New Results
Whole genome sequencing for diagnosis of neurological repeat expansion disorders
Kristina Ibanez, James Polke, Tanner Hagelstrom, View ORCID ProfileEgor Dolzhenko, Dorota Pasko, Ellen Thomas, Louise Daugherty, Dalia Kasperaviciute, Ellen M McDonagh, Katherine R Smith, Antonio Rueda Martin, Dimitris Polychronopoulos, Heather Angus-Leppan, Kailash P Bhatia, James E Davison, Richard Festenstein, Pietro Fratta, Paola Giunti, Robin Howard, Laxmi Venkata Prasad Korlipara, Matilde Laurá, Meriel McEntagart, Lara Menzies, Huw Morris, Mary M Reilly, Robert Robinson, Elisabeth Rosser, Francesca Faravelli, Anette Schrag, Jonathan M Schott, Thomas T Warner, Nicholas W Wood, David Bourn, Kelly Eggleton, Robyn Labrum, Philip Twiss, Stephen Abbs, Liana Santos, Ghareesa Almheiri, Isabella Sheikh, Jana Vandrovcova, Christine Patch, Ana Lisa Taylor Tavares, Zerin Hyder, Anna Need, Helen Brittain, Emma Baple, Loukas Moutsianas, Genomics England Research Consortium, Viraj Deshpande, Denise L Perry, Shankar Ajay, Aditi Chawla, Vani Rajan, Kathryn Oprych, Patrick F Chinnery, Angela Douglas, Gill Wilson, Sian Ellard, Karen Temple, Andrew Mumford, Dom McMullan, Kikkeri Naresh, Frances Flinter, Jenny C Taylor, Lynn Greenhalgh, William Newman, Paul Brennan, John A. Sayer, F Lucy Raymond, Lyn S Chitty, Zandra C Deans, Sue Hill, Tom Fowler, Richard Scott, Henry Houlden, Augusto Rendon, Mark J Caulfield, View ORCID ProfileMichael A Eberle, Ryan J Taft, Arianna Tucci
doi: https://doi.org/10.1101/2020.11.06.371716
Kristina Ibanez
1Genomics England, Queen Mary University of London, Charterhouse Square, London, EC1M, UK
2William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, UK
PhDJames Polke
3Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London, UK
PhDTanner Hagelstrom
4Illumina, Inc, 5200 Illumina Way, San Diego, California, 92122, USA
PhDEgor Dolzhenko
4Illumina, Inc, 5200 Illumina Way, San Diego, California, 92122, USA
PhDDorota Pasko
1Genomics England, Queen Mary University of London, Charterhouse Square, London, EC1M, UK
PhDEllen Thomas
1Genomics England, Queen Mary University of London, Charterhouse Square, London, EC1M, UK
MRCPC PhDLouise Daugherty
1Genomics England, Queen Mary University of London, Charterhouse Square, London, EC1M, UK
5Healx Ltd., Charter House, 66-68 Hills Rd, Cambridge, CB2 1LA, UK
Dalia Kasperaviciute
1Genomics England, Queen Mary University of London, Charterhouse Square, London, EC1M, UK
2William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, UK
PhDEllen M McDonagh
1Genomics England, Queen Mary University of London, Charterhouse Square, London, EC1M, UK
6Open Targets and European Molecular Biology Laboratory - European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, CB10 1SD, UK
PhDKatherine R Smith
1Genomics England, Queen Mary University of London, Charterhouse Square, London, EC1M, UK
PhDAntonio Rueda Martin
1Genomics England, Queen Mary University of London, Charterhouse Square, London, EC1M, UK
Dimitris Polychronopoulos
1Genomics England, Queen Mary University of London, Charterhouse Square, London, EC1M, UK
PhDHeather Angus-Leppan
7Royal Free London NHS Foundation Trust, London, UK
8UCL Queen Square Institute of Neurology London, London, UK
MBBS (Hons) MSc MD FRACP FRCPKailash P Bhatia
9Department of Movement and Clinical Neuroscience, UCL Queen Square Institute of Neurology, University College London, London, UK
MDJames E Davison
10Metabolic Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
PhDRichard Festenstein
11Gene Control Mechanisms and Disease Group, Faculty of Medicine, Department of Brain Sciences and MRC, London, UK
12Institute for Medical Sciences, Imperial College London, Hammersmith Hospital, London, UK
MB BS FRCP PhDPietro Fratta
13Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, UK
MD PhDPaola Giunti
14National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS trust, London, UK
9Department of Movement and Clinical Neuroscience, UCL Queen Square Institute of Neurology, University College London, London, UK
MDRobin Howard
14National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS trust, London, UK
PhDLaxmi Venkata Prasad Korlipara
15UCL Movement Disorders Centre, Institute of Neurology, London, UK
PhD MBBS FRCPMatilde Laurá
16Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
MD PhDMeriel McEntagart
17St George’s, University of London, London, UK
MDLara Menzies
18Department of Clinical Genetics, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
PhDHuw Morris
19Department of Movement and Clinical Neuroscience, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK
