Journal article
Whole-exome sequencing in evaluation of patients with venous thromboembolism
Blood advances, Vol.1(16), pp.1224-1237
06/29/2017
DOI: 10.1182/bloodadvances.2017005249
PMCID: PMC5728544
PMID: 29296762
Abstract
Using WES, we designed an extended thrombophilia panel consisting of 55 genes of significance to thrombosis.
The extended thrombophilia panel identified multiple novel genetic variants with predicted roles in thrombosis or thrombophilia.
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.
Details
- Title: Subtitle
- Whole-exome sequencing in evaluation of patients with venous thromboembolism
- Creators
- Eun-Ju Lee - Weill Cornell MedicineDaniel J. Dykas - Yale School of MedicineAndrew D. Leavitt - University of California, San FranciscoRodney M. Camire - University of PennsylvaniaEduard Ebberink - SanquinPablo García de Frutos - Department of Cell Death and Proliferation, Institute of Biochemical Research, Barcelona, SpainKavitha Gnanasambandan - Florida CollegeSean X. Gu - Roy J. and Lucille A. Carver College of MedicineJames A. Huntington - University of CambridgeSteven R. Lentz - University of IowaKoen Mertens - SanquinChristopher R. Parish - Australian National UniversityAlireza R. Rezaie - Oklahoma Medical Research FoundationPeter P. Sayeski - Florida CollegeCaroline Cromwell - Icahn School of Medicine at Mount SinaiNoffar Bar - Yale UniversityStephanie Halene - Yale UniversityNatalia Neparidze - Yale UniversityTerri L. Parker - Yale UniversityAdrienne J. Burns - Yale Cancer CenterAnne Dumont - Yale Cancer CenterXiaopan Yao - AnalyticaCassius Iyad Ochoa Chaar - Yale UniversityJean M. Connors - Brigham and Women's HospitalAllen E. Bale - Yale School of MedicineAlfred Ian Lee - Yale University
- Resource Type
- Journal article
- Publication Details
- Blood advances, Vol.1(16), pp.1224-1237
- Publisher
- American Society of Hematology
- DOI
- 10.1182/bloodadvances.2017005249
- PMID
- 29296762
- PMCID
- PMC5728544
- ISSN
- 2473-9529
- eISSN
- 2473-9537
- Language
- English
- Date published
- 06/29/2017
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359688302771
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