Elucidating the role of DEAF1 in neurodevelopment and shared molecular pathways in high-risk autism genes using cortical organoids.

Abstract

Neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD) and intellectual disability (ID), are genetically heterogeneous. DEAF1 has emerged as a key NDD risk gene, with pathogenic variants linked to DEAF1-associated neurodevelopmental disorder (DAND), but its role in human neurodevelopment remains unclear. Human cortical organoids (hCOs) provide a physiologically relevant model that recapitulates fetal brain development with an authentic human genetic background. Here, we show that a DEAF1 mutation in human embryonic stem cells disrupts chromatin accessibility at neuronal gene loci, leading to significant transcriptional alterations. In hCOs, this mutation results in aberrant progenitor proliferation, disrupted cortical lamination, and impaired neuronal differentiation. Furthermore, we identify WNT signaling, TGFβ superfamily signaling, and cell cycle regulation as commonly dysregulated pathways across multiple ASD-associated genetic perturbations. Pharmacological inhibition of WNT signaling with a Porcupine inhibitor partially rescues phenotypic defects in DEAF1-mutant hCOs. Our findings identify DEAF1 as a critical regulator of neurodevelopment and support pathway-targeted, mutation-independent therapeutic strategies for ASD and related disorders.