Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders

Kate Downes*, Karyn Megy, Daniel Duarte, Minka Vries, Johanna Gebhart, Stefanie Hofer, Olga Shamardina, Sri V.V. Deevi, Jonathan Stephens, Rutendo Mapeta, Salih Tuna, Namir Al Hasso, Martin W. Besser, Nichola Cooper, Louise Daugherty, Nick Gleadall, Daniel Greene, Matthias Haimel, Howard Martin, Sofia PapadiaShoshana Revel-Vilk, Suthesh Sivapalaratnam, Emily Symington, Will Thomas, Chantal Thys, Alexander Tolios, Christopher J. Penkett, Nihr BioResource, Willem H. Ouwehand, Stephen Abbs, Michael A. Laffan, Ernest Turro, Ilenia Simeoni, Andrew D. Mumford, Yvonne M.C. Henskens, Ingrid Pabinger, Keith Gomez, Kathleen Freson

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

121 Citations (Scopus)
173 Downloads (Pure)


A targeted high-throughput sequencing (HTS) panel test for clinical diagnostics requires careful consideration of the inclusion of appropriate diagnostic-grade genes, the ability to detect multiple types of genomic variation with high levels of analytic sensitivity and reproducibility, and variant interpretation by a multidisciplinary team (MDT) in the context of the clinical phenotype. We have sequenced 2396 index patients using the ThromboGenomics HTS panel test of diagnostic-grade genes known to harbor variants associated with rare bleeding, thrombotic, or platelet disorders (BTPDs). The molecular diagnostic rate was determined by the clinical phenotype, with an overall rate of 49.2% for all thrombotic, coagulation, platelet count, and function disorder patients and a rate of 3.2% for patients with unexplained bleeding disorders characterized by normal hemostasis test results. The MDT classified 745 unique variants, including copy number variants (CNVs) and intronic variants, as pathogenic, likely pathogenic, or variants of uncertain significance. Half of these variants (50.9%) are novel and 41 unique variants were identified in 7 genes recently found to be implicated in BTPDs. Inspection of canonical hemostasis pathways identified 29 patients with evidence of oligogenic inheritance. A molecular diagnosis has been reported for 894 index patients providing evidence that introducing an HTS genetic test is a valuable addition to laboratory diagnostics in patients with a high likelihood of having an inherited BTPD.

Original languageEnglish
Pages (from-to)2082-2091
Number of pages10
Issue number23
Early online date7 May 2019
Publication statusPublished - 5 Dec 2019

Bibliographical note

Copyright © 2019 American Society of Hematology.


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