1. Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study
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Kristina Ibañez, James Polke, R Tanner Hagelstrom, Egor Dolzhenko, Dorota Pasko, Ellen Rachel Amy Thomas, Louise C Daugherty, Dalia Kasperaviciute, Katherine R Smith, Zandra C Deans, Sue Hill, Tom Fowler, Richard H Scott, John Hardy, Patrick F Chinnery, Henry Houlden, Augusto Rendon, Mark J Caulfield, Michael A Eberle, Ryan J Taft, Arianna Tucci, Ellen M McDonagh, Antonio Rueda, Dimitris Polychronopoulos, Georgia Chan, Heather Angus-Leppan, Kailash P Bhatia, James E Davison, Richard Festenstein, Pietro Fratta, Paola Giunti, Robin Howard, Laxmi Venkata, 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, Viraj Deshpande, Denise L Perry, Subramanian S. Ajay, Aditi Chawla, Vani Rajan, Kathryn Oprych, Angela Douglas, Gill Wilson, Sian Ellard, I Karen Temple, Andrew Mumford, Dom McMullan, Kikkeri Naresh, Frances A Flinter, Jenny C Taylor, Lynn Greenhalgh, William Newman, Paul Brennan, John A Sayer, F Lucy Raymond, Lyn S Chitty, John C. Ambrose, Prabhu Arumugam, Marta Bleda, Freya Boardman-Pretty, Jeanne M. Boissiere, Christopher R. Boustred, Clare E.H. Craig, Anna de Burca, Andrew Devereau, Greg Elgar, Rebecca E. Foulger, Pedro Furió-Tarí, Joanne Hackett, Dina Halai, Angela Hamblin, Shirley Henderson, James Holman, Tim J.P. Hubbard, Rob Jackson, Louise J. Jones, Melis Kayikci, Lea Lahnstein, Kay Lawson, Sarah E.A. Leigh, Ivonne U.S. Leong, Javier F. Lopez, Fiona Maleady-Crowe, Joanne Mason, Michael Mueller, Nirupa Murugaesu, Chris A. Odhams, Daniel Perez-Gil, John Pullinger, Tahrima Rahim, Pablo Riesgo-Ferreiro, Tim Rogers, Mina Ryten, Kevin Savage, Kushmita Sawant, Afshan Siddiq, Alexander Sieghart, Damian Smedley, Alona Sosinsky, William Spooner, Helen E. Stevens, Alexander Stuckey, Razvan Sultana, Simon R. Thompson, Carolyn Tregidgo, Emma Walsh, Sarah A. Watters, Matthew J. Welland, Eleanor Williams, Katarzyna Witkowska, Suzanne M. Wood, and Magdalena Zarowiecki
- Subjects
Fragile X Mental Retardation Protein ,DNA Repeat Expansion ,Whole Genome Sequencing ,Whole Genome Sequencing/methods ,Humans ,Neurology (clinical) ,Prospective Studies ,Child ,Fragile X Mental Retardation Protein/genetics ,State Medicine ,United Kingdom ,Retrospective Studies - 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.
- Published
- 2022
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