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However, traditional PCR amplification and short\u2010read next\u2010generation sequencing\u2010based methods often fail to detect large\u2010scale, complex expansions and to capture methylation information. Thus, this study aimed to modify an amplification\u2010free nanopore Cas9\u2010targeted sequencing (nCATS) platform to achieve uniform coverage across 56 currently defined STR loci using a single test with genomic DNA from patient\u2010derived blood cells and to develop a dedicated analysis algorithm, STRiker, capable of identifying internal motif contexts and\n                    <jats:italic>de novo<\/jats:italic>\n                    repeat structures. Ultimately, this study identified pathogenic repeat expansions in 12 of 37 patients (32.4%) with cerebellar ataxia who remained genetically undiagnosed despite extensive prior genetic testing, in\n                    <jats:italic>FGF14<\/jats:italic>\n                    (\n                    <jats:italic>n<\/jats:italic>\n                    = 4),\n                    <jats:italic>ATXN8OS<\/jats:italic>\n                    ,\n                    <jats:italic>NOP56<\/jats:italic>\n                    ,\n                    <jats:italic>RFC1<\/jats:italic>\n                    (\n                    <jats:italic>n<\/jats:italic>\n                    = 2 each), and\n                    <jats:italic>PRNP<\/jats:italic>\n                    and\n                    <jats:italic>NOTCH2NLC<\/jats:italic>\n                    (\n                    <jats:italic>n<\/jats:italic>\n                    = 1 each). Additionally, family\u2010based cascade screening revealed six relatives with repeat expansions in five families. These results demonstrate a broader diversity of pathogenic repeat structures, particularly in\n                    <jats:italic>FGF14<\/jats:italic>\n                    , and illustrate that CpG methylation can mitigate the pathogenic effects of repeat expansions. This nCATS\u2013STRiker workflow offers a powerful strategy for improving the diagnosis of STR\u2010related neurogenetic diseases, such as cerebellar ataxia and other diseases.\n                  <\/jats:p>","DOI":"10.1002\/advs.77475","type":"journal-article","created":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T11:06:14Z","timestamp":1788001574000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optimized Cas9\u2010Enriched Nanopore Sequencing and Analysis Workflow for Clinical Diagnosis of Repeat Expansion Disorders"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3145-8714","authenticated-orcid":false,"given":"Seungbok","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Genomic Medicine Seoul National University Hospital  Seoul South Korea"},{"name":"Department of Pediatrics Seoul National University College of Medicine Seoul National University Children's 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Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang Kun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Neurology Seoul National University College of Medicine and Seoul National University Hospital  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8219-9663","authenticated-orcid":false,"given":"Han\u2010Joon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Neurology Seoul National University College of Medicine and Seoul National University Hospital  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong\u2010Hee","family":"Chae","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine Seoul National University Hospital  Seoul South Korea"},{"name":"Department of Pediatrics Seoul National University College of Medicine Seoul National University Children's Hospital  Seoul South 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