PGBD5 is a domesticated DNA transposase-derived gene that mediates sequence-specific genomic rearrangements through retained nuclease activity 1. The protein recognizes piggyBac-like transposable elements and induces DNA breaks and somatic genome rearrangements, processes essential for normal mammalian brain development 12. PGBD5 deficiency causes neurodevelopmental disease characterized by intellectual disability, movement disorders, and seizures due to aberrant neuronal differentiation and gene expression, particularly in glutamatergic neurons 12. Clinically, PGBD5 functions as an oncogenic mutator in childhood cancers. It promotes tumor development in medulloblastoma and rhabdoid tumors through generation of genomic rearrangements bearing PGBD5-specific signal (PSS) sequences at breakpoints that recurrently inactivate tumor suppressors 34. PGBD5 expression is active in the majority of childhood solid tumors 3. The protein's oncogenic activity requires intact transposase catalytic residues and end-joining DNA repair machinery 3. Recent studies identify PGBD5-dependent DNA damage as therapeutically actionable in SMARCB1-deficient sarcomas, where combined EZH2 and ATR inhibition exploits the EZH2-PGBD5 synthetic lethal dependency 5. Thus PGBD5 represents a developmental mutator with distinct roles in normal neurodevelopment and cancer pathogenesis.