20UCL Movement Disorders Centre, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK
MDMary M Reilly
14National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS trust, London, UK
16Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
MDRobert Robinson
21Great Ormond Street Hospital for Children National Health Service Trust, London, UK
PhDElisabeth Rosser
18Department of Clinical Genetics, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
MDFrancesca Faravelli
18Department of Clinical Genetics, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
Anette Schrag
22Department of Movement and Clinical Neuroscience, UCL Queen Square Institute of Neurology, University College London, London, WCN 3BG, UK
MDJonathan M Schott
23Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, London, WCN 3BG, UK
MDThomas T Warner
9Department of Movement and Clinical Neuroscience, UCL Queen Square Institute of Neurology, University College London, London, UK
24Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK
25Reta Lila Weston Institute of Neurological Studies, UCL Queen Square Institute of Neurology, London, UK
FRCP PhDNicholas W Wood
9Department of Movement and Clinical Neuroscience, UCL Queen Square Institute of Neurology, University College London, London, UK
14National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS trust, London, UK
MDDavid Bourn
26Northern Genetics Service, Institute of Genetic Medicine, Central Parkway, Newcastle Upon Tyne, UK
Kelly Eggleton
3Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London, UK
Robyn Labrum
3Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London, UK
Philip Twiss
27East Midlands and East of England NHS Genomic Laboratory Hub, Addenbrooke’s Treatment Centre, Cambridge, UK
Stephen Abbs
27East Midlands and East of England NHS Genomic Laboratory Hub, Addenbrooke’s Treatment Centre, Cambridge, UK
Liana Santos
3Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London, UK
Ghareesa Almheiri
13Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, UK
Isabella Sheikh
13Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, UK
Jana Vandrovcova
13Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, UK
PhDChristine Patch
1Genomics England, Queen Mary University of London, Charterhouse Square, London, EC1M, UK
Ana Lisa Taylor Tavares
1Genomics England, Queen Mary University of London, Charterhouse Square, London, EC1M, UK
MDZerin Hyder
1Genomics England, Queen Mary University of London, Charterhouse Square, London, EC1M, UK
MDAnna Need
1Genomics England, Queen Mary University of London, Charterhouse Square, London, EC1M, UK
PhDHelen Brittain
1Genomics England, Queen Mary University of London, Charterhouse Square, London, EC1M, UK
MDEmma Baple
1Genomics England, Queen Mary University of London, Charterhouse Square, London, EC1M, UK
28University of Exeter Medical School, Exeter, EX2 5DW, UK
29Peninsula Clinical Genetics Service, Royal Devon & Exeter Hospital (Heavitree), Gladstone Road, Exeter, EX1 2ED, UK
MBBS, PhDLoukas Moutsianas
1Genomics England, Queen Mary University of London, Charterhouse Square, London, EC1M, UK
2William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, UK
PhD30Genomics England, Queen Mary University of London, London, EC1M, UK
Viraj Deshpande
4Illumina, Inc, 5200 Illumina Way, San Diego, California, 92122, USA
PhDDenise L Perry
4Illumina, Inc, 5200 Illumina Way, San Diego, California, 92122, USA
MSShankar Ajay
4Illumina, Inc, 5200 Illumina Way, San Diego, California, 92122, USA
PhDAditi Chawla
4Illumina, Inc, 5200 Illumina Way, San Diego, California, 92122, USA
PhDVani Rajan
4Illumina, Inc, 5200 Illumina Way, San Diego, California, 92122, USA
MSKathryn Oprych
31Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
32UCL GOS Institute of Child Health, London, UK
MDPatrick F Chinnery
33MRC Mitochondrial Biology Unit & Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
FRCPAngela Douglas
34Liverpool Women’s NHS Foundation Trust., Crown street, Liverpool, L8 7SS, UK
PhD FRCPathGill Wilson
35Sheffield Children’s Hospital Clarkson St, Broomhall, Sheffiel, S10 2TH, UK
FRCPSian Ellard
36University of Exeter Medical School, Royal Devon and Exeter Hospital, Wonford, Barrack Road, Exeter, EX2 5DW, UK
PhD FRCPathKaren Temple
37University of Southampton, University Road, Southampton, SO17 1BJ, UK
38Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK
PhD FRCPAndrew Mumford
39School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK
PhD FRCPDom McMullan
40Birmingham Women’s Hospital, Mindelsohn Way, Edgbaston, Birmingham, B15 2TG, UK
Kikkeri Naresh
