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

Neurobiol Aging. 2023 Feb:122:76-87. doi: 10.1016/j.neurobiolaging.2022.11.010. Epub 2022 Nov 17.

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.

Keywords: Amyotrophic Lateral Sclerosis; Genetic modifiers; Post-zygotic mutations; Repeat expansions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis* / genetics
  • Humans
  • Mutation / genetics
  • Neurodegenerative Diseases*
  • Twins, Monozygotic / genetics
  • Whole Genome Sequencing