A novel 33-Gene targeted resequencing panel provides accurate, clinical-grade diagnosis and improves patient management for rare inherited anaemias

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dc.contributor.author Roy, Noémi B. A.
dc.contributor.author Wilson, Edward A.
dc.contributor.author Henderson, Shirley
dc.contributor.author Wray, Katherine
dc.contributor.author Babbs, Christian
dc.contributor.author Okoli, Steven
dc.contributor.author Atoyebi, Wale
dc.contributor.author Mixon, Avery
dc.contributor.author Cahill, Mary R.
dc.contributor.author Carey, Peter
dc.contributor.author Cullis, Jonathan
dc.contributor.author Curtin, Julie
dc.contributor.author Dreau, Helene
dc.contributor.author Ferguson, David J. P.
dc.contributor.author Gibson, Brenda
dc.contributor.author Hall, Georgina
dc.contributor.author Mason, Joanne
dc.contributor.author Morgan, Mary
dc.contributor.author Proven, Melanie
dc.contributor.author Qureshi, Amrana
dc.contributor.author Sanchez Garcia, Joaquin
dc.contributor.author Sirachainan, Nongnuch
dc.contributor.author Teo, Juliana
dc.contributor.author Tedgård, Ulf
dc.contributor.author Higgs, Doug
dc.contributor.author Roberts, David
dc.contributor.author Roberts, Irene
dc.contributor.author Schuh, Anna
dc.date.accessioned 2019-11-01T07:58:18Z
dc.date.available 2019-11-01T07:58:18Z
dc.date.issued 2016-10-12
dc.identifier.citation Roy, N. B. A., Wilson, E. A., Henderson, S., Wray, K., Babbs, C., Okoli, S., Atoyebi, W., Mixon, A., Cahill, M. R., Carey, P., Cullis, J., Curtin, J., Dreau, H., Ferguson, D. J. P., Gibson, B., Hall, G., Mason, J., Morgan, M., Proven, M., Qureshi, A., Sanchez Garcia, J., Sirachainan, N., Teo, J., Tedgård, U., Higgs, D., Roberts, D., Roberts, I. and Schuh, A. (2016) 'A novel 33-Gene targeted resequencing panel provides accurate, clinical-grade diagnosis and improves patient management for rare inherited anaemias', British Journal of Haematology, 175(2), pp. 318-330. DOI: 10.1111/bjh.14221 en
dc.identifier.volume 175 en
dc.identifier.issued 2 en
dc.identifier.startpage 318 en
dc.identifier.endpage 330 en
dc.identifier.issn 0007-1048
dc.identifier.uri http://hdl.handle.net/10468/8937
dc.identifier.doi 10.1111/bjh.14221 en
dc.description.abstract Accurate diagnosis of rare inherited anaemias is challenging, requiring a series of complex and expensive laboratory tests. Targeted next-generation-sequencing (NGS) has been used to investigate these disorders, but the selection of genes on individual panels has been narrow and the validation strategies used have fallen short of the standards required for clinical use. Clinical-grade validation of negative results requires the test to distinguish between lack of adequate sequencing reads at the locations of known mutations and a real absence of mutations. To achieve a clinically-reliable diagnostic test and minimize false-negative results we developed an open-source tool (CoverMi) to accurately determine base-coverage and the ‘discoverability’ of known mutations for every sample. We validated our 33-gene panel using Sanger sequencing and microarray. Our panel demonstrated 100% specificity and 99·7% sensitivity. We then analysed 57 clinical samples: molecular diagnoses were made in 22/57 (38·6%), corresponding to 32 mutations of which 16 were new. In all cases, accurate molecular diagnosis had a positive impact on clinical management. Using a validated NGS-based platform for routine molecular diagnosis of previously undiagnosed congenital anaemias is feasible in a clinical diagnostic setting, improves precise diagnosis and enhances management and counselling of the patient and their family. en
dc.description.sponsorship Henry Smith Charity (GN2300); Action Medical Research (GN2300); Oxford University Hospitals NHS Foundation Trust (Blood Theme and BRC/NHS Translational Molecular Diagnostics Centre); University of Oxford (MRC Molecular Haematology Unit) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher Wiley en
dc.relation.uri https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.14221
dc.rights © 2016, The Authors. British Journal of Haematology published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. en
dc.rights.uri http://creativecommons.org/licenses/by/4.0/ en
dc.subject Inherited anaemia en
dc.subject Congenital dyserythropoietic anaemia en
dc.subject Molecular genetics en
dc.subject Pyruvate kinase deficiency en
dc.subject Next-generation sequencing en
dc.title A novel 33-Gene targeted resequencing panel provides accurate, clinical-grade diagnosis and improves patient management for rare inherited anaemias en
dc.type Article (peer-reviewed) en
dc.internal.authorcontactother Mary Cahill, School of Pathology and Department of Haematology, University College Cork, Cork, Ireland. +353-21-490-3000 en
dc.internal.availability Full text available en
dc.description.version Published Version en
dc.contributor.funder University of Oxford en
dc.contributor.funder National Institute for Health Research en
dc.contributor.funder Henry Smith Charity en
dc.contributor.funder Action Medical Research en
dc.contributor.funder Oxford University Hospitals NHS Foundation Trust en
dc.description.status Peer reviewed en
dc.identifier.journaltitle British Journal of Haematology en
dc.identifier.eissn 1365-2141


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© 2016, The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.  This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Except where otherwise noted, this item's license is described as © 2016, The Authors. British Journal of Haematology published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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