Functional neurogenomics in autism spectrum disorders: A decade of progress.

ABSTRACT

Advances in autism spectrum disorder (ASD) genetics have identified many genetic causes, reflecting remarkable progress while at the same time identifying challenges such as heterogeneity and pleiotropy, which complicate attempts to connect genetic risk to mechanisms. High-throughput functional genomic approaches have yielded progress by defining a molecular pathology in the brain of individuals with ASD and in identifying convergent biological pathways through which risk genes are predicted to act. These studies indicate that ASD genetic risk converges in early brain development, primarily during the period of cortical neurogenesis. Over development, genetic perturbations in turn lead to broad neuronal signaling dysregulation, most prominent in glutamatergic cortical-cortical projecting neurons and somatostatin positive interneurons, which is accompanied by glial dyshomeostasis throughout the cerebral cortex. Connecting these developmental perturbations to disrupted neuronal and glial function in the postnatal brain is an important direction in current research. Coupling functional genomic approaches with advances in induced pluripotent stem cell-derived neural organoid development provides a promising avenue for connecting brain pathology to developmental mechanisms.