Neuron, Volume 100, 24 October 2018,
Recent progress in the genomics of non-syndromic autism spectrum disorder (nsASD) highlights rare, large-effect, germline, heterozygous de novo coding mutations. This distinguishes nsASD from later-onset psychiatric disorders where gene discovery efforts have predominantly yielded common alleles of small effect. These differences point to distinctive opportunities for clarifying the neurobiology of nsASD and developing novel treatments. We argue that the path ahead also presents key challenges, including distinguishing human pathophysiology from the potentially pleiotropic neurobiology mediated by established risk genes. We present our view of some of the conceptual limitations of traditional studies of model organisms, suggest a strategy focused on investigating the convergence of multiple nsASD genes, and propose that the detailed characterization of the molecular and cellular landscapes of developing human brain is essential to illuminate disease mechanisms. Finally, we address how recent advances are leading to novel strategies for therapeutics that target various points along the path from genes to behavior. Sestan and State propose that the distinctive genomic findings in autism spectrum disorder, the deepening understanding of developing human brain, and the identification of spatiotemporal convergence of large-effect risk genes will help clarify pathophysiological mechanisms and identify novel treatment approaches.
Allele; Autism; Autism Spectrum Disorder; Brain; Brain Development; Convergence; Convergence Neuroscience; De Novo Mutation; Disease Classification; Gene Control; Gene Identification; Gene Mutation; Gene Therapy; Genetic Risk; Genetic Therapy; Genetic Transcription; Genetic Variability; Genetics; Genome-wide Association Study; Genomics; Haploinsufficiency; Heterozygote; Human; Human Brain Development; Humans; Loss Of Function Mutation; Mutation; Neurodevelopmental Disorders; Non-syndromic Autism Spectrum Disorder; Nonhuman; Pathophysiology; Physiology; Population Risk; Priority Journal; Procedures; Review; Synaptic Transmission; Transcriptomics; Trends; Global