Whole-exome sequencing in evaluation of patients with venous thromboembolism

Abstract

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%) ( < .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 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.

What is currently known about the genetics of venous thromboembolism at the dawn of next generation sequencing technologies

“…This is particularly relevant regarding the search for genetic defects located in the antithrombin, PROC and PS genes, as the surrogate measurment of these molecules in plasma does not always allow detection of the causal mutation, as is the case for PS Heerlen (Suchon et al , ) or antithrombin Dublin (Navarro‐Fernández et al , ) variations mentioned above. A recent pilot study highlighted the promise of the whole exome sequencing approach in the context of clinical VTE (Lee et al , ). In 40 patients for whom clinical thrombophilia testing remained unfruitful, 2 patients (5%) were found to harbour probable disease‐causing mutations when the genetic data analysis was restricted to 55 candidate VTE genes.…”

Diagnostic work up of patients with increased bleeding tendency

“…[6][7][8][9][10][11][12][13] Recently, several studies described the value of next-generation sequencing. 5,[32][33][34] In our clinic, whole exome sequencing (WES) was recently incorporated in the diagnostic trajectory of patients without a definite diagnosis but with a high bleeding score (cut-off BAT score ≥ 10). 35 The possibility of analysing many genes at once is a huge advantage.…”

Exome Sequencing in Clinical Hepatology

“…Notably, the vast majority of these studies have been performed in pediatric populations and in cancer patients. Hence, the value of WES in the diagnosis and management of adult patients with nononcological diseases is only recently emerging . In fact, in adult hepatology clinic, Wilson's disease, hemochromatosis, and alpha‐1 antitrypsin deficiency are routinely investigated as part of a comprehensive work‐up for liver test abnormalities and/or advanced liver disease by using single gene and/or gene panel test(s).…”

“…Hence, the value of WES in the diagnosis and management of adult patients with nononcological diseases is only recently emerging. (25,(33)(34)(35)(36) In fact, in adult hepatology clinic, Wilson's disease, hemochromatosis, and alpha-1 antitrypsin deficiency are routinely investigated as part of a comprehensive work-up for liver test abnormalities and/or advanced liver disease by using single gene and/or gene panel test(s). When this work-up is unrevealing, it usually stops there.…”