{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T09:22:15Z","timestamp":1790155335755,"version":"4.0.1"},"reference-count":60,"publisher":"BMJ","issue":"9","funder":[{"DOI":"10.13039\/501100001349","name":"National Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2017,5,26]]},"published-print":{"date-parts":[[2017,9]]},"abstract":"<jats:p>C9orf72 repeat expansions is a major cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) worldwide. Sizes of &lt;20\u2009hexanucleotide repeats are observed in controls, while up to thousands associate with disease. Intermediate C9orf72 repeat lengths, however, remain uncertain. We systematically reviewed the role of intermediate C9orf72 alleles in C9orf72-related neurological disorders. We identified 49 studies with adequate available data on normal or intermediate C9orf72 repeat length, involving subjects with FTD, ALS, Parkinson\u2019s disease (PD), atypical parkinsonism, Alzheimer\u2019s disease (AD) and other aetiologies. We found that, overall, normal or intermediate C9orf72 repeat lengths are not associated with higher disease risk across these disorders, but intermediate allele sizes appear to associate more frequently with neuropsychiatric phenotypes. Intermediate sizes were detected in subjects with personal or family history of FTD and\/or psychiatric illness, parkinsonism complicated by psychosis and rarely in psychiatric cohorts. Length of the hexanucleotide repeat may be influenced by ethnicity (with Asian controls displaying shorter normal repeat lengths compared with Caucasians) and underlying haplotype, with more patients and controls carrying the \u2018risk\u2019 haplotype rs3849942 displaying intermediate alleles. There is some evidence that intermediate alleles display increased methylation levels and affect normal transcriptional activity of the C9orf72 promoter, but the \u2018critical\u2019 repeat size required for initiation of neurodegeneration remains unknown and requires further study. In common neurological diseases, intermediate C9orf72 repeats do not influence disease risk but may associate with higher frequency of neuropsychiatric symptoms. This has important clinical relevance as intermediate carriers pose a challenge for genetic counselling.<\/jats:p>","DOI":"10.1136\/jmedgenet-2017-104752","type":"journal-article","created":{"date-parts":[[2017,7,8]],"date-time":"2017-07-08T20:20:15Z","timestamp":1499545215000},"page":"591-597","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":54,"title":["Intermediate C9orf72 alleles in neurological disorders: does size really matter?"],"prefix":"10.1136","volume":"54","author":[{"given":"Adeline S L","family":"Ng","sequence":"first","affiliation":[{"name":"Department of Neurology, National Neuroscience Institute, Tan Tock Seng Hospital, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9928-4805","authenticated-orcid":false,"given":"Eng-King","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Singapore"},{"name":"Neuroscience and Behavioural Disorders, Duke-NUS Graduate Medical School, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2017,7,8]]},"reference":[{"key":"2025101710244256000_54.9.591.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.09.011"},{"key":"2025101710244256000_54.9.591.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.09.010"},{"key":"2025101710244256000_54.9.591.3","doi-asserted-by":"publisher","DOI":"10.1111\/nyas.12638"},{"key":"2025101710244256000_54.9.591.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.01.011"},{"key":"2025101710244256000_54.9.591.5","doi-asserted-by":"publisher","DOI":"10.3810\/pgm.2011.09.2466"},{"key":"2025101710244256000_54.9.591.6","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.64.10.1510"},{"key":"2025101710244256000_54.9.591.7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1219643110"},{"key":"2025101710244256000_54.9.591.8","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e31827f08ea"},{"key":"2025101710244256000_54.9.591.9","doi-asserted-by":"crossref","first-page":"148","DOI":"10.3109\/21678421.2013.838586","article-title":"Intermediate repeat expansion length in C9orf72 may be