{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T19:26:50Z","timestamp":1781551610997,"version":"3.54.5"},"reference-count":12,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T00:00:00Z","timestamp":1738022400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council Clinician Scientist Award","doi-asserted-by":"publisher","award":["MR\/S006753\/1"],"award-info":[{"award-number":["MR\/S006753\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Short tandem repeat expansions are the most common cause of inherited neurological diseases. These disorders are clinically and genetically heterogeneous, such as in myotonic dystrophy and spinocerebellar ataxia, and they are caused by different repeat motifs in different genomic locations. Major advances in bioinformatic tools used to detect repeat expansions from short read sequencing data in the last few years have led to the implementation of these workflows into next generation sequencing pipelines in healthcare. Here, we aimed to evaluate the clinical utility of analysing repeat expansions through exome sequencing in a large cohort of genetically undiagnosed patients with neurological disorders. Methods: We here analyse 27 disease-causing DNA repeats found in the coding, intronic and untranslated regions in 12,496 exomes in patients with a range of neurogenetic conditions. Results: We identified\u2014and validated by polymerase chain reaction\u201429 repeat expansions across a range of loci, 48% (n = 14) of which were diagnostic. We then analysed the genotyping performance across all repeat loci and found that, despite high coverage in most repeats in coding regions, some loci had low genotyping rates, such as those that cause spinocerebellar ataxia 2 (ATXN2, 0.1\u20138.4%) and Huntington disease (HTT, 0.2\u201358.2%), depending on the capture kit. Conversely, while most intronic repeats were not genotyped, we found a high genotyping rate in the intronic locus that causes spinocerebellar ataxia 36 (NOP56, 30.1\u201398.3%) and in the one that causes myotonic dystrophy type 1 (DMPK, myotonic dystrophy type 1). Conclusions: We show that the key factors that influence the genotyping rate of repeat expansion loci analysis are the sequencing read length and exome capture kit. These results provide important information about the performance of exome sequencing as a genetic test for repeat expansion disorders.<\/jats:p>","DOI":"10.3390\/genes16020169","type":"journal-article","created":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T06:47:29Z","timestamp":1738046849000},"page":"169","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Analysis of Short Tandem Repeat Expansions in a Cohort of 12,496 Exomes from Patients with Neurological Diseases Reveals Variable Genotyping Rate Dependent on Exome Capture Kits"],"prefix":"10.3390","volume":"16","author":[{"given":"Clarissa","family":"Rocca","sequence":"first","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Murphy","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Clarkson","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3343-1547","authenticated-orcid":false,"given":"Matteo","family":"Zanovello","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delia","family":"Gagliardi","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK"},{"name":"William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, UK"},{"name":"Department of Pathophysiology and Transplantation (DEPT), University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Queen Square","family":"Genomics","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rauan","family":"Kaiyrzhanov","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javeria","family":"Alvi","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neurology, The Children\u2019s Hospital and the University of Child Health Sciences, Lahore 54000, Punjab, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reza","family":"Maroofian","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4900-9877","authenticated-orcid":false,"given":"Stephanie","family":"Efthymiou","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tipu","family":"Sultan","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neurology, The Children\u2019s Hospital and the University of Child Health Sciences, Lahore 54000, Punjab, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Vandrovcova","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Polke","sequence":"additional","affiliation":[{"name":"Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robyn","family":"Labrum","sequence":"additional","affiliation":[{"name":"Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Houlden","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5644-0070","authenticated-orcid":false,"given":"Arianna","family":"Tucci","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, UK"},{"name":"Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s13073-022-01026-w","article-title":"A guide for the diagnosis of rare and undiagnosed disease: Beyond the exome","volume":"14","author":"Marwaha","year":"2022","journal-title":"Genome Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1136\/pn-2023-004083","article-title":"Lessons and pitfalls of whole genome sequencing","volume":"24","author":"Record","year":"2024","journal-title":"Pract. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.isci.2019.06.035","article-title":"Sequencing Technologies and Analyses: Where Have We Been and Where Are We Going?","volume":"18","author":"Bansal","year":"2019","journal-title":"IScience"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/S1474-4422(21)00462-2","article-title":"Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: A retrospective diagnostic accuracy and prospective clinical validation study","volume":"21","author":"Polke","year":"2022","journal-title":"Lancet Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1038\/s41436-021-01174-1","article-title":"Systematic analysis of short tandem repeats in 38,095 exomes provides an additional diagnostic yield","volume":"23","author":"Corominas","year":"2021","journal-title":"Genet. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4754","DOI":"10.1093\/bioinformatics\/btz431","article-title":"Expansion Hunter: A sequence-graph-based tool to analyze variation in short tandem repeat regions","volume":"35","author":"Dolzhenko","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows\u2013Wheeler transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_8","first-page":"11.10.1","article-title":"From FastQ data to high confidence variant calls: The Genome Analysis Toolkit best practices pipeline","volume":"43","author":"Carneiro","year":"2013","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.ajhg.2017.01.017","article-title":"Who\u2019s who? Detecting and resolving sample anomalies in human DNA sequencing studies with peddy","volume":"100","author":"Pedersen","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.tig.2013.07.006","article-title":"Finding the lost treasures in exome sequencing data","volume":"29","author":"Samuels","year":"2013","journal-title":"Trends Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1136\/jmg-2022-108924","article-title":"Fast and reliable detection of repeat expansions in spinocerebellar ataxia using exomes","volume":"60","author":"Davoine","year":"2023","journal-title":"J. Med. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1038\/s41431-024-01542-w","article-title":"Diagnostic uplift through the implementation of short tandem repeat analysis using exome sequencing","volume":"32","author":"Yoon","year":"2024","journal-title":"Eur. J. Hum. Genet."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/2\/169\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:37:45Z","timestamp":1759919865000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/2\/169"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,28]]},"references-count":12,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["genes16020169"],"URL":"https:\/\/doi.org\/10.3390\/genes16020169","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,28]]}}}