41Imperial College Healthcare NHS Trust Hammersmith Hospital, Du Cane Road, London, W12 0HS, UK
Frances Flinter
42Clinical Genetics Department, Guy’s & St Thomas’ NHS Foundation Trust, London, SE1 9RT, UK
MDJenny C Taylor
43NIHR Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK
PhDLynn Greenhalgh
34Liverpool Women’s NHS Foundation Trust., Crown street, Liverpool, L8 7SS, UK
FRCPWilliam Newman
44Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PL, UK
MD PhDPaul Brennan
45North East & North Cumbria Genomic Medicine Centre, UK
FRCPJohn A. Sayer
46Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK
47National Institute for Health Research Newcastle Biomedical Research Centre, Newcastle upon Tyne, UK
48Renal Services, The Newcastle Upon Tyne Hospitals National Health Service Trust, Newcastle upon Tyne, NE77DN, UK
FRCP PhDF Lucy Raymond
49NIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK
50Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK
MDLyn S Chitty
31Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
32UCL GOS Institute of Child Health, London, UK
PhD MRCOGZandra C Deans
51UK National External Quality Assessment Service for Molecular Genetics/Genomics Quality Assessment, Department of Laboratory Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK
Sue Hill
52NHS England and NHS Improvement, London, UK
FMedSciTom Fowler
1Genomics England, Queen Mary University of London, Charterhouse Square, London, EC1M, UK
2William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, UK
FFPH PhD MPHRichard Scott
1Genomics England, Queen Mary University of London, Charterhouse Square, London, EC1M, UK
MRCPCH PhDHenry Houlden
3Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London, UK
13Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, UK
MD PhDAugusto Rendon
1Genomics England, Queen Mary University of London, Charterhouse Square, London, EC1M, UK
PhDMark J Caulfield
1Genomics England, Queen Mary University of London, Charterhouse Square, London, EC1M, UK
2William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, UK
FRCP FMedSciMichael A Eberle
4Illumina, Inc, 5200 Illumina Way, San Diego, California, 92122, USA
PhDRyan J Taft
4Illumina, Inc, 5200 Illumina Way, San Diego, California, 92122, USA
PhDArianna Tucci
2William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, UK
1Genomics England, Queen Mary University of London, Charterhouse Square, London, EC1M, UK
MD PhD
ABSTRACT
Background Repeat expansion (RE) disorders affect ~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 under diagnosis of atypical clinical presentations, especially in paediatric patients without a prior positive family history. Whole genome sequencing (WGS) is emerging as a first-line test for rare genetic disorders, but until recently REs were thought to be undetectable by this approach.
Methods WGS pipelines for RE disorder detection were deployed by the 100,000 Genomes Project and Illumina Clinical Services Laboratory. Performance was retrospectively assessed across the 13 most common neurological RE loci using 793 samples with prior orthogonal testing (182 with expanded alleles and 611 with alleles within normal size) and prospectively interrogated in 13,331 patients with suspected genetic neurological disorders.
Findings WGS RE detection showed minimum 97·3% sensitivity and 99·6% specificity across all 13 disease-associated loci. Applying the pipeline to patients from the 100,000 Genomes Project identified pathogenic repeat expansions which were confirmed in 69 patients, including seven paediatric patients with no reported family history of RE disorders, with a 0.09% false positive rate.
Interpretation We show here for the first time that WGS enables the detection of causative repeat expansions with high sensitivity and specificity, and that it can be used to resolve previously undiagnosed neurological disorders. This includes children with no prior suspicion of a RE disorder. These findings are leading to diagnostic implementation of this analytical pipeline in the NHS Genomic Medicine Centres in England.
Funding Medical Research Council, Department of Health and Social Care, National Health Service England, National Institute for Health Research, Illumina Inc
Competing Interest Statement
Genomics England Ltd is a wholly owned Department of Health and Social Care company created in 2013 to introduce WGS into healthcare in conjunction with NHS England. All Genomics England affiliated authors are, or were, salaried by or seconded to Genomics England. RJT, ME, ED, RTH are employees and shareholders of Illumina Inc.
