underlying thrombophilic disorders. Patients with venous thrombosis caused by PROS1 mutations could receive rivaroxaban as the first choice of anticoagulation therapy.