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Cited by 187Genetic Neurodegenerative DiseasesGenomics and Rare DiseasesHereditary Neurological Disorders

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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Ibañez, Kristina, Polke, James, Hagelstrom, R Tanner, Dolzhenko, Egor, Pasko, Dorota, Thomas, Ellen Rachel Amy, Daugherty, Louise C, Kasperaviciute, Dalia +132 more·2022·The Lancet Neurology
DOI 10.1016/s1474-4422(21)00462-2PMC PMC8850201
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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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  • The accuracy of the STR caller in distinguishing expanded from nonexpanded STRs over clinically relevant loci has been characterized, achieving 97.3% sensitivity (215/221) and 99.6% specificity (1316/1321) across the 13 disease-associated loci compared to PCR test results.

    “The accuracy of the STR caller in distinguishing expanded from nonexpanded STRs over clinically relevant loci has been extensively characterized in a recent publication74, achieving 97.3% sensitivity (215/221) and 99.6% specificity (1316/1321) across the 13 disease-associated loci compared to PCR test results.”

    From Comprehensive genome analysis and variant detection at scale using DRAGEN (2025) · cites this paper as [74]

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Authors
Ibañez, K., Polke, J., Hagelstrom, R. T., Dolzhenko, E., Pasko, D., Thomas, E. R. A., Daugherty, L. C., Kasperaviciute, D., Smith, K. R., McDonagh, E. M., Rueda, A., Polychronopoulos, D., Chan, G., Angus-Leppan, H., Bhatia, K. P., Davison, J. E., Festenstein, R., Fratta, P., Giunti, P., Howard, R., Venkata, L., Laurá, M., McEntagart, M., Menzies, L., Morris, H., Reilly, M. M., Robinson, R., Rosser, E., Faravelli, F., Schrag, A., Schott, J. M., Warner, T. T., Wood, N. W., Bourn, D., Eggleton, K., Labrum, R., Twiss, P., Abbs, S., Santos, L., Almheiri, G., Sheikh, I., Vandrovcova, J., Patch, C., Taylor Tavares, A. L., Hyder, Z., Need, A., Brittain, H., Baple, E., Moutsianas, L., Deshpande, V., Perry, D. L., Ajay, S. S., Chawla, A., Rajan, V., Oprych, K., Chinnery, P. F., Douglas, A., Wilson, G., Ellard, S., Temple, I. K., Mumford, A., McMullan, D., Naresh, K., Flinter, F. A., Taylor, J. C., Greenhalgh, L., Newman, W., Brennan, P., Sayer, J. A., Raymond, F. L., Chitty, L. S., Deans, Z. C., Hill, S., Fowler, T., Scott, R. H., Hardy, J., Chinnery, P. F., Houlden, H., Rendon, A., Caulfield, M. J., Eberle, M. A., Taft, R. J., Tucci, A., Ambrose, J. C., Arumugam, P., Bleda, M., Boardman-Pretty, F., Boissiere, J. M., Boustred, C. R., Craig, C. E. H., de Burca, A., Devereau, A., Elgar, G., Foulger, R. E., Furió-Tarí, P., Hackett, J., Halai, D., Hamblin, A., Henderson, S., Holman, J., Hubbard, T. J. P., Jackson, R., Jones, L. J., Kayikci, M., Lahnstein, L., Lawson, K., Leigh, S. E. A., Leong, I. U. S., Lopez, J. F., Maleady-Crowe, F., Mason, J., Mueller, M., Murugaesu, N., Odhams, C. A., Perez-Gil, D., Polychronopoulos, D., Pullinger, J., Rahim, T., Riesgo-Ferreiro, P., Rogers, T., Ryten, M., Savage, K., Sawant, K., Siddiq, A., Sieghart, A., Smedley, D., Sosinsky, A., Spooner, W., Stevens, H. E., Stuckey, A., Sultana, R., Thompson, S. R., Tregidgo, C., Walsh, E., Watters, S. A., Welland, M. J., Williams, E., Witkowska, K., Wood, S. M., & Zarowiecki, M.
Affiliations
  • Queen Mary University of London (GB)
  • National Hospital for Neurology and Neurosurgery (GB)
  • Illumina (United States) (US)
  • Genomics England (GB)
  • Edinburgh Royal Infirmary (GB)
  • NHS England (GB)
  • UCL Queen Square Institute of Neurology (GB)
Corresponding author
  • Taft, Ryan J
  • Tucci, Arianna
ORCID
Venue
The Lancet Neurology
Publisher
Elsevier BV
Published
2022-03
Volume
21
Issue
3
Pages
234-245
ISSN
1474-4422 (ISSN-L)
DOI
10.1016/s1474-4422(21)00462-2
PMC
PMC8850201
OpenAlex
W4212820494
Cited by
187
References
1
Citations by year
2026: 30 · 2025: 51 · 2024: 49 · 2023: 39 · 2022: 17 · 2021: 1
FWCI
17.24
Type
journal article
Language
en
Open access
Licence
Locations
  • The Lancet Neurology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion, other-oa)
  • ePrints Soton (University of Southampton) (acceptedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Leverhulme Trust (MR/S035699/1, RPG-2018–408)
  • Department of Health and Social Care
  • Wellcome Trust
  • Cancer Research UK
  • Heart of England NHS Foundation Trust
  • Alzheimer's Society (AS-PG-18b-022)
  • Medical Research Council (MC_UU_00015/9, MR/S006753/1)
  • University College London (212219/Z/18/Z)
  • National Institute for Health and Care Research
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Keywords
repeat expansion disorders, short tandem repeat expansions, whole genome sequencing, diagnostic accuracy, CAG repeat expansion, C9orf72, ATN1, ataxin-1, huntingtin, FMR1 gene, frataxin, DMPK, CACNA1A, 100,000 Genomes Project, neurodegenerative diseases, ataxia, spastic paraplegia, motor neuron disease, intellectual disability, neuromuscular disorders
MeSH terms
Whole Genome Sequencing, Child, United Kingdom, Humans, Prospective Studies, Retrospective Studies, State Medicine, DNA Repeat Expansion, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1

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