The University of Southampton
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Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study

Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study
Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study

Background: repeat expansion disorders affect about 1 in 3000 individuals and are clinically heterogeneous diseases caused by expansions of short tandem DNA repeats. Genetic testing is often locus-specific, resulting in underdiagnosis of people who have atypical clinical presentations, especially in paediatric patients without a previous positive family history. Whole genome sequencing is increasingly used as a first-line test for other rare genetic disorders, and we aimed to assess its performance in the diagnosis of patients with neurological repeat expansion disorders.

Methods: we retrospectively assessed the diagnostic accuracy of whole genome sequencing to detect the most common repeat expansion loci associated with neurological outcomes (AR, ATN1, ATXN1, ATXN2, ATXN3, ATXN7, C9orf72, CACNA1A, DMPK, FMR1, FXN, HTT, and TBP) using samples obtained within the National Health Service in England from patients who were suspected of having neurological disorders; previous PCR test results were used as the reference standard. The clinical accuracy of whole genome sequencing to detect repeat expansions was prospectively examined in previously genetically tested and undiagnosed patients recruited in 2013–17 to the 100 000 Genomes Project in the UK, who were suspected of having a genetic neurological disorder (familial or early-onset forms of ataxia, neuropathy, spastic paraplegia, dementia, motor neuron disease, parkinsonian movement disorders, intellectual disability, or neuromuscular disorders). If a repeat expansion call was made using whole genome sequencing, PCR was used to confirm the result.

Findings: the diagnostic accuracy of whole genome sequencing to detect repeat expansions was evaluated against 793 PCR tests previously performed within the NHS from 404 patients. Whole genome sequencing correctly classified 215 of 221 expanded alleles and 1316 of 1321 non-expanded alleles, showing 97·3% sensitivity (95% CI 94·2–99·0) and 99·6% specificity (99·1–99·9) across the 13 disease-associated loci when compared with PCR test results. In samples from 11 631 patients in the 100 000 Genomes Project, whole genome sequencing identified 81 repeat expansions, which were also tested by PCR: 68 were confirmed as repeat expansions in the full pathogenic range, 11 were non-pathogenic intermediate expansions or premutations, and two were non-expanded repeats (16% false discovery rate). Interpretation: In our study, whole genome sequencing for the detection of repeat expansions showed high sensitivity and specificity, and it led to identification of neurological repeat expansion disorders in previously undiagnosed patients. These findings support implementation of whole genome sequencing in clinical laboratories for diagnosis of patients who have a neurological presentation consistent with a repeat expansion disorder. Funding: Medical Research Council, Department of Health and Social Care, National Health Service England, National Institute for Health Research, and Illumina.

1474-4422
234-245
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Ibañez, Kristina, Polke, James, Hagelstrom, R Tanner, Dolzhenko, Egor, Pasko, Dorota, Thomas, Ellen Rachel Amy, Daugherty, Louise C, Kasperaviciute, Dalia, Smith, Katherine R, Deans, Zandra C, Hill, Sue, Fowler, Tom, Scott, Richard H, Hardy, John, Chinnery, Patrick F, Houlden, Henry, Rendon, Augusto, Caulfield, Mark J, Eberle, Michael A, Taft, Ryan J, Tucci, Arianna, Ambrose, John C., Arumugam, Prabhu, Bleda, Marta, Boardman-pretty, Freya, Boissiere, Jeanne M., Boustred, Christopher R., Craig, Clare E.h., De Burca, Anna, Devereau, Andrew, Elgar, Greg, Foulger, Rebecca E., Furió-tarí, Pedro, Hackett, Joanne, Halai, Dina, Hamblin, Angela, Henderson, Shirley, Holman, James, Hubbard, Tim J.p., Jackson, Rob, Jones, Louise J., Kayikci, Melis, Lahnstein, Lea, Lawson, Kay, Leigh, Sarah E.a., Leong, Ivonne U.s., Lopez, Javier F., Maleady-crowe, Fiona, Mason, Joanne, Mueller, Michael, Murugaesu, Nirupa, Odhams, Chris A., Perez-gil, Daniel, Polychronopoulos, Dimitris, Pullinger, John, Rahim, Tahrima, Riesgo-ferreiro, Pablo, Rogers, Tim, Ryten, Mina, Savage, Kevin, Sawant, Kushmita, Siddiq, Afshan, Sieghart, Alexander, Smedley, Damian, Sosinsky, Alona, Spooner, William, Stevens, Helen E., Stuckey, Alexander, Sultana, Razvan, Thompson, Simon R., Tregidgo, Carolyn, Walsh, Emma, Watters, Sarah A., Welland, Matthew J., Williams, Eleanor, Witkowska, Katarzyna, Wood, Suzanne M., Zarowiecki, Magdalena and Temple, Karen (2022) Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study. The Lancet Neurology, 21 (3), 234-245. (doi:10.1016/S1474-4422(21)00462-2).

