Strategies for dissecting the complexity of neurodevelopmental disorders.

Neurodevelopmental disorders (NDDs) are complex disorders with variable clinical features caused by a wide range of genetic variants which disrupt genes with pleiotropic effects. Model organisms allow for recapitulation of phenotypes related to the disorder and characterization of molecular mechanisms at varying throughput and resolution. Human induced pluripotent stem cells allow for evaluating patient-specific and cell-type-specific effects. The massively parallel reporter assay (MPRA) uses high-throughput sequencing to screen thousands of genomic fragments containing patient-specific noncoding mutations to quantify their regulatory effects. Single-cell RNA sequencing and its combination with CRISPR-based screens – such as CRISPR droplet sequencing (CROP-seq) and Perturb-seq – provide promising platforms to understand gene function during brain development. Neurodevelopmental disorders (NDDs) are associated with a wide range of clinical features, affecting multiple pathways involved in brain development and function. Recent advances in high-throughput sequencing have unveiled numerous genetic variants associated with NDDs, which further contribute to disease complexity and make it challenging to infer disease causation and underlying mechanisms. Herein, we review current strategies for dissecting the complexity of NDDs using model organisms, induced pluripotent stem cells, single-cell sequencing technologies, and massively parallel reporter assays. We further highlight single-cell CRISPR-based screening techniques that allow genomic investigation of cellular transcriptomes with high efficiency, accuracy, and throughput. Overall, we provide an integrated review of experimental approaches that can be applicable for investigating a broad range of complex disorders. [ABSTRACT FROM AUTHOR]