16p11.2 copy number variants drive convergent cell-type specific disruptions in corticogenesis

Here, Van Enoo et al. generate isogenic CRISPR/Cas9-engineered iPSC-derived cortical organoids (COs) to investigate the cellular and molecular consequences of 16p11.2 copy number variants (CNVs) during early human neurogenesis. Single-nuclei RNA sequencing reveals progenitor depletion, premature cell cycle exit, and accelerated gliogenesis, leading to the emergence of a neuronal subpopulation enriched for neurodevelopmental disorder (NDD) risk genes. Single-nucleus RNA sequencing was performed on cortical organoids derived from induced pluripotent stem cell (iPSC) lines carrying 16p11.2 copy number variants (deletion or duplication) and isogenic wild-type controls. Organoids were harvested at 2 months of differentiation to capture dynamic changes during cortical development. All samples were processed using the 10x Genomics Chromium platform and sequenced on a NovaSeq 6000. The experimental design enables comparative analysis of transcriptomic profiles across genotypes.