Single cell transcriptomic profiling of human brain organoids reveals developmental timing- and cell-type-specific vulnerabilities induced by NRXN1 CNVs in schizophrenia

De novo mutations and copy number variations (CNVs) in NRXN1 (2p16.3) pose a significant risk for schizophrenia (SCZ). How NRXN1 CNVs impact cortical development in a cell type-specific manner and how disease genetic background modulates these phenotypes are unclear. Here, we leveraged human pluripotent stem cell-derived brain organoid models carrying NRXN1 heterozygous deletions in isogenic and SCZ patient genetic backgrounds and conducted single cell transcriptomic analysis over the course of cortical brain organoid development from 3 weeks to 3.5 months. We identified maturing glutamatergic and GABAergic neurons as being consistently impacted due to NRXN1 CNVs irrespective of genetic background, contributed in part by altered gene modules in ubiquitin-mediated pathways, splicing, and synaptic signaling. Moreover, while isogenic NRXN1 CNVs impact differentiation and maturation of neurons and astroglia, cell composition and developmental trajectories of early neural progenitors are affected in SCZ- NRXN1 CNVs. Our study reveals developmental timing dependent NRXN1 CNV-induced cellular mechanisms in SCZ at single cell resolution and highlights the emergence of disease-specific transcriptomic signatures and cellular vulnerabilities, which can arise from interaction between genetic variants and disease background. ### Competing Interest Statement The authors have declared no competing interest.