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

Neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD) and intellectual disability (ID), are highly heterogeneous conditions with strong genetic underpinnings. Among the numerous risk genes implicated in NDDs, DEAF1 has emerged as a key candidate, with pathogenic variants linked to ASD and DEAF1-associated neurodevelopmental disorder (DAND). However, its precise role in human neurodevelopment remains poorly understood. Human cortical organoids (hCOs) provide a physiologically relevant model that retains the authentic human genetic background, faithfully recapitulating fetal brain development while minimizing extrapolation errors associated with genetic variability. In this study, we investigate the role of DEAF1 in neurodevelopment and its implications for NDDs using hCOs. We demonstrate that DEAF1 mutations disrupt chromatin accessibility at neuronal gene loci in human embryonic stem cells (hESCs), leading to significant transcriptional alterations.