Somatic instability of the C9orf72 repeat expansion in blood differs between patients with amyotrophic lateral sclerosis or frontotemporal dementia
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: ABSTRACT Individuals carrying a G4C2 repeat expansion in C9orf72 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 (>2000 G4C2), in particular those exceeding 4000 repeats, increased along with the age at sampling in presymptomatic carriers and FTD cases (p <1.10 −e4 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 C9orf72 pathogenic expansion in blood linked to the clinical evolution. These findings provide new insights into the relationship between expansion profiles and clinical variability.
Source: medRxiv
Authors: Mathieu Barbier, Mounir Ichalalen, Maria-Del-Mar Amador, Julie F. H. De Houwer, EunRan Suh, François-Xavier Lejeune, Théophile Bieth, Cécile Reyes, Emilie Henry, Allyson E. Hinks, Philippe Martin-Hardy, Daisy Rinaldi, Lara Araktingi, Harro Seelaar, Carole Roué-Jagot, Julien Lagarde, Marie Sarazin, François Salachas, Gaëlle Bruneteau, Marc Teichmann, Richard Levy, Elsa Bernard, Laura Donker Kaat, Viviana Van Deerlin, Georg Haase, John van Swieten, Audrey Rapinat, David Gentien, Isabelle Le Ber
Institutions: Centre National de la Recherche Scientifique, Inserm, Sorbonne Université, Pitié-Salpêtrière Hospital, Institut du Cerveau, Université Paris Sciences et Lettres, Institut Curie, Assistance Publique – Hôpitaux de Paris, Erasmus MC, University of Pennsylvania, GHU Paris psychiatrie & neurosciences, Université Paris Cité, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Université Paris-Saclay, CEA Paris-Saclay, Laboratoire d'Imagerie Biomédicale Multimodale Paris-Saclay, Aix-Marseille Université, Institut de Neurosciences des Systèmes, Institut Gustave Roussy, Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7221037204