Record type: Article

Abstract

Background: repeat expansion disorders affect about 1 in 3000 individuals and are clinically heterogeneous diseases caused by expansions of short tandem DNA repeats. Genetic testing is often locus-specific, resulting in underdiagnosis of people who have atypical clinical presentations, especially in paediatric patients without a previous positive family history. Whole genome sequencing is increasingly used as a first-line test for other rare genetic disorders, and we aimed to assess its performance in the diagnosis of patients with neurological repeat expansion disorders.

Methods: we retrospectively assessed the diagnostic accuracy of whole genome sequencing to detect the most common repeat expansion loci associated with neurological outcomes (AR, ATN1, ATXN1, ATXN2, ATXN3, ATXN7, C9orf72, CACNA1A, DMPK, FMR1, FXN, HTT, and TBP) using samples obtained within the National Health Service in England from patients who were suspected of having neurological disorders; previous PCR test results were used as the reference standard. The clinical accuracy of whole genome sequencing to detect repeat expansions was prospectively examined in previously genetically tested and undiagnosed patients recruited in 2013–17 to the 100 000 Genomes Project in the UK, who were suspected of having a genetic neurological disorder (familial or early-onset forms of ataxia, neuropathy, spastic paraplegia, dementia, motor neuron disease, parkinsonian movement disorders, intellectual disability, or neuromuscular disorders). If a repeat expansion call was made using whole genome sequencing, PCR was used to confirm the result.

Findings: the diagnostic accuracy of whole genome sequencing to detect repeat expansions was evaluated against 793 PCR tests previously performed within the NHS from 404 patients. Whole genome sequencing correctly classified 215 of 221 expanded alleles and 1316 of 1321 non-expanded alleles, showing 97·3% sensitivity (95% CI 94·2–99·0) and 99·6% specificity (99·1–99·9) across the 13 disease-associated loci when compared with PCR test results. In samples from 11 631 patients in the 100 000 Genomes Project, whole genome sequencing identified 81 repeat expansions, which were also tested by PCR: 68 were confirmed as repeat expansions in the full pathogenic range, 11 were non-pathogenic intermediate expansions or premutations, and two were non-expanded repeats (16% false discovery rate). Interpretation: In our study, whole genome sequencing for the detection of repeat expansions showed high sensitivity and specificity, and it led to identification of neurological repeat expansion disorders in previously undiagnosed patients. These findings support implementation of whole genome sequencing in clinical laboratories for diagnosis of patients who have a neurological presentation consistent with a repeat expansion disorder. Funding: Medical Research Council, Department of Health and Social Care, National Health Service England, National Institute for Health Research, and Illumina.

