<i>GTF2I</i> dosage regulates neuronal differentiation and social behavior in 7q11.23 neurodevelopmental disorders.

Abstract

Copy number variations at 7q11.23 cause neurodevelopmental disorders with shared and opposite manifestations. Deletion causes Williams-Beuren syndrome featuring hypersociability, while duplication causes 7q11.23 microduplication syndrome (7Dup), frequently exhibiting autism spectrum disorder (ASD). Converging evidence indicates <i>GTF2I</i> as key mediator of the cognitive-behavioral phenotypes, yet its role in cortical development and behavioral hallmarks remains largely unknown. We integrated proteomic and transcriptomic profiling of patient-derived cortical organoids, including longitudinally at single-cell resolution, to dissect 7q11.23 dosage-dependent and <i>GTF2I</i>-specific disease mechanisms. We observed dosage-dependent impaired dynamics of neural progenitor proliferation, transcriptional imbalances, and highly specific alterations in neuronal output, leading to precocious excitatory neuron production in 7Dup, which was rescued by restoring physiological <i>GTF2I</i> levels. Transgenic mice with <i>Gtf2i</i> duplication recapitulated progenitor proliferation and neuronal differentiation defects alongside ASD-like behaviors. Consistently, inhibition of lysine demethylase 1 (LSD1), a <i>GTF2I</i> effector, was sufficient to rescue ASD-like phenotypes in transgenic mice, establishing <i>GTF2I</i>-LSD1 axis as a molecular pathway amenable to therapeutic intervention in ASD.