Single-cell Technology Grows Up: Leveraging High-resolution Omics Approaches to Understand Neurodevelopmental Disorders

The identification of hundreds of neurodevelopmental disorder (NDD) genes in the last decade led to numerous genetic models for understanding NDD gene mutation consequences and delineating putative neurobiological mediators of disease. In parallel, single-cell and single-nucleus genomic technologies have been developed and implemented to create high-resolution atlases of cell composition, gene expression, and circuit connectivity in the brain. Here, we discuss the opportunities to leverage mutant models (or human tissue, where available) and genomics approaches to systematically define NDD etiology at cellular resolution. We review progress in applying single-cell and spatial transcriptomics to interrogate developmental trajectories, cellular composition, circuit activity, and connectivity across human tissue and NDD models. We discuss considerations for implementing these approaches at scale to maximize insights and facilitate reproducibility. Finally, we highlight how standardized application of these technologies promises to not only define etiologies of individual disorders but also identify molecular, cellular, and circuit level convergence across NDDs.