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e-pub ahead of print date: 16 February 2022
Published date: 1 March 2022
Additional Information: Funding Information: Genomics England and the 100?000 Genomes Project was funded by the National Institute for Health Research (NIHR), the Wellcome Trust, the Medical Research Council, Cancer Research UK, the Department of Health and Social Care, and NHS England. We thank all the patients and health-care teams at the 13 NHS Genomic Medicine Centres in England, where around 5000 multidisciplinary staff enrolled patients to the 100?000 Genomes Project. Patients were also enrolled to the 100?000 Genomes Project from Scotland by the Scottish Genomes Project, and across Wales and Northern Ireland. This work forms part of the portfolio of translational research at the NIHR Biomedical Research Centres at Barts, Birmingham, Bristol, Cambridge, Great Ormond Street Foundation, Guy's and St Thomas?, Imperial, Leeds, Leicester, Manchester, Maudsley, Moorfields, Newcastle, Nottingham, Oxford, Royal Marsden, Sheffield, Southampton, and University College London. This work was made possible through the generosity of NHS patients and their families and uses clinical data from the NHS and NHS Digital. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. MJC is an NIHR senior investigator. PFC is a Wellcome Trust principal research fellow (212219/Z/18/Z), and an NIHR senior investigator, who receives support from the MRC Mitochondrial Biology Unit (MC_UU_00015/9), the MRC International Centre for Genomic Medicine in Neuromuscular Disease (MR/S005021/1), the Leverhulme Trust (RPG-2018?408), an MRC research grant (MR/S035699/1), and an Alzheimer's Society Project Grant (AS-PG-18b-022). AT is an MRC clinician scientist (MR/S006753/1). We thank Illumina Clinical Laboratory Sciences (San Diego, CA, USA), Illumina (San Diego, CA, USA), and Granta Park (Cambridge, UK) for undertaking whole genome sequencing and validation of true positives and negatives. We are grateful to the team at NHS England and for the work to fund and establish the 13 Genomic Medicine Centres. This enabled the NHS contribution to the 100?000 Genomes Project by enrolment of patients, receipt of the results, and, in some cases, orthogonal validation using standardised approaches, including return of findings for direct patient benefit. Funding Information: Genomics England is a company wholly owned by the UK Department of Health and Social Care and was created in 2013 to introduce whole genome sequencing into health care in conjunction with NHS England. All authors affiliated with Genomics England (KI, DP, ERAT, LCD, DK, KRS, TF, RHS, AR, MJC, and AT) are, or were, salaried by or seconded to Genomics England. RJT, MAE, ED, and RTH are employees and shareholders of Illumina. PFC is in receipt of a grant from the Wellcome Trust Medical Research Council (MRC). All other named authors declare no competing interests. Declarations of interests for members of the WGS for Neurological Diseases Group are provided in the appendix (p 14) . Funding Information: Genomics England and the 100 000 Genomes Project was funded by the National Institute for Health Research (NIHR), the Wellcome Trust, the Medical Research Council, Cancer Research UK, the Department of Health and Social Care, and NHS England. We thank all the patients and health-care teams at the 13 NHS Genomic Medicine Centres in England, where around 5000 multidisciplinary staff enrolled patients to the 100 000 Genomes Project. Patients were also enrolled to the 100 000 Genomes Project from Scotland by the Scottish Genomes Project, and across Wales and Northern Ireland. This work forms part of the portfolio of translational research at the NIHR Biomedical Research Centres at Barts, Birmingham, Bristol, Cambridge, Great Ormond Street Foundation, Guy's and St Thomas’, Imperial, Leeds, Leicester, Manchester, Maudsley, Moorfields, Newcastle, Nottingham, Oxford, Royal Marsden, Sheffield, Southampton, and University College London. This work was made possible through the generosity of NHS patients and their families and uses clinical data from the NHS and NHS Digital. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. Funding Information: MJC is an NIHR senior investigator. PFC is a Wellcome Trust principal research fellow (212219/Z/18/Z), and an NIHR senior investigator, who receives support from the MRC Mitochondrial Biology Unit (MC_UU_00015/9), the MRC International Centre for Genomic Medicine in Neuromuscular Disease (MR/S005021/1), the Leverhulme Trust (RPG-2018–408), an MRC research grant (MR/S035699/1), and an Alzheimer's Society Project Grant (AS-PG-18b-022). AT is an MRC clinician scientist (MR/S006753/1). We thank Illumina Clinical Laboratory Sciences (San Diego, CA, USA), Illumina (San Diego, CA, USA), and Granta Park (Cambridge, UK) for undertaking whole genome sequencing and validation of true positives and negatives. We are grateful to the team at NHS England and for the work to fund and establish the 13 Genomic Medicine Centres. This enabled the NHS contribution to the 100 000 Genomes Project by enrolment of patients, receipt of the results, and, in some cases, orthogonal validation using standardised approaches, including return of findings for direct patient benefit. Publisher Copyright: © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Copyright: Copyright 2022 Elsevier B.V., All rights reserved.

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Local EPrints ID: 455528
URI: http://eprints.soton.ac.uk/id/eprint/455528
ISSN: 1474-4422
PURE UUID: 4eb108f7-a00d-4fd0-919e-da14b88b7af1
ORCID for Karen Temple: ORCID iD orcid.org/0000-0002-6045-1781

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Date deposited: 24 Mar 2022 17:35
Last modified: 17 Mar 2024 02:48

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Author: Kristina Ibañez
Author: James Polke
Author: R Tanner Hagelstrom
Author: Egor Dolzhenko
Author: Dorota Pasko
Author: Ellen Rachel Amy Thomas
Author: Louise C Daugherty
Author: Dalia Kasperaviciute
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Author: Michael Mueller
Author: Nirupa Murugaesu
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Author: Pablo Riesgo-ferreiro
Author: Tim Rogers
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Author: Kevin Savage
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Author: Alona Sosinsky
Author: William Spooner
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Author: Simon R. Thompson
Author: Carolyn Tregidgo
Author: Emma Walsh
Author: Sarah A. Watters
Author: Matthew J. Welland
Author: Eleanor Williams
Author: Katarzyna Witkowska
Author: Suzanne M. Wood
Author: Magdalena Zarowiecki
Author: Karen Temple ORCID iD

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