{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T14:20:40Z","timestamp":1791814840741,"version":"4.3.4"},"reference-count":18,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2021,4,23]],"date-time":"2021-04-23T00:00:00Z","timestamp":1619136000000},"content-version":"vor","delay-in-days":22,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005202","name":"Muscular Dystrophy Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005202","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000971","name":"ALS Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000971","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006827","name":"Florida Department of Health","doi-asserted-by":"publisher","award":["9AZ08"],"award-info":[{"award-number":["9AZ08"]}],"id":[{"id":"10.13039\/100006827","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21 NS110994"],"award-info":[{"award-number":["R21 NS110994"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21 NS099631"],"award-info":[{"award-number":["R21 NS099631"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35 NS097261"],"award-info":[{"award-number":["R35 NS097261"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35 NS097273"],"award-info":[{"award-number":["R35 NS097273"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P50 AG016574"],"award-info":[{"award-number":["P50 AG016574"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01 NS084974"],"award-info":[{"award-number":["P01 NS084974"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01 AG045390"],"award-info":[{"award-number":["U01 AG045390"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U54 NS092089"],"award-info":[{"award-number":["U54 NS092089"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AG037491"],"award-info":[{"award-number":["R01 AG037491"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,5,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>To examine the length of a hexanucleotide expansion in C9orf72, which represents the most frequent genetic cause of frontotemporal lobar degeneration and motor neuron disease, we employed a targeted amplification-free long-read sequencing technology: No-Amp sequencing. In our cross-sectional study, we assessed cerebellar tissue from 28 well-characterized C9orf72 expansion carriers. We obtained 3507 on-target circular consensus sequencing reads, of which 814 bridged the C9orf72 repeat expansion (23%). Importantly, we observed a significant correlation between expansion sizes obtained using No-Amp sequencing and Southern blotting (P\u2009=\u20095.0\u2009\u00d7\u200910\u22124). Interestingly, we also detected a significant survival advantage for individuals with smaller expansions (P\u2009=\u20090.004). Additionally, we uncovered that smaller expansions were significantly associated with higher levels of C9orf72 transcripts containing intron 1b (P\u2009=\u20090.003), poly(GP) proteins (P\u2009=\u20091.3\u2009\u00d7\u200910\u2212\u20095), and poly(GA) proteins (P\u2009=\u20090.005). Thorough examination of the composition of the expansion revealed that its GC content was extremely high (median: 100%) and that it was mainly composed of GGGGCC repeats (median: 96%), suggesting that expanded C9orf72 repeats are quite pure. Taken together, our findings demonstrate that No-Amp sequencing is a powerful tool that enables the discovery of relevant clinicopathological associations, highlighting the important role played by the cerebellar size of the expanded repeat in C9orf72-linked diseases.<\/jats:p>","DOI":"10.1093\/brain\/awab006","type":"journal-article","created":{"date-parts":[[2021,1,15]],"date-time":"2021-01-15T12:19:22Z","timestamp":1610713162000},"page":"1082-1088","source":"Crossref","is-referenced-by-count":35,"title":["Long-read targeted sequencing uncovers clinicopathological associations for<i>C9orf72<\/i>-linked diseases"],"prefix":"10.1093","volume":"144","author":[{"given":"Mariely","family":"DeJesus-Hernandez","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross A","family":"Aleff","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jazmyne L","family":"Jackson","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"NiCole A","family":"Finch","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew C","family":"Baker","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania F","family":"Gendron","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa E","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian J","family":"McLaughlin","sequence":"additional","affiliation":[{"name":"Pacific Biosciences of California, Inc., Menlo Park, CA 94025, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R","family":"Harting","sequence":"additional","affiliation":[{"name":"Pacific Biosciences of California, Inc., Menlo Park, CA 94025, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neill R","family":"Graff-Radford","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1725-9866","authenticated-orcid":false,"given":"Bj\u00f6rn","family":"Oskarsson","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S","family":"Knopman","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2930-8634","authenticated-orcid":false,"given":"Keith A","family":"Josephs","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley F","family":"Boeve","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald C","family":"Petersen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D","family":"Fryer","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Scottsdale, AZ 85259, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonard","family":"Petrucelli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7189-7917","authenticated-orcid":false,"given":"Dennis W","family":"Dickson","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4049-0863","authenticated-orcid":false,"given":"Rosa","family":"Rademakers","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark T W","family":"Ebbert","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric D","family":"Wieben","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marka","family":"van