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Currently, much remains unknown about which variables may modify these diseases. We sought to investigate associations between <jats:italic>C9orf72<\/jats:italic> promoter methylation, RNA expression levels, and repeat length, their potential effects on disease features, as well as changes over time and within families.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>All samples were obtained through the ALS Center at Mayo Clinic Florida. Our primary cohort included 75 unrelated patients with an expanded <jats:italic>C9orf72<\/jats:italic> repeat, 33 patients who did not possess this expansion, and 20 control subjects without neurodegenerative diseases. Additionally, 67 members from 17 independent <jats:italic>C9orf72<\/jats:italic> families were selected of whom 33 harbored this expansion. Longitudinally collected samples were available for 35 <jats:italic>C9orf72<\/jats:italic> expansion carriers. To increase our understanding of <jats:italic>C9orf72<\/jats:italic>-related diseases, we performed quantitative methylation-sensitive restriction enzyme-based assays, digital molecular barcoding, quantitative real-time PCR, and Southern blotting.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>In our primary cohort, higher methylation levels were observed in patients with a <jats:italic>C9orf72<\/jats:italic> repeat expansion than in patients without this expansion (<jats:bold><jats:italic>p<\/jats:italic><\/jats:bold>\u2009=\u20091.7e-13) or in control subjects (<jats:bold><jats:italic>p<\/jats:italic><\/jats:bold>\u2009=\u20093.3e-07). Moreover, we discovered that an increase in methylation levels was associated with a decrease in total <jats:italic>C9orf72<\/jats:italic> transcript levels (<jats:bold><jats:italic>p<\/jats:italic><\/jats:bold>\u2009=\u20095.5e-05). These findings aligned with our observation that <jats:italic>C9orf72<\/jats:italic> expansion carriers had lower expression levels of total <jats:italic>C9orf72<\/jats:italic> transcripts than patients lacking this expansion (<jats:bold><jats:italic>p<\/jats:italic><\/jats:bold>\u2009=\u20093.7e-07) or control subjects (<jats:bold><jats:italic>p<\/jats:italic><\/jats:bold>\u2009=\u20099.1e-05). We also detected an elevation of transcripts containing intron 1a (upstream of the repeat) in patients carrying a <jats:italic>C9orf72<\/jats:italic> repeat expansion compared to (disease) controls (<jats:bold><jats:italic>p<\/jats:italic><\/jats:bold>\u2009\u2264\u20090.01), an indication of abortive transcripts and\/or a switch in transcription start site usage. While methylation and expression levels were relatively stable over time, fluctuations were seen in repeat length. Interestingly, contractions occurred frequently in parent-offspring transmissions (&gt;\u200950%), especially in paternal transmissions. Furthermore, smaller repeat lengths were detected in currently unaffected individuals than in affected individuals (<jats:bold><jats:italic>p<\/jats:italic><\/jats:bold>\u2009=\u20098.9e-04) and they were associated with an earlier age at collection (<jats:bold><jats:italic>p<\/jats:italic><\/jats:bold>\u2009=\u20090.008).<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusions<\/jats:title>\n<jats:p>In blood from <jats:italic>C9orf72<\/jats:italic> expansion carriers, we found elevated methylation levels, reduced expression levels, and unstable expansions that tend to contract in successive generations, arguing against anticipation.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s13024-020-0359-8","type":"journal-article","created":{"date-parts":[[2020,1,30]],"date-time":"2020-01-30T13:03:13Z","timestamp":1580389393000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Elevated methylation levels, reduced expression levels, and frequent contractions in a clinical cohort of C9orf72 expansion carriers"],"prefix":"10.1186","volume":"15","author":[{"given":"Jazmyne L.","family":"Jackson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"NiCole A.","family":"Finch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew C.","family":"Baker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer M.","family":"Kachergus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariely","family":"DeJesus-Hernandez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Pereira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Christopher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mercedes","family":"Prudencio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael G.","family":"Heckman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. Aubrey","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis W.","family":"Dickson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaimin","family":"Shah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Oskarsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonard","family":"Petrucelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Rademakers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3054-7053","authenticated-orcid":false,"given":"Marka","family":"van Blitterswijk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,1,30]]},"reference":[{"key":"359_CR1","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.neuron.2011.09.011","volume":"72","author":"M DeJesus-Hernandez","year":"2011","unstructured":"DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J, et al. 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Am J Hum Genet. 1997;61:101\u201310.","journal-title":"Am J Hum Genet"}],"container-title":["Molecular Neurodegeneration"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13024-020-0359-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13024-020-0359-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13024-020-0359-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,29]],"date-time":"2021-01-29T00:22:08Z","timestamp":1611879728000},"score":1,"resource":{"primary":{"URL":"https:\/\/molecularneurodegeneration.biomedcentral.com\/articles\/10.1186\/s13024-020-0359-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,30]]},"references-count":28,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["359"],"URL":"https:\/\/doi.org\/10.1186\/s13024-020-0359-8","relation":{},"ISSN":["1750-1326"],"issn-type":[{"value":"1750-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,30]]},"assertion":[{"value":"29 October 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 January 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 January 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All subjects agreed to be in the study, and biological specimens were obtained after informed consent with approval from the Mayo Clinic Institutional Review Board (IRB).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"MDJ and RR hold a patent on methods to screen for the hexanucleotide repeat expansion in the <i>C9orf72<\/i> gene. No other competing interests were declared.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"7"}}