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Harold and Leila Y. Mathers Foundation"}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,1,16]]},"abstract":"<jats:p>Vertebrate brain development is associated with prominent neuronal cell death and DNA breaks, but their causes and functions are not well understood. DNA transposable elements could contribute to somatic genome rearrangements; however, their contributions to brain development are largely unknown. PiggyBac transposable element derived 5 (PGBD5) is an evolutionarily conserved vertebrate DNA transposase\u2013derived gene with DNA remodeling activities in human cells. Here, we show that PGBD5 contributes to normal brain development in mice and humans, and its deficiency causes disorder of intellectual disability, movement disorders, and epilepsy. In mice, Pgbd5 is required for the developmental induction of postmitotic DNA breaks and recurrent somatic brain genome rearrangements. In the cerebral cortex, loss of Pgbd5 leads to aberrant neuronal gene expression, including of specific types of glutamatergic neurons, which partly explains the features of PGBD5 deficiency in humans. 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