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A high-throughput sequencing test for diagnosing inherited bleeding, thrombotic, and platelet disorders

Simeoni, Ilenia; Stephens, Jonathan C.; Hu, Fengyuan; Deevi, Sri V. V.; Megy, Karyn; Bariana, Tadbir K.; Lentaigne, Claire; Schulman, Sol; Sivapalaratnam, Suthesh; Vries, Minka J. A.; Westbury, Sarah K.; Greene, Daniel; Papadia, Sofia; Alessi, Marie Christine; Attwood, Antony P.; Ballmaier, Matthias; Baynam, Gareth; Bermejo, Emilse; Bertoli, Marta; Bray, Paul F.; Bury, Loredana; Cattaneo, Marco; Collins, Peter; Daugherty, Louise C.; Favier, Remi; French, Deborah L.; Furie, Bruce; Gattens, Michael; Germeshausen, Manuela; Ghevaert, Cedric; Goodeve, Anne C.; Guerrero, Jose A.; Hampshire, Daniel J.; Hart, Daniel P.; Heemskerk, Johan W. M.; Henskens, Yvonne M. C.; Hill, Marian; Hogg, Nancy; Jolley, Jennifer D.; Kahr, Walter H.; Kelly, Anne M.; Kerr, Ron; Kostadima, Myrto; Kunishima, Shinji; Lambert, Michele P.; Liesner, Ri; Lopez, Jose A.; Mapeta, Rutendo P.; Mathias, Mary; Millar, Carolyn M.; Nathwani, Amit; Neerman-Arbez, Marguerite; Nurden, Alan T.; Nurden, Paquita; Othman, Maha; Peerlin...


Ilenia Simeoni

Jonathan C. Stephens

Fengyuan Hu

Sri V. V. Deevi

Karyn Megy

Tadbir K. Bariana

Claire Lentaigne

Sol Schulman

Suthesh Sivapalaratnam

Minka J. A. Vries

Sarah K. Westbury

Daniel Greene

Sofia Papadia

Marie Christine Alessi

Antony P. Attwood

Matthias Ballmaier

Gareth Baynam

Emilse Bermejo

Marta Bertoli

Paul F. Bray

Loredana Bury

Marco Cattaneo

Peter Collins

Louise C. Daugherty

Remi Favier

Deborah L. French

Bruce Furie

Michael Gattens

Manuela Germeshausen

Cedric Ghevaert

Anne C. Goodeve

Jose A. Guerrero

Daniel P. Hart

Johan W. M. Heemskerk

Yvonne M. C. Henskens

Marian Hill

Nancy Hogg

Jennifer D. Jolley

Walter H. Kahr

Anne M. Kelly

Ron Kerr

Myrto Kostadima

Shinji Kunishima

Michele P. Lambert

Ri Liesner

Jose A. Lopez

Rutendo P. Mapeta

Mary Mathias

Carolyn M. Millar

Amit Nathwani

Marguerite Neerman-Arbez

Alan T. Nurden

Paquita Nurden

Maha Othman

Kathelijne Peerlinck

David J. Perry

Pawan Poudel

Pieter Reitsma

Matthew T. Rondina

Peter A. Smethurst

William Stevenson

Artur Szkotak

Salih Tuna

Christel Van Geet

Deborah Whitehorn

David A. Wilcox

Bin Zhang

Shoshana Revel-Vilk

Paolo Gresele

Daniel B. Bellissimo

Christopher J. Penkett

Michael A. Laffan

Andrew D. Mumford

Augusto Rendon

Keith Gomez

Kathleen Freson

Willem H. Ouwehand

Ernest Turro


Inherited bleeding, thrombotic, and platelet disorders (BPDs) are diseases that affect ∼300 individuals per million births. With the exception of hemophilia and von Willebrand disease patients, a molecular analysis for patients with a BPD is often unavailable. Many specialized tests are usually required to reach a putative diagnosis and they are typically performed in a step-wise manner to control costs. This approach causes delays and a conclusive molecular diagnosis is often never reached, which can compromise treatment and impede rapid identification of affected relatives. To address this unmet diagnostic need, we designed a high-throughput sequencing platform targeting 63 genes relevant for BPDs. The platform can call single nucleotide variants, short insertions/deletions, and large copy number variants (though not inversions) which are subjected to automated filtering for diagnostic prioritization, resulting in an average of 5.34 candidate variants per individual. We sequenced 159 and 137 samples, respectively, from cases with and without previously known causal variants. Among the latter group, 61 cases had clinical and laboratory phenotypes indicative of a particular molecular etiology, whereas the remainder had an a priori highly uncertain etiology. All previously detected variants were recapitulated and, when the etiology was suspected but unknown or uncertain, a molecular diagnosis was reached in 56 of 61 and only 8 of 76 cases, respectively. The latter category highlights the need for further research into novel causes of BPDs. The ThromboGenomics platform thus provides an affordable DNA-based test to diagnose patients suspected of having a known inherited BPD.


Simeoni, I., Stephens, J. C., Hu, F., Deevi, S. V. V., Megy, K., Bariana, T. K., …Turro, E. (2016). A high-throughput sequencing test for diagnosing inherited bleeding, thrombotic, and platelet disorders. Blood, 127(23), 2791-2803.

Journal Article Type Article
Acceptance Date Apr 7, 2016
Online Publication Date Apr 15, 2016
Publication Date Jun 9, 2016
Deposit Date Apr 10, 2019
Journal Blood
Print ISSN 0006-4971
Electronic ISSN 1528-0020
Publisher American Society of Hematology
Peer Reviewed Peer Reviewed
Volume 127
Issue 23
Pages 2791-2803
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