Targeted single-nucleus sequencing of 39,800 neurons reveals extensive low-frequency somatic variants
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Recent evidence implicates somatic mutations in disease-associated genes across multiple neurodegenerative disorders, including the identification of two somatic TARDBP variants as a putative cause of frontotemporal lobar degeneration with TDP-43 pathology type C (FTLD-TDP type C). However, these findings remain anecdotal. We performed single-nucleus amplicon sequencing of 39,800 neurons from the superior temporal gyrus of sporadic FTLD-TDP type C patients (34,738 neurons, 52 individuals) and non-demented controls (5,062 neurons, 26 individuals) using the Mission Bio Tapestri platform and investigated somatic variants in TARDBP and other FTLD-TDP-associated genes in a case-control setting. We uncovered an extensive landscape of ultra-low-frequency (<1%) somatic mutations across all analysed genes, including TARDBP . Rare somatic occurrences of known ALS/FTD-associated germline TARDBP variants, including p.N267S and p.M337V, were identified exclusively in patients. Among all targeted genes, TARDBP had the highest proportion of neurons harbouring a somatic variant, and this mutational burden was lower in individuals who died at an older age. Strikingly, the C-terminal domain of TDP-43, where most ALS/FTD germline pathogenic variants reside, exhibited a lower neuronal mutational burden than its other domains. This suggests that neurons harbouring damaging mutations may undergo progressive loss prior to autopsy, leaving only rare survivors at frequencies too low to detect by bulk or small-scale single-cell approaches. Together, our findings provide an unprecedented resolution into the somatic mutational landscape of post-mitotic neurons in FTLD-TDP type C and reveal a gene-specific layer of neuronal mosaicism that current single-cell WGS studies fail to detect.
Authors: Vanshika Bidhan, Sarah Wynants, Toon Swings, Cristina T. Vicente, Fahri Küçükali, Marleen Van den Broeck, Jeroen GJ. van Rooij, Merel O. Mol, Laura L. Donker Kaat, Safa Al-Sarraj, Istvan Bodi, Andrew King, Claire Troakes, Christos Proukakis, Jolien Schaeverbeke, Dietmar R. Thal, Rik Vandenberghe, Mathieu Vandenbulcke, Aivi T. Nguyen, R. Ross Reichard, Julia Kofler, Oscar L. Lopez, Charles L. White, Bradley F. Boeve, Neill R. Graff-Radford, Keith A. Josephs, Ronald C. Petersen, Nikhil B. Ghayal, Melissa E. Murray, Dennis W. Dickson, John C. van Swieten, Kristel Sleegers, Harro Seelaar, Wouter De Coster, Rosa Rademakers
Institutions: University of Antwerp, VIB-UAntwerp Center for Molecular Neurology, Erasmus MC, King's College London, King's College Hospital NHS Foundation Trust, King's College Hospital, UCL Queen Square Institute of Neurology, University College London, KU Leuven, Universitair Ziekenhuis Leuven, Mayo Clinic, University of Pittsburgh, The University of Texas Southwestern Medical Center, Mayo Clinic in Florida
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Comprehensive genomic and transcriptomic analyses of FTLD-TDP type A patients to identify molecular disease mechanisms and explore candidate biomarkers., LASTIG-FTD: Large-scale Application of Sequencing Technologies for Identifying Genomic factors in Frontotemporal Dementia, Understanding the role of TDP-43 in Alzheimer’s disease and FTLD, Mayo Alzheimer's Disease Research Center
OpenAlex ID: W7214112229