pathological in amyotrophic lateral sclerosis","volume":"15","author":"Byrne","year":"2014","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"key":"2025101710244256000_54.9.591.10","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3182684634"},{"key":"2025101710244256000_54.9.591.11","doi-asserted-by":"crossref","first-page":"1850.e1","DOI":"10.1016\/j.neurobiolaging.2012.02.017","article-title":"Screening for C9ORF72 repeat expansion in FTLD","volume":"33","author":"Ferrari","year":"2012","journal-title":"Neurobiol Aging"},{"key":"2025101710244256000_54.9.591.12","doi-asserted-by":"crossref","first-page":"192.e13","DOI":"10.1016\/j.neurobiolaging.2016.02.001","article-title":"Analysis of C9orf72 in patients with frontotemporal dementia and amyotrophic lateral sclerosis from Argentina","volume":"40","author":"Itzcovich","year":"2016","journal-title":"Neurobiol Aging"},{"key":"2025101710244256000_54.9.591.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2013.10.001"},{"key":"2025101710244256000_54.9.591.14","doi-asserted-by":"crossref","first-page":"59","DOI":"10.3389\/fneur.2014.00059","article-title":"Lack of c9orf72 repeat expansion in taiwanese patients with mixed neurodegenerative disorders","volume":"5","author":"Lin","year":"2014","journal-title":"Front Neurol"},{"key":"2025101710244256000_54.9.591.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2012.07.005"},{"key":"2025101710244256000_54.9.591.16","doi-asserted-by":"publisher","DOI":"10.1001\/archneurol.2012.2016"},{"key":"2025101710244256000_54.9.591.17","doi-asserted-by":"crossref","first-page":"1311.e3","DOI":"10.1016\/j.neurobiolaging.2012.09.002","article-title":"Screening for C9orf72 repeat expansions in parkinsonian syndromes","volume":"34","author":"Yeh","year":"2013","journal-title":"Neurobiol Aging"},{"key":"2025101710244256000_54.9.591.18","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.parkreldis.2012.06.019","article-title":"Analyses of the MAPT, PGRN, and C9orf72 mutations in Japanese patients with FTLD, PSP, and CBS","volume":"19","author":"Ogaki","year":"2013","journal-title":"Parkinsonism Relat Disord"},{"key":"2025101710244256000_54.9.591.19","doi-asserted-by":"crossref","first-page":"235.e11","DOI":"10.1016\/j.neurobiolaging.2016.05.013","article-title":"Analyses MAPT, GRN, and C9orf72 mutations in Chinese patients with frontotemporal dementia","volume":"46","author":"Tang","year":"2016","journal-title":"Neurobiol Aging"},{"key":"2025101710244256000_54.9.591.20","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awr353"},{"key":"2025101710244256000_54.9.591.21","doi-asserted-by":"crossref","first-page":"1221.e1","DOI":"10.1016\/j.neurobiolaging.2014.08.024","article-title":"The analysis of C9orf72 repeat expansions in a large series of clinically and pathologically diagnosed cases with atypical parkinsonism","volume":"36","author":"Schottlaender","year":"2015","journal-title":"Neurobiol Aging"},{"key":"2025101710244256000_54.9.591.22","doi-asserted-by":"crossref","first-page":"2908.e5","DOI":"10.1016\/j.neurobiolaging.2015.07.004","article-title":"C9ORF72 hexanucleotide repeat expansion in ALS patients from the Central European Russia population","volume":"36","author":"Abramycheva","year":"2015","journal-title":"Neurobiol Aging"},{"key":"2025101710244256000_54.9.591.23","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(12)70014-5"},{"key":"2025101710244256000_54.9.591.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2013.06.009"},{"key":"2025101710244256000_54.9.591.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2015.06.002"},{"key":"2025101710244256000_54.9.591.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2012.09.004"},{"key":"2025101710244256000_54.9.591.27","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2012-302272"},{"key":"2025101710244256000_54.9.591.28","doi-asserted-by":"crossref","first-page":"1851.e1","DOI":"10.1016\/j.neurobiolaging.2012.02.021","article-title":"High frequency of the expanded C9ORF72 hexanucleotide repeat in familial and sporadic Greek ALS patients","volume":"33","author":"Mok","year":"2012","journal-title":"Neurobiol Aging"},{"key":"2025101710244256000_54.9.591.