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A high-throughput sequencing test for diagnosing inherited bleeding, thrombotic, and platelet disorders
File | Description | Size | Format | |
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TG-20151216.pdf | Accepted version | 412.76 kB | Adobe PDF | View/Open |
Title: | A high-throughput sequencing test for diagnosing inherited bleeding, thrombotic, and platelet disorders |
Authors: | Simeoni, I Stephens, JC Hu, F Deevi, SV Megy, K Bariana, TK Lentaigne, C Schulman, S Sivapalaratnam, S Vries, MJ Westbury, SK Greene, D Papadia, S Alessi, MC Attwood, AP Ballmaier, M Baynam, G Bermejo, E Bertoli, M Bray, PF Bury, L Cattaneo, M Collins, P Daugherty, LC Favier, R French, DL Furie, B Gattens, M Germeshausen, M Ghevaert, C Goodeve, A Guerrero, J Hampshire, DJ Hart, DP Heemskerk, JW Henskens, YM Hill, M Hogg, N Jolley, JD Kahr, WH Kelly, AM Kerr, R Kostadima, M Kunishima, S Lambert, MP Liesner, R Lopez, J Mapeta, RP Mathias, M Millar, CM Nathwani, A Neerman-Arbez, M Nurden, AT Nurden, P Othman, M Peerlinck, K Perry, DJ Poudel, P Reitsma, P Rondina, M Smethurst, PA Stevenson, W Szkotak, A Tuna, S Van Geet, C Whitehorn, D Wilcox, DA Zhang, B Revel-Vilk, S Gresele, P Bellissimo, D Penkett, CJ Laffan, MA Mumford, AD Rendon, A Gomez, K Freson, K Ouwehand, WH Turro, E |
Item Type: | Journal Article |
Abstract: | Inherited bleeding, thrombotic and platelet disorders (BPDs) are diseases affecting approximately 300 individuals per million births. With the exception of haemophilia and von Willebrand disease patients, a molecular analysis for patients with a BPD is often unavailable. Many specialised 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 (HTS) platform targeting 63 genes relevant for BPDs. The platform can call single nucleotide variants (SNVs), short insertions/deletions (indels) and large copy number variants (CNVs), 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 while the remainder had ana priorihighly 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 eight 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. |
Issue Date: | 9-Jun-2016 |
Date of Acceptance: | 7-Apr-2016 |
URI: | http://hdl.handle.net/10044/1/32189 |
DOI: | 10.1182/blood-2015-12-688267 |
ISSN: | 0006-4971 |
Publisher: | American Society of Hematology |
Start Page: | 2791 |
End Page: | 2803 |
Journal / Book Title: | Blood |
Volume: | 127 |
Issue: | 23 |
Copyright Statement: | Copyright the authors. |
Sponsor/Funder: | Medical Research Council (MRC) |
Funder's Grant Number: | MR/J011711/1 |
Keywords: | Science & Technology Life Sciences & Biomedicine Hematology VON-WILLEBRAND-DISEASE WISKOTT-ALDRICH SYNDROME FACTOR-VIII GENE UNITED-KINGDOM GENOME MANAGEMENT MUTATIONS LINKAGE POLYMORPHISMS POPULATION Blood Platelet Disorders Case-Control Studies DNA Copy Number Variations Female Genetic Association Studies Genetic Predisposition to Disease Hemorrhage High-Throughput Nucleotide Sequencing Humans Male Mutation Polymorphism, Single Nucleotide Sequence Analysis, DNA Thrombosis Humans Thrombosis Blood Platelet Disorders Genetic Predisposition to Disease Hemorrhage Case-Control Studies Sequence Analysis, DNA Mutation Polymorphism, Single Nucleotide Female Male Genetic Association Studies DNA Copy Number Variations High-Throughput Nucleotide Sequencing Immunology 1102 Cardiorespiratory Medicine and Haematology 1103 Clinical Sciences 1114 Paediatrics and Reproductive Medicine |
Publication Status: | Published |
Online Publication Date: | 2016-06-09 |
Appears in Collections: | Department of Immunology and Inflammation Faculty of Medicine |