Post-zygotic rescue of meiotic errors causes brain mosaicism and focal epilepsy

Nat Genet. 2023 Nov;55(11):1920-1928. doi: 10.1038/s41588-023-01547-z. Epub 2023 Oct 23.


Somatic mosaicism is a known cause of neurological disorders, including developmental brain malformations and epilepsy. Brain mosaicism is traditionally attributed to post-zygotic genetic alterations arising in fetal development. Here we describe post-zygotic rescue of meiotic errors as an alternate origin of brain mosaicism in patients with focal epilepsy who have mosaic chromosome 1q copy number gains. Genomic analysis showed evidence of an extra parentally derived chromosome 1q allele in the resected brain tissue from five of six patients. This copy number gain is observed only in patient brain tissue, but not in blood or buccal cells, and is strongly enriched in astrocytes. Astrocytes carrying chromosome 1q gains exhibit distinct gene expression signatures and hyaline inclusions, supporting a novel genetic association for astrocytic inclusions in epilepsy. Further, these data demonstrate an alternate mechanism of brain chromosomal mosaicism, with parentally derived copy number gain isolated to brain, reflecting rescue in other tissues during development.

MeSH terms

  • Brain
  • Epilepsies, Partial* / genetics
  • Humans
  • Mosaicism*
  • Mouth Mucosa
  • Mutation