{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:37Z","timestamp":1792790377676,"version":"4.5.0"},"posted":{"date-parts":[[2026,10,7]]},"group-title":"Genetic and Genomic Medicine","reference-count":27,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"funder":[{"name":"Programme Hospitalier de Recherche Clinique"},{"name":"Pfizer [Innovative Target Exploration Network (ITEN) program]"},{"name":"ANR Investissements d\u2019avenir","award":["ANR-10- IAIHU-0006"],"award-info":[{"award-number":["ANR-10- IAIHU-0006"]}]},{"name":"Fondation pour la Recherche sur Alzheimer","id":[{"id":"https:\/\/ror.org\/01z0nmr69","id-type":"ROR","asserted-by":"crossref"}]},{"name":"France-DFT"},{"name":"Region Ile France","award":["SESAME 2019"],"award-info":[{"award-number":["SESAME 2019"]}]},{"name":"EU Joint Programme - Neurodegenerative Disease Research","award":["01ED2203"],"award-info":[{"award-number":["01ED2203"]}]},{"name":"NIH","award":["P30-AG-072979"],"award-info":[{"award-number":["P30-AG-072979"]}]},{"name":"NIH","award":["P01-AG-066597"],"award-info":[{"award-number":["P01-AG-066597"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Individuals carrying a G4C2 repeat expansion in\n                  <jats:italic>C9orf72<\/jats:italic>\n                  can develop amyotrophic lateral sclerosis (ALS) and\/or frontotemporal dementia (FTD), at various and unpredictable ages. The contribution of the expansion to this extreme clinical variability remained a matter of debate. In this work, we validated the use of optical genome mapping to efficiently size this expansion from blood and applied this method to a cohort of 54 repeat expansion carriers including patients with FTD (n = 23), ALS (n = 22) and presymptomatic individuals (n = 9). Despite the high variability in expansion profiles, distinct groups can be inferred. Although consensus repeat profiles were similar between FTD and ALS patients, relationships between repeat number, indexes of repeat instability, and the age at sampling differed between clinical conditions. An age at sampling-dependent increase of repeat instability in blood was observed in presymptomatic carriers and FTD patients (p = 0.01 and p = 0.04 respectively), in contrast to patients with ALS (p = 0.9). The proportion of shorter repeats ([500-1500 repeats]) increased with the age at sampling in ALS patients but decreased in presymptomatic and FTD cohorts, while the proportion of larger repeats (&gt;2000 G4C2), in particular those exceeding 4000 repeats, increased along with the age at sampling in presymptomatic carriers and FTD cases (p &lt;1.10\n                  <jats:sup>\u2212e4<\/jats:sup>\n                  and p = 0.006 respectively) conversely to patients with ALS (p = 0.98). In conclusion, this work strongly supports different dynamics of repeat instability of the\n                  <jats:italic>C9orf72<\/jats:italic>\n                  pathogenic expansion in blood linked to the clinical evolution. These findings provide new insights into the relationship between expansion profiles and clinical variability.\n                <\/jats:p>","DOI":"10.64898\/2026.10.06.26364580","type":"posted-content","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:12Z","timestamp":1791417612000},"source":"Crossref","is-referenced-by-count":0,"title":["Somatic instability of the\n                  <i>C9orf72<\/i>\n                  repeat expansion in blood differs between patients with amyotrophic lateral sclerosis or frontotemporal dementia"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5154-2163","authenticated-orcid":false,"given":"Mathieu","family":"Barbier","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9, Paris Brain Institute-Institut du Cerveau, ICM, Inserm U1127, CNRS UMR 7225 APHP-H\u00f4pital Piti\u00e9-Salp\u00eatri\u00e8re, Paris 75013, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mounir","family":"Ichalalen","sequence":"additional","affiliation":[{"name":"Genomics Platform, Translational Research Department, Institut Curie Research Center, PSL Research University, Institut Curie, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2667-0785","authenticated-orcid":false,"given":"Maria-Del-Mar","family":"Amador","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Paris Brain Institute-Institut du Cerveau, ICM, Inserm U1127, CNRS UMR 7225 APHP-H\u00f4pital Piti\u00e9-Salp\u00eatri\u00e8re, Paris 75013, France"},{"name":"Paris ALS Center, Department of Neurology, Assistance Publique H\u00f4pitaux de Paris (APHP), centre de r\u00e9f\u00e9rence SLA Ile de France, H\u00f4pital de la Piti\u00e9-Salp\u00eatri\u00e8re, DMU Neurosciences, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8180-0158","authenticated-orcid":false,"given":"Julie F. H.","family":"De Houwer","sequence":"additional","affiliation":[{"name":"Department of Neurology, Erasmus MC University Medical Centre, Rotterdam 3015GD, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"EunRan","family":"Suh","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6229-5364","authenticated-orcid":false,"given":"Fran\u00e7ois-Xavier","family":"Lejeune","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Paris Brain Institute-Institut du Cerveau, ICM, Inserm U1127, CNRS UMR 7225 APHP-H\u00f4pital Piti\u00e9-Salp\u00eatri\u00e8re, Paris 75013, France"},{"name":"Data Analysis Core Facility (RRID:SCR_026138), Paris Brain Institute-Institut du Cerveau, ICM, Sorbonne Universit\u00e9, Inserm U1127, CNRS UMR 7225, APHP-H\u00f4pital Piti\u00e9 Salp\u00eatri\u00e8re, Paris 75013, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Th\u00e9ophile","family":"Bieth","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Paris Brain Institute-Institut du Cerveau, ICM, Inserm U1127, CNRS UMR 7225 APHP-H\u00f4pital Piti\u00e9-Salp\u00eatri\u00e8re, Paris 75013, France"},{"name":"D\u00e9partement de Neurologie, Reference Center for Rare or Early-Onset Dementias, IM2A, AP-HP-H\u00f4pital Piti\u00e9-Salp\u00eatri\u00e8re, Paris 75013, France"},{"name":"Sorbonne Universit\u00e9, Paris Brain Institute-Institut du Cerveau, ICM, Inserm U1127, CNRS UMR 7225 APHP-H\u00f4pital Piti\u00e9-Salp\u00eatri\u00e8re, DMU Neuroscience, Paris 75013, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9cile","family":"Reyes","sequence":"additional","affiliation":[{"name":"Genomics Platform, Translational Research Department, Institut Curie Research 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C9orf72 repeat expansion creates the unstable folate-sensitive fragile site FRA9A. NAR Mol. Med. 1, ugae019 (2024).","DOI":"10.1093\/narmme\/ugae019"},{"key":"2026101119401825000_2026.10.06.26364580v1.25","doi-asserted-by":"crossref","unstructured":"Jackson, J. L. et al. Elevated methylation levels, reduced expression levels, and frequent contractions in a clinical cohort of C9orf72 expansion carriers. Mol. Neurodegener. 15, 7 (2020).","DOI":"10.1186\/s13024-020-0359-8"},{"key":"2026101119401825000_2026.10.06.26364580v1.26","unstructured":"Jiang, X. et al. Blocking RAN translation without altering repeat RNAs rescues C9ORF72-related ALS and FTD phenotypes. 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