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2012.05.011"},{"key":"2025101710244256000_54.9.591.30","doi-asserted-by":"crossref","first-page":"26","DOI":"10.3109\/17482968.2012.725415","article-title":"No GGGGCC-hexanucleotide repeat expansion in C9ORF72 in parkinsonism patients in Sweden","volume":"14","author":"Akimoto","year":"2013","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"key":"2025101710244256000_54.9.591.31","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.parkreldis.2012.09.013","article-title":"Analysis of the C9orf72 repeat in Parkinson\u2019s disease, essential tremor and restless legs syndrome","volume":"19","author":"Dejesus-Hernandez","year":"2013","journal-title":"Parkinsonism Relat Disord"},{"key":"2025101710244256000_54.9.591.32","doi-asserted-by":"crossref","first-page":"1519.e1","DOI":"10.1016\/j.neurobiolaging.2012.10.001","article-title":"Parkinson disease is not associated with C9ORF72 repeat expansions","volume":"34","author":"Harms","year":"2013","journal-title":"Neurobiol Aging"},{"key":"2025101710244256000_54.9.591.33","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aws357"},{"key":"2025101710244256000_54.9.591.34","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1111\/ahg.12033","article-title":"C9ORF72 intermediate repeat copies are a significant risk factor for Parkinson disease","volume":"77","author":"Nuytemans","year":"2013","journal-title":"Ann Hum Genet"},{"key":"2025101710244256000_54.9.591.35","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(12)70043-1"},{"key":"2025101710244256000_54.9.591.36","doi-asserted-by":"crossref","first-page":"1710.e7","DOI":"10.1016\/j.neurobiolaging.2012.11.025","article-title":"Investigation of C9orf72 repeat expansions in Parkinson\u2019s disease","volume":"34","author":"Daoud","year":"2013","journal-title":"Neurobiol Aging"},{"key":"2025101710244256000_54.9.591.37","doi-asserted-by":"publisher","DOI":"10.1002\/mds.25838"},{"key":"2025101710244256000_54.9.591.38","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1212\/WNL.0000000000001012","article-title":"Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease","volume":"83","author":"Theuns","year":"2014","journal-title":"Neurology"},{"key":"2025101710244256000_54.9.591.39","doi-asserted-by":"crossref","first-page":"1223.e1","DOI":"10.1016\/j.neurobiolaging.2014.08.033","article-title":"Multiple system atrophy is not caused by C9orf72 hexanucleotide repeat expansions","volume":"36","author":"Scholz","year":"2015","journal-title":"Neurobiol Aging"},{"key":"2025101710244256000_54.9.591.40","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1159\/000445872","article-title":"C9orf72 Hexanucleotide Repeat Analysis in Cases with Pathologically Confirmed Dementia with Lewy Bodies","volume":"16","author":"Geiger","year":"2016","journal-title":"Neurodegener Dis"},{"key":"2025101710244256000_54.9.591.41","doi-asserted-by":"crossref","first-page":"214.e13","DOI":"10.1016\/j.neurobiolaging.2016.08.023","article-title":"Analysis of C9orf72 repeat expansions in a large international cohort of dementia with Lewy bodies","volume":"49","author":"Kun-Rodrigues","year":"2017","journal-title":"Neurobiol Aging"},{"key":"2025101710244256000_54.9.591.42","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1007\/s00415-015-7873-6","article-title":"C9ORF72 intermediate repeat expansion in patients affected by atypical parkinsonian syndromes or Parkinson\u2019s disease complicated by psychosis or dementia in a Sardinian population","volume":"262","author":"Cannas","year":"2015","journal-title":"J Neurol"},{"key":"2025101710244256000_54.9.591.43","doi-asserted-by":"crossref","first-page":"1846.e5","DOI":"10.1016\/j.neurobiolaging.2012.01.109","article-title":"Analysis of the hexanucleotide repeat in C9ORF72 in Alzheimer\u2019s disease","volume":"33","author":"Rollinson","year":"2012","journal-title":"Neurobiol Aging"},{"key":"2025101710244256000_54.9.591.44","doi-asserted-by":"crossref","first-page":"1519.e5","DOI":"10.1016\/j.neurobiolaging.2012.10.003","article-title":"Repeat expansions in the C9ORF72 gene contribute to Alzheimer\u2019s disease in Caucasians","volume":"34","author":"Kohli","year":"2013","journal-title":"Neurobiol Aging"},{"key":"2025101710244256000_54.9.591.