Footnotes
↵† joint last authors
Copyright
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Posted November 06, 2020.
Whole genome sequencing for diagnosis of neurological repeat expansion disorders
Kristina Ibanez, James Polke, Tanner Hagelstrom, Egor Dolzhenko, Dorota Pasko, Ellen Thomas, Louise Daugherty, Dalia Kasperaviciute, Ellen M McDonagh, Katherine R Smith, Antonio Rueda Martin, Dimitris Polychronopoulos, Heather Angus-Leppan, Kailash P Bhatia, James E Davison, Richard Festenstein, Pietro Fratta, Paola Giunti, Robin Howard, Laxmi Venkata Prasad Korlipara, Matilde Laurá, Meriel McEntagart, Lara Menzies, Huw Morris, Mary M Reilly, Robert Robinson, Elisabeth Rosser, Francesca Faravelli, Anette Schrag, Jonathan M Schott, Thomas T Warner, Nicholas W Wood, David Bourn, Kelly Eggleton, Robyn Labrum, Philip Twiss, Stephen Abbs, Liana Santos, Ghareesa Almheiri, Isabella Sheikh, Jana Vandrovcova, Christine Patch, Ana Lisa Taylor Tavares, Zerin Hyder, Anna Need, Helen Brittain, Emma Baple, Loukas Moutsianas, Genomics England Research Consortium, Viraj Deshpande, Denise L Perry, Shankar Ajay, Aditi Chawla, Vani Rajan, Kathryn Oprych, Patrick F Chinnery, Angela Douglas, Gill Wilson, Sian Ellard, Karen Temple, Andrew Mumford, Dom McMullan, Kikkeri Naresh, Frances Flinter, Jenny C Taylor, Lynn Greenhalgh, William Newman, Paul Brennan, John A. Sayer, F Lucy Raymond, Lyn S Chitty, Zandra C Deans, Sue Hill, Tom Fowler, Richard Scott, Henry Houlden, Augusto Rendon, Mark J Caulfield, Michael A Eberle, Ryan J Taft, Arianna Tucci
bioRxiv 2020.11.06.371716; doi: https://doi.org/10.1101/2020.11.06.371716
Whole genome sequencing for diagnosis of neurological repeat expansion disorders
Kristina Ibanez, James Polke, Tanner Hagelstrom, Egor Dolzhenko, Dorota Pasko, Ellen Thomas, Louise Daugherty, Dalia Kasperaviciute, Ellen M McDonagh, Katherine R Smith, Antonio Rueda Martin, Dimitris Polychronopoulos, Heather Angus-Leppan, Kailash P Bhatia, James E Davison, Richard Festenstein, Pietro Fratta, Paola Giunti, Robin Howard, Laxmi Venkata Prasad Korlipara, Matilde Laurá, Meriel McEntagart, Lara Menzies, Huw Morris, Mary M Reilly, Robert Robinson, Elisabeth Rosser, Francesca Faravelli, Anette Schrag, Jonathan M Schott, Thomas T Warner, Nicholas W Wood, David Bourn, Kelly Eggleton, Robyn Labrum, Philip Twiss, Stephen Abbs, Liana Santos, Ghareesa Almheiri, Isabella Sheikh, Jana Vandrovcova, Christine Patch, Ana Lisa Taylor Tavares, Zerin Hyder, Anna Need, Helen Brittain, Emma Baple, Loukas Moutsianas, Genomics England Research Consortium, Viraj Deshpande, Denise L Perry, Shankar Ajay, Aditi Chawla, Vani Rajan, Kathryn Oprych, Patrick F Chinnery, Angela Douglas, Gill Wilson, Sian Ellard, Karen Temple, Andrew Mumford, Dom McMullan, Kikkeri Naresh, Frances Flinter, Jenny C Taylor, Lynn Greenhalgh, William Newman, Paul Brennan, John A. Sayer, F Lucy Raymond, Lyn S Chitty, Zandra C Deans, Sue Hill, Tom Fowler, Richard Scott, Henry Houlden, Augusto Rendon, Mark J Caulfield, Michael A Eberle, Ryan J Taft, Arianna Tucci
bioRxiv 2020.11.06.371716; doi: https://doi.org/10.1101/2020.11.06.371716
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