Blitterswijk","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,4,23]]},"reference":[{"key":"2021070719503661800_awab006-B1","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.neuron.2011.09.011","article-title":"Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS","volume":"72","author":"DeJesus-Hernandez","year":"2011","journal-title":"Neuron"},{"key":"2021070719503661800_awab006-B2","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.neuron.2011.09.010","article-title":"A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD","volume":"72","author":"Renton","year":"2011","journal-title":"Neuron"},{"key":"2021070719503661800_awab006-B3","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.neuron.2013.02.004","article-title":"Unconventional Translation of C9ORF72 GGGGCC Expansion Generates Insoluble Polypeptides Specific to c9FTD\/ALS","volume":"77","author":"Ash","year":"2013","journal-title":"Neuron"},{"key":"2021070719503661800_awab006-B4","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1126\/science.1232927","article-title":"The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD\/ALS","volume":"339","author":"Mori","year":"2013","journal-title":"Science"},{"key":"2021070719503661800_awab006-B5","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1016\/S1474-4422(13)70210-2","article-title":"Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72): A cross-sectional cohort study","volume":"12","author":"Van Blitterswijk","year":"2013","journal-title":"Lancet Neurol"},{"key":"2021070719503661800_awab006-B6","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1101\/gr.225672.117","article-title":"Detection of long repeat expansions from PCR-free whole-genome sequence data","volume":"27","author":"Dolzhenko","year":"2017","journal-title":"Genome Res"},{"key":"2021070719503661800_awab006-B7","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s13024-018-0274-4","article-title":"Long-read sequencing across the C9orf72 \u2018GGGGCC\u2019 repeat expansion: implications for clinical use and genetic discovery efforts in human disease","volume":"13","author":"Ebbert","year":"2018","journal-title":"Mol Neurodegener"},{"key":"2021070719503661800_awab006-B8","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1038\/s41587-019-0293-x","article-title":"Analysis of short tandem repeat expansions and their methylation state with nanopore sequencing","volume":"37","author":"Giesselmann","year":"2019","journal-title":"Nat Biotechnol"},{"key":"2021070719503661800_awab006-B9","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1002\/humu.23580","article-title":"Detailed analysis of HTT repeat elements in human blood using targeted amplification-free long-read sequencing","volume":"39","author":"Hoijer","year":"2018","journal-title":"Hum Mutat"},{"key":"2021070719503661800_awab006-B10","doi-asserted-by":"crossref","first-page":"e0219446","DOI":"10.1371\/journal.pone.0219446","article-title":"Amplification-free long-read sequencing of TCF4 expanded trinucleotide repeats in Fuchs Endothelial Corneal Dystrophy","volume":"14","author":"Wieben","year":"2019","journal-title":"PLoS One"},{"key":"2021070719503661800_awab006-B11","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/s00401-017-1725-7","article-title":"In-depth clinico-pathological examination of RNA foci in a large cohort of C9ORF72 expansion carriers","volume":"134","author":"DeJesus-Hernandez","year":"2017","journal-title":"Acta Neuropathol"},{"key":"2021070719503661800_awab006-B12","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1186\/s40478-019-0797-0","article-title":"Extensive transcriptomic study emphasizes importance of vesicular transport in C9orf72 expansion carriers","volume":"7","author":"Dickson","year":"2019","journal-title":"Acta Neuropathol Commun"},{"key":"2021070719503661800_awab006-B13","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1007\/s00401-015-1474-4","article-title":"Cerebellar c9RAN proteins associate with clinical and neuropathological characteristics of C9ORF72 repeat expansion carriers","volume":"130","author":"Gendron","year":"2015","journal-title":"Acta Neuropathol"},{"key":"2021070719503661800_awab006-B14","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1007\/s00401-015-1480-6","article-title":"Novel clinical associations with specific C9ORF72 transcripts in patients with repeat expansions in C9ORF72","volume":"130","author":"Van Blitterswijk","year":"2015","journal-title":"Acta Neuropathol"},{"key":"2021070719503661800_awab006-B15","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1212\/WNL.0b013e3182a8250c","article-title":"C9ORF72 repeat expansions in cases with previously identified pathogenic mutations","volume":"81","author":"Van Blitterswijk","year":"2013","journal-title":"Neurology"},{"key":"2021070719503661800_awab006-B16","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate - a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J R Stat Soc B"},{"key":"2021070719503661800_awab006-B17","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1007\/s00401-017-1793-8","article-title":"Sense-encoded poly-GR dipeptide repeat proteins correlate to neurodegeneration and uniquely co-localize with TDP-43 in dendrites of repeat-expanded C9orf72 amyotrophic lateral sclerosis","volume":"135","author":"Saberi","year":"2018","journal-title":"Acta Neuropathol"},{"key":"2021070719503661800_awab006-B18","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s40478-018-0564-7","article-title":"Poly-GR dipeptide repeat polymers correlate with neurodegeneration and Clinicopathological subtypes in C9ORF72-related brain disease","volume":"6","author":"Sakae","year":"2018","journal-title":"Acta Neuropathol Commun"}],"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awab006\/37305966\/awab006.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/brain\/article-pdf\/144\/4\/1082\/37903261\/awab006.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/brain\/article-pdf\/144\/4\/1082\/37903261\/awab006.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T13:00:41Z","timestamp":1724331641000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/article\/144\/4\/1082\/6247188"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,1]]},"references-count":18,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4,23]]},"published-print":{"date-parts":[[2021,5,7]]}},"URL":"https:\/\/doi.org\/10.1093\/brain\/awab006","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,4,1]]},"published":{"date-parts":[[2021,4,1]]}}}