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2012.12.019"},{"key":"2025101710244256000_54.9.591.46","doi-asserted-by":"crossref","unstructured":"Galimberti D , Reif A , Dell\u2019osso B , Kittel-Schneider S , Leonhard C , Herr A , Palazzo C , Villa C , Fenoglio C , Serpente M , Cioffi SMG , Prunas C , Paoli RA , Altamura AC . Scarpini E. C9ORF72 hexanucleotide repeat expansion is a rare cause of schizophrenia. Neurobiol Aging 2014.","DOI":"10.1111\/bdi.12169"},{"key":"2025101710244256000_54.9.591.47","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1097\/YPG.0000000000000118","article-title":"The C9ORF72 expansion sizes in patients with psychosis: a population-based study on the Northern Finland Birth Cohort 1966","volume":"26","author":"Solje","year":"2016","journal-title":"Psychiatr Genet"},{"key":"2025101710244256000_54.9.591.48","doi-asserted-by":"crossref","first-page":"1510.e1","DOI":"10.1016\/j.neurobiolaging.2013.12.003","article-title":"Analysis of the hexanucleotide repeat expansion and founder haplotype at C9ORF72 in an Irish psychosis case-control sample","volume":"35","author":"Fahey","year":"2014","journal-title":"Neurobiol Aging"},{"key":"2025101710244256000_54.9.591.49","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2012.98"},{"key":"2025101710244256000_54.9.591.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2011.08.005"},{"key":"2025101710244256000_54.9.591.51","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22244"},{"key":"2025101710244256000_54.9.591.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.04.017"},{"key":"2025101710244256000_54.9.591.53","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1038\/mp.2015.159","article-title":"The C9orf72 repeat size correlates with onset age of disease, DNA methylation and transcriptional downregulation of the promoter","volume":"21","author":"Gijselinck","year":"2016","journal-title":"Mol Psychiatry"},{"key":"2025101710244256000_54.9.591.54","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(13)70210-2"},{"key":"2025101710244256000_54.9.591.55","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt460"},{"key":"2025101710244256000_54.9.591.56","doi-asserted-by":"crossref","first-page":"546.e1","DOI":"10.1016\/j.neurobiolaging.2014.07.037","article-title":"Screening a UK amyotrophic lateral sclerosis cohort provides evidence of multiple origins of the C9orf72 expansion","volume":"36","author":"Fratta","year":"2015","journal-title":"Neurobiol Aging"},{"key":"2025101710244256000_54.9.591.57","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv064"},{"key":"2025101710244256000_54.9.591.58","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1007\/s00401-015-1473-5","article-title":"A 30-unit hexanucleotide repeat expansion in C9orf72 induces pathological lesions with dipeptide-repeat proteins and RNA foci, but not TDP-43 inclusions and clinical disease","volume":"130","author":"Gami","year":"2015","journal-title":"Acta Neuropathol"},{"key":"2025101710244256000_54.9.591.59","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2014-102360"},{"key":"2025101710244256000_54.9.591.60","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.mcp.2016.06.001","article-title":"Improved PCR based methods for detecting C9orf72 hexanucleotide repeat expansions","volume":"30","author":"Cleary","year":"2016","journal-title":"Mol Cell Probes"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmedgenet-2017-104752","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T17:24:53Z","timestamp":1760721893000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmedgenet-2017-104752"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,7,8]]},"references-count":60,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2017,8,22]]},"published-print":{"date-parts":[[2017,9]]}},"alternative-id":["10.1136\/jmedgenet-2017-104752"],"URL":"https:\/\/doi.org\/10.1136\/jmedgenet-2017-104752","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,7,8]]}}}