Targeted single-nucleus sequencing of 39,800 neurons reveals extensive low-frequency somatic variants
- 1VIB-UAntwerp Center for Molecular Neurology, Antwerp 2610, Belgium
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 undergoprogressive 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.
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BibTeX
@misc{bidhan2026targeted,
title = {{Targeted single-nucleus sequencing of 39,800 neurons reveals extensive low-frequency somatic variants}},
author = {V. Bidhan and S. Wynants and T. Swings and C. T. Vicente and F. Kucukali and M. Van den Broeck and J. G. van Rooij and M. O. Mol and L. L. Donker Kaat and S. Al-Sarraj and I. Bodi and A. King and C. Troakes and C. Proukakis and J. Schaeverbeke and D. R. Thal and R. Vandenberghe and M. Vandenbulcke and A. T. Nguyen and R. R. Reichard and J. Kofler and O. L. Lopez and , C. L. White and B. F. Boeve and N. R. Graff-Radford and K. A. Josephs and R. C. Petersen and N. B. Ghayal and M. E. Murray and D. W. Dickson and J. C. van Swieten and K. Sleegers and H. Seelaar and W. De Coster and R. Rademakers},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.21.753260},
url = {https://www.biorxiv.org/content/10.64898/2026.09.21.753260v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Targeted single-nucleus sequencing of 39,800 neurons reveals extensive low-frequency somatic variants
AU - V. Bidhan
AU - S. Wynants
AU - T. Swings
AU - C. T. Vicente
AU - F. Kucukali
AU - M. Van den Broeck
AU - J. G. van Rooij
AU - M. O. Mol
AU - L. L. Donker Kaat
AU - S. Al-Sarraj
AU - I. Bodi
AU - A. King
AU - C. Troakes
AU - C. Proukakis
AU - J. Schaeverbeke
AU - D. R. Thal
AU - R. Vandenberghe
AU - M. Vandenbulcke
AU - A. T. Nguyen
AU - R. R. Reichard
AU - J. Kofler
AU - O. L. Lopez
AU - , C. L. White
AU - B. F. Boeve
AU - N. R. Graff-Radford
AU - K. A. Josephs
AU - R. C. Petersen
AU - N. B. Ghayal
AU - M. E. Murray
AU - D. W. Dickson
AU - J. C. van Swieten
AU - K. Sleegers
AU - H. Seelaar
AU - W. De Coster
AU - R. Rademakers
PY - 2026
DA - 2026/09/21
PB - bioRxiv
DO - 10.64898/2026.09.21.753260
UR - https://www.biorxiv.org/content/10.64898/2026.09.21.753260v1
AB - 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 undergoprogressive 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.
ER -