{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T06:59:58Z","timestamp":1789541998096,"version":"build-2803163510"},"reference-count":73,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T00:00:00Z","timestamp":1665619200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Medical Genetics Center Munich"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,5,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Instability of simple DNA repeats has been known as a common cause of hereditary ataxias for over 20 years. Routine genetic diagnostics of these phenotypically similar diseases still rely on an iterative workflow for quantification of repeat units by PCR-based methods of limited precision.<\/jats:p>\n                  <jats:p>We established and validated clinical nanopore Cas9-targeted sequencing, an amplification-free method for simultaneous analysis of 10 repeat loci associated with clinically overlapping hereditary ataxias. The method combines target enrichment by CRISPR\u2013Cas9, Oxford Nanopore long-read sequencing and a bioinformatics pipeline using the tools STRique and Megalodon for parallel detection of length, sequence, methylation and composition of the repeat loci.<\/jats:p>\n                  <jats:p>Clinical nanopore Cas9-targeted sequencing allowed for the precise and parallel analysis of 10 repeat loci associated with adult-onset ataxia and revealed additional parameter such as FMR1 promotor methylation and repeat sequence required for diagnosis at the same time. Using clinical nanopore Cas9-targeted sequencing we analysed 100 clinical samples of undiagnosed ataxia patients and identified causative repeat expansions in 28 patients. Parallel repeat analysis enabled a molecular diagnosis of ataxias independent of preconceptions on the basis of clinical presentation. Biallelic expansions within RFC1 were identified as the most frequent cause of ataxia. We characterized the RFC1 repeat composition of all patients and identified a novel repeat motif, AGGGG.<\/jats:p>\n                  <jats:p>Our results highlight the power of clinical nanopore Cas9-targeted sequencing as a readily expandable workflow for the in-depth analysis and diagnosis of phenotypically overlapping repeat expansion disorders.<\/jats:p>","DOI":"10.1093\/brain\/awac377","type":"journal-article","created":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T17:29:54Z","timestamp":1665595794000},"page":"1831-1843","source":"Crossref","is-referenced-by-count":44,"title":["Parallel in-depth analysis of repeat expansions in ataxia patients by long-read sequencing"],"prefix":"10.1093","volume":"146","author":[{"given":"Hannes","family":"Erdmann","sequence":"first","affiliation":[{"name":"Medical Genetics Center (MGZ) , Munich, 80335 , Germany"},{"name":"Friedrich-Baur-Institute, Department of Neurology, Klinikum der Universit\u00e4t, Ludwig-Maximilians-Universit\u00e4t , Munich, 80336 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Sch\u00f6berl","sequence":"additional","affiliation":[{"name":"Department of Neurology, Klinikum der Universit\u00e4t, Ludwig-Maximilians-Universit\u00e4t , Munich, 81377 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u0103d\u0103lina","family":"Giurgiu","sequence":"additional","affiliation":[{"name":"Medical Genetics Center (MGZ) , Munich, 80335 , Germany"},{"name":"Experimental and Clinical Research Center of the Max Delbr\u00fcck Center for Molecular Medicine and Charit\u00e9-Universit\u00e4tsmedizin Berlin , Berlin, 13125, Deutschland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafaela Magalhaes","family":"Leal Silva","sequence":"additional","affiliation":[{"name":"Medical Genetics Center (MGZ) , Munich, 80335 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Scholz","sequence":"additional","affiliation":[{"name":"Medical Genetics Center (MGZ) , Munich, 80335 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florentine","family":"Scharf","sequence":"additional","affiliation":[{"name":"Medical Genetics Center (MGZ) , Munich, 80335 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Wendlandt","sequence":"additional","affiliation":[{"name":"Medical Genetics Center (MGZ) , Munich, 80335 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Kleinle","sequence":"additional","affiliation":[{"name":"Medical Genetics Center (MGZ) , Munich, 80335 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Deschauer","sequence":"additional","affiliation":[{"name":"Department of Neurology, Klinikum Rechts der Isar, Technical University of Munich , Munich, 81675 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"N\u00fcbling","sequence":"additional","affiliation":[{"name":"Department of Neurology, Klinikum der Universit\u00e4t, Ludwig-Maximilians-Universit\u00e4t , Munich, 81377 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Heide","sequence":"additional","affiliation":[{"name":"Department of Neurology, General Hospital Celle , Celle, 29223 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sait Seymen","family":"Babacan","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Intensive Care, Klinikum Darmstadt , Darmstadt, 64283 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Center Augsburg , Augsburg, 86156 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Neuhann","sequence":"additional","affiliation":[{"name":"Medical Genetics Center (MGZ) , Munich, 80335 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Hahn","sequence":"additional","affiliation":[{"name":"Department of Neurology and Experimental Neurology, Charit\u00e9 Berlin , Berlin, 10117 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedikt","family":"Schoser","sequence":"additional","affiliation":[{"name":"Friedrich-Baur-Institute, Department of Neurology, Klinikum der Universit\u00e4t, Ludwig-Maximilians-Universit\u00e4t , Munich, 80336 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elke","family":"Holinski-Feder","sequence":"additional","affiliation":[{"name":"Medical Genetics Center (MGZ) , Munich, 80335 , Germany"},{"name":"Department of Medicine IV, Klinikum der Universit\u00e4t, Ludwig-Maximilians-Universit\u00e4t , Munich, 80336 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dieter A","family":"Wolf","sequence":"additional","affiliation":[{"name":"Medical Genetics Center (MGZ) , Munich, 80335 , Germany"},{"name":"Department of Medicine II, Klinikum rechts der Isar, Technical University Munich , Munich, 81675 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2757-8131","authenticated-orcid":false,"given":"Angela","family":"Abicht","sequence":"additional","affiliation":[{"name":"Medical Genetics Center (MGZ) , Munich, 80335 , Germany"},{"name":"Friedrich-Baur-Institute, Department of Neurology, Klinikum der Universit\u00e4t, Ludwig-Maximilians-Universit\u00e4t , Munich, 80336 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,10,13]]},"reference":[{"key":"2023050200170631200_awac377-B1","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1038\/nrg.2016.86","article-title":"Towards precision medicine","volume":"17","author":"Ashley","year":"2016","journal-title":"Nat Rev Genet"},{"key":"2023050200170631200_awac377-B2","doi-asserted-by":"crossref","first-page":"426","DOI":"10.3389\/fgene.2019.00426","article-title":"Long-read sequencing emerging in medical genetics","volume":"10","author":"Mantere","year":"2019","journal-title":"Front Genet"},{"key":"2023050200170631200_awac377-B3","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1186\/s13059-020-02017-z","article-title":"Expansion hunter de novo: A computational method for locating known and novel repeat expansions in short-read sequencing data","volume":"21","author":"Dolzhenko","year":"2020","journal-title":"Genome 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