Whole genome sequencing analysis reveals post-zygotic mutation variability in monozygotic twins discordant for amyotrophic lateral sclerosis

Gijs H.P. Tazelaar*, Paul J. Hop, Meinie Seelen, Joke J.F.A. van Vugt, Wouter van Rheenen, Lindy Kool, Kristel R. van Eijk, Marleen Gijzen, Dennis Dooijes, Matthieu Moisse, Andrea Calvo, Cristina Moglia, Maura Brunetti, Antonio Canosa, Angelica Nordin, Jesus S.Mora Pardina, John Ravits, Ammar Al-Chalabi, Adriano Chio, Russell L. McLaughlinOrla Hardiman, Philip Van Damme, Mamede de Carvalho, Christoph Neuwirth, Markus Weber, Peter M. Andersen, Leonard H. van den Berg, Jan H. Veldink, Michael A. van Es

*Corresponding author for this work

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Abstract

Amyotrophic lateral sclerosis is a heterogeneous, fatal neurodegenerative disease, characterized by motor neuron loss and in 50% of cases also by cognitive and/or behavioral changes. Mendelian forms of ALS comprise approximately 10-15% of cases. The majority is however considered sporadic, but also with a high contribution of genetic risk factors. To explore the contribution of somatic mutations and/or epigenetic changes to disease risk, we performed whole genome sequencing and methylation analyses using samples from multiple tissues on a cohort of 26 monozygotic twins discordant for ALS, followed by in-depth validation and replication experiments. The results of these analyses implicate several mechanisms in ALS pathophysiology, which include a role for de novo mutations, defects in DNA damage repair and accelerated aging.

Original languageEnglish
Pages (from-to)76-87
Number of pages12
JournalNeurobiology of Aging
Volume122
DOIs
Publication statusPublished - Feb 2023

Keywords

  • Amyotrophic Lateral Sclerosis
  • Genetic modifiers
  • Post-zygotic mutations
  • Repeat expansions

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