{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:35:12Z","timestamp":1790692512123,"version":"4.1.0"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2025,5,17]],"date-time":"2025-05-17T00:00:00Z","timestamp":1747440000000},"content-version":"vor","delay-in-days":136,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006065","name":"WA Department of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001232","name":"RACP","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001232","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Bryant Stokes Neurological Research Fund"},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Less than half of the individuals with hereditary cerebellar ataxia receives a genetic diagnosis. Repeat expansions account for disproportionate number of hereditary cerebellar ataxia and have genetically heterogeneous causes. These genetic loci include ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, ATXN8OS, ATXN10, PPP2R2B, TBP, ATN1, FMR1, BEAN1, NOP56, GLS, THAP11, GAA-FGF14, ZFHX3, FXN and RFC1. This study aims to assess the yield of short-read whole genome sequencing in the molecular diagnosis of hereditary cerebellar ataxia. We recruited 380 patients (351 probands) from a national ataxia centre in United Kingdom. They underwent short-read whole genome sequencing as a part of the 100 000 Genomes Project. Bioinformatic pipeline of whole genome sequencing include variant prioritization in selected virtual gene panels, customized analysis with a focus on repeat expansions, structural variants and recently reported hereditary cerebellar ataxia genes. All potential genetic variants were reviewed in a multidisciplinary team, and further confirmation tests were performed as appropriate. Whole genome sequencing identified causative variants in 115 (33%) out of 351 probands. We established 46 distinct presumptive molecular diagnoses with the most frequent being SPG7 (n = 22), RFC1 (n = 20) and CACNA1A (n = 10). However, it failed to detect any probands with novel ataxia gene GAA-FGF14, which was subsequently identified on polymerase chain reaction screening in 10 unsolved probands. In conclusion, whole genome sequencing is a useful diagnostic test in hereditary cerebellar ataxia patients and can be used to detect repeat expansions, structural and mitochondrial variants. However, identification of complex structural variants and sizing of large repeat expansions remains a challenge and require alternative molecular testing techniques.<\/jats:p>","DOI":"10.1093\/braincomms\/fcaf188","type":"journal-article","created":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T08:11:34Z","timestamp":1747383094000},"source":"Crossref","is-referenced-by-count":16,"title":["Diagnostic yield and limitations of whole-genome sequencing for hereditary cerebellar ataxia"],"prefix":"10.1093","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6284-9163","authenticated-orcid":false,"given":"Wai Yan","family":"Yau","sequence":"first","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG ,","place":["United Kingdom"]},{"name":"Perron Institute for Neurological and Translational Science, the University of Western Australia , Nedlands, Western Australia 6009 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roisin","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emer","family":"O\u2019Connor","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Pellerin","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael H","family":"Parkinson","sequence":"additional","affiliation":[{"name":"Ataxia Centre, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG ,","place":["UK"]},{"name":"National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust , London WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3508-4788","authenticated-orcid":false,"given":"Paola","family":"Giunti","sequence":"additional","affiliation":[{"name":"Ataxia Centre, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG ,","place":["UK"]},{"name":"National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust , London WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Jos\u00e9e","family":"Dicaire","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill University , Montreal, QC , , H3A 2B4","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt C","family":"Danzi","sequence":"additional","affiliation":[{"name":"Dr John T Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine , Miami, FL 33136 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8498-5235","authenticated-orcid":false,"given":"Stephan","family":"Z\u00fcchner","sequence":"additional","affiliation":[{"name":"Dr John T Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine , Miami, FL 33136 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1394-3561","authenticated-orcid":false,"given":"Bernard","family":"Brais","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill University , Montreal, QC , , H3A 2B4","place":["Canada"]},{"name":"Department of Human Genetics, McGill University , Montreal, QC , , H3A 2B4","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas W","family":"Wood","sequence":"additional","affiliation":[{"name":"National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust , London WC1N 3BG ,","place":["UK"]},{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology , London WC1N 3BG ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2866-7777","authenticated-orcid":false,"given":"Henry","family":"Houlden","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG ,","place":["United Kingdom"]},{"name":"National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust , London WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9508-0477","authenticated-orcid":false,"given":"Jana","family":"Vandrovcova","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,5,17]]},"reference":[{"issue":"3","key":"2025060607215316200_fcaf188-B1","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1159\/000358801","article-title":"The global epidemiology of hereditary ataxia and spastic paraplegia: A systematic review of prevalence studies","volume":"42","author":"Ruano","year":"2014","journal-title":"Neuroepidemiology"},{"issue":"2","key":"2025060607215316200_fcaf188-B2","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1007\/s00415-018-9076-4","article-title":"Spinocerebellar ataxia: An update","volume":"266","author":"Sullivan","year":"2019","journal-title":"J Neurol"},{"issue":"7","key":"2025060607215316200_fcaf188-B3","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1002\/mds.27415","article-title":"The genetic nomenclature of recessive cerebellar ataxias","volume":"33","author":"Rossi","year":"2018","journal-title":"Mov Disord"},{"issue":"2","key":"2025060607215316200_fcaf188-B4","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1038\/ng1001-184","article-title":"Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene","volume":"29","author":"Date","year":"2001","journal-title":"Nat Genet"},{"issue":"4","key":"2025060607215316200_fcaf188-B5","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1038\/s41588-019-0372-4","article-title":"Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia","volume":"51","author":"Cortese","year":"2019","journal-title":"Nat Genet"},{"issue":"2","key":"2025060607215316200_fcaf188-B6","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1136\/jnnp-2023-331490","article-title":"Intronic FGF14 GAA repeat expansions are a common cause of ataxia syndromes with neuropathy and bilateral vestibulopathy","volume":"95","author":"Pellerin","year":"2024","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"2","key":"2025060607215316200_fcaf188-B7","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1002\/humu.23946","article-title":"A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders","volume":"41","author":"Ngo","year":"2019","journal-title":"Hum Mutat"},{"issue":"20","key":"2025060607215316200_fcaf188-B8","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1056\/NEJMoa2035790","article-title":"100,000 genomes pilot on rare-disease diagnosis in health care\u2014Preliminary report","volume":"385","author":"Genomes Project Pilot Investigators","year":"2021","journal-title":"N Engl J Med"},{"key":"2025060607215316200_fcaf188-B9","unstructured":"Genomics England . 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