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

Simple item page
dc.contributor.authorRoy, Noémi B. A.
dc.contributor.authorWilson, Edward A.
dc.contributor.authorHenderson, Shirley
dc.contributor.authorWray, Katherine
dc.contributor.authorBabbs, Christian
dc.contributor.authorOkoli, Steven
dc.contributor.authorAtoyebi, Wale
dc.contributor.authorMixon, Avery
dc.contributor.authorCahill, Mary R.
dc.contributor.authorCarey, Peter
dc.contributor.authorCullis, Jonathan
dc.contributor.authorCurtin, Julie
dc.contributor.authorDreau, Helene
dc.contributor.authorFerguson, David J. P.
dc.contributor.authorGibson, Brenda
dc.contributor.authorHall, Georgina
dc.contributor.authorMason, Joanne
dc.contributor.authorMorgan, Mary
dc.contributor.authorProven, Melanie
dc.contributor.authorQureshi, Amrana
dc.contributor.authorSanchez Garcia, Joaquin
dc.contributor.authorSirachainan, Nongnuch
dc.contributor.authorTeo, Juliana
dc.contributor.authorTedgård, Ulf
dc.contributor.authorHiggs, Doug
dc.contributor.authorRoberts, David
dc.contributor.authorRoberts, Irene
dc.contributor.authorSchuh, Anna
dc.contributor.funderUniversity of Oxforden
dc.contributor.funderNational Institute for Health Researchen
dc.contributor.funderHenry Smith Charityen
dc.contributor.funderAction Medical Researchen
dc.contributor.funderOxford University Hospitals NHS Foundation Trusten
dc.date.accessioned2019-11-01T07:58:18Z
dc.date.available2019-11-01T07:58:18Z
dc.date.issued2016-10-12
dc.description.abstractAccurate 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.sponsorshipHenry 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.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationRoy, 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.14221en
dc.identifier.doi10.1111/bjh.14221en
dc.identifier.eissn1365-2141
dc.identifier.endpage330en
dc.identifier.issn0007-1048
dc.identifier.issued2en
dc.identifier.journaltitleBritish Journal of Haematologyen
dc.identifier.startpage318en
dc.identifier.urihttps://hdl.handle.net/10468/8937
dc.identifier.volume175en
dc.language.isoenen
dc.publisherWileyen
dc.relation.urihttps://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.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectInherited anaemiaen
dc.subjectCongenital dyserythropoietic anaemiaen
dc.subjectMolecular geneticsen
dc.subjectPyruvate kinase deficiencyen
dc.subjectNext-generation sequencingen
dc.titleA novel 33-Gene targeted resequencing panel provides accurate, clinical-grade diagnosis and improves patient management for rare inherited anaemiasen
dc.typeArticle (peer-reviewed)en
Files
Original bundle
Now showing 1 - 5 of 5
Thumbnail Image
Name:
Roy_et_al-2016-British_Journal_of_Haematology.pdf
Size:
457.96 KB
Format:
Adobe Portable Document Format
Description:
Published version
Download
Thumbnail Image
Name:
bjh14221-sup-0001-figs1.pdf
Size:
310.14 KB
Format:
Adobe Portable Document Format
Description:
Supplementary file 1
Download
Thumbnail Image
Name:
bjh14221-sup-0002-figs2.pdf
Size:
309.27 KB
Format:
Adobe Portable Document Format
Description:
Supplementary file 2
Download
Thumbnail Image
Name:
bjh14221-sup-0003-figs3.pdf
Size:
491.98 KB
Format:
Adobe Portable Document Format
Description:
Supplementary file 3
Download
Thumbnail Image
Name:
bjh14221-sup-0004-tables1-s4.docx
Size:
76.28 KB
Format:
Microsoft Word XML
Description:
Supplementary file 4
Download
License bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
license.txt
Size:
2.71 KB
Format:
Item-specific license agreed upon to submission
Description:
Download
Collections
Pathology - Journal Articles