Autism spectrum disorders: from genes to neurobiology

• High throughput genomic methods are rapidly increasing the pool of ASD genes.
• Heterogeneity, pleiotropy, and brain complexity complicate translation to biology.
• Monogenic syndromes have provided the first insights into the neuropathology of ASD.
• Leveraging multidimensional data from the brain offers a new complementary approach.
• Recent results localize a subset of ASD risk to specific spatiotemporal windows.

Advances in genome-wide technology, coupled with the availability of large cohorts, are finally yielding a steady stream of autism spectrum disorder (ASD) genes carrying mutations of large effect. These findings represent important molecular clues, but at the same time present notable challenges to traditional strategies for moving from genes to neurobiology. A remarkable degree of genetic heterogeneity, the biological pleiotropy of ASD genes, and the tremendous complexity of the human brain are prompting the development of new strategies for translating genetic discoveries into therapeutic targets. Recent developments in systems biology approaches that ‘contextualize’ these genetic findings along spatial, temporal, and cellular axes of human brain development are beginning to bridge the gap between high-throughput gene discovery and testable pathophysiological hypotheses.