{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T07:15:01Z","timestamp":1792826101114,"version":"4.5.0"},"reference-count":46,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T00:00:00Z","timestamp":1740441600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The hereditary spastic\u2010ataxia spectrum disorders are a group of disabling neurological diseases. The traditional genetic testing pathway is complex, multistep and leaves many cases unsolved. We aim to streamline and improve this process using long\u2010read sequencing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We developed a targeted long\u2010read sequencing strategy with the capacity to characterise the genetic variation of all types and sizes within 469 disease\u2010associated genes, in a single assay. We applied this to a cohort of 34 individuals with unsolved spastic\u2010ataxia. An additional five individuals with a known genetic diagnosis were included as positive controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified causative pathogenic variants that would be sufficient for genetic diagnosis in 14\/34 (41%) unsolved participants. The success rate was 5\/11 (45%) in those who were na\u00efve to genetic testing and 9\/23 (39%) in those who were undiagnosed after prior genetic testing, completed on a clinical basis. Short tandem repeat expansions in\n                      <jats:italic>FGF14<\/jats:italic>\n                      were the most common (7\/34, 21%). Two individuals (2\/34, 6%) had biallelic pathogenic expansions in\n                      <jats:italic>RFC1<\/jats:italic>\n                      and one individual had a monoallelic pathogenic expansion in\n                      <jats:italic>ATXN8OS<\/jats:italic>\n                      \/\n                      <jats:italic>ATXN8<\/jats:italic>\n                      . Causative pathogenic sequence variants other than short tandem repeat expansions were found in four individuals, including in\n                      <jats:italic>VCP<\/jats:italic>\n                      ,\n                      <jats:italic>STUB1<\/jats:italic>\n                      ,\n                      <jats:italic>ANO10<\/jats:italic>\n                      and\n                      <jats:italic>SPG7<\/jats:italic>\n                      . Furthermore, all five positive controls were identified.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>Our results demonstrate the utility of targeted long\u2010read sequencing in the genetic evaluation of patients with spastic\u2010ataxia spectrum disorders, highlighting both the capacity to increase overall diagnostic yield and to streamline the testing pathway by capturing all known genetic causes in a single assay.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.70008","type":"journal-article","created":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T01:41:58Z","timestamp":1740534118000},"page":"832-841","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Targeted Long\u2010Read Sequencing as a Single Assay Improves the Diagnosis of Spastic\u2010Ataxia Disorders"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1100-319X","authenticated-orcid":false,"given":"Laura Ivete","family":"Rudaks","sequence":"first","affiliation":[{"name":"Molecular Medicine Laboratory and Neurology Department Concord Repatriation General Hospital  Concord New South Wales Australia"},{"name":"Faculty of Medicine and Health University of Sydney  Camperdown New South Wales Australia"},{"name":"Genomic and Inherited Disease Program The Garvan Institute of Medical Research  Darlinghurst New South Wales Australia"},{"name":"Clinical Genetics Unit Royal North Shore Hospital  St Leonards New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7713-1979","authenticated-orcid":false,"given":"Igor","family":"Stevanovski","sequence":"additional","affiliation":[{"name":"Genomic and Inherited Disease Program The Garvan Institute of Medical Research  Darlinghurst New South Wales Australia"},{"name":"Centre for Population Genomics The Garvan Institute of Medical Research  Darlinghurst New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Yeow","sequence":"additional","affiliation":[{"name":"Molecular Medicine Laboratory and Neurology Department Concord Repatriation General Hospital  Concord New South Wales Australia"},{"name":"Faculty of Medicine and Health University of Sydney  Camperdown New South Wales Australia"},{"name":"Genomic and Inherited Disease Program The Garvan Institute of Medical Research  Darlinghurst New South Wales Australia"},{"name":"Neurodegenerative Service Prince of Wales Hospital  Randwick New South Wales Australia"},{"name":"Neuroscience Research Australia  Randwick New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre L. M.","family":"Reis","sequence":"additional","affiliation":[{"name":"Genomic and Inherited Disease Program The Garvan Institute of Medical Research  Darlinghurst New South Wales Australia"},{"name":"Centre for Population Genomics The Garvan Institute of Medical Research  Darlinghurst New South Wales Australia"},{"name":"Faculty of Medicine University of New South Wales  Kensington New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjog R.","family":"Chintalaphani","sequence":"additional","affiliation":[{"name":"Genomic and Inherited Disease Program The Garvan Institute of Medical Research  Darlinghurst New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pak Leng","family":"Cheong","sequence":"additional","affiliation":[{"name":"Molecular Medicine Laboratory and Neurology Department Concord Repatriation General Hospital  Concord New South Wales Australia"},{"name":"Faculty of Medicine and Health University of Sydney  Camperdown New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hasindu","family":"Gamaarachchi","sequence":"additional","affiliation":[{"name":"Genomic and Inherited Disease Program The Garvan Institute of Medical Research  Darlinghurst New South Wales Australia"},{"name":"Centre for Population Genomics The Garvan Institute of Medical Research  Darlinghurst New South Wales Australia"},{"name":"School of Computer Science and Engineering University of New South Wales  Kensington New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Worgan","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health University of Sydney  Camperdown New South Wales Australia"},{"name":"Clinical Genetics Service Royal Prince Alfred Hospital  Camperdown New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Neurology Department Royal North Shore Hospital  St Leonards New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Hayes","sequence":"additional","affiliation":[{"name":"Molecular Medicine Laboratory and Neurology Department Concord Repatriation General Hospital  Concord New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Hannaford","sequence":"additional","affiliation":[{"name":"Molecular Medicine Laboratory and Neurology Department Concord Repatriation General Hospital  Concord New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Kim","sequence":"additional","affiliation":[{"name":"Movement Disorders Unit, Neurology Department Westmead Hospital  Westmead New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor S. 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