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Blood Adv. 2017 Jun 29;1(16):1224-1237. doi: 10.1182/bloodadvances.2017005249. eCollection 2017 Jul 11.

Whole-exome sequencing in evaluation of patients with venous thromboembolism.

Author information

Division of Hematology, Department of Internal Medicine, Weill Cornell Medical College, New York, NY.
DNA Diagnostic Laboratory, Department of Genetics, Yale School of Medicine, New Haven, CT.
Department of Laboratory Medicine and.
Department of Medicine, University of California, San Francisco, San Francisco, CA.
Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA.
Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands.
Department of Cell Death and Proliferation, Institute of Biochemical Research, Barcelona, Spain.
Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL.
Division of Hematology, Oncology, and Blood & Bone Marrow Transplantation, University of Iowa Carver College of Medicine, Iowa City, IA.
Department of Haematology, University of Cambridge, Cambridge, United Kingdom.
Department of Cancer Biology and Therapeutics, Australian National University, Canberra, Australia.
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK.
Division of Hematology and Medical Oncology, Mount Sinai School of Medicine, New York, NY.
Section of Hematology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT.
Yale Cancer Center, New Haven, CT.
Yale Center for Analytical Sciences, New Haven, CT.
Section of Vascular Surgery, Department of Surgery, Yale School of Medicine, New Haven, CT; and.
Division of Hematology, Department of Internal Medicine, Brigham and Women's Hospital, Boston, MA.


Genetics play a significant role in venous thromboembolism (VTE), yet current clinical laboratory-based testing identifies a known heritable thrombophilia (factor V Leiden, prothrombin gene mutation G20210A, or a deficiency of protein C, protein S, or antithrombin) in only a minority of VTE patients. We hypothesized that a substantial number of VTE patients could have lesser-known thrombophilia mutations. To test this hypothesis, we performed whole-exome sequencing (WES) in 64 patients with VTE, focusing our analysis on a novel 55-gene extended thrombophilia panel that we compiled. Our extended thrombophilia panel identified a probable disease-causing genetic variant or variant of unknown significance in 39 of 64 study patients (60.9%), compared with 6 of 237 control patients without VTE (2.5%) (P < .0001). Clinical laboratory-based thrombophilia testing identified a heritable thrombophilia in only 14 of 54 study patients (25.9%). The majority of WES variants were either associated with thrombosis based on prior reports in the literature or predicted to affect protein structure based on protein modeling performed as part of this study. Variants were found in major thrombophilia genes, various SERPIN genes, and highly conserved areas of other genes with established or potential roles in coagulation or fibrinolysis. Ten patients (15.6%) had >1 variant. Sanger sequencing performed in family members of 4 study patients with and without VTE showed generally concordant results with thrombotic history. WES and extended thrombophilia testing are promising tools for improving our understanding of VTE pathogenesis and identifying inherited thrombophilias.

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