Autism Spectrum Disorder Genetics and the Search for Pathological Mechanisms

Abstract

Recent progress in the identification of genes and genomic regions contributing to autism spectrum disorder (ASD) has had a broad impact on our understanding of the nature of genetic risk for a range of psychiatric disorders, on our understanding of ASD biology, and on defining the key challenges now facing the field in efforts to translate gene discovery into an actionable understanding of pathology. While these advances have not yet had a transformative impact on clinical practice, there is nonetheless cause for real optimism: reliable lists of risk genes are large and growing rapidly; the identified encoded proteins have already begun to point to a relatively small number of areas of biology, where parallel advances in neuroscience and functional genomics are yielding profound insights; there is strong evidence pointing to mid-fetal prefrontal cortical development as one nexus of vulnerability for some of the largest-effect ASD risk genes; and there are multiple plausible paths forward toward rational therapeutics development that, while admittedly challenging, constitute fundamental departures from what was possible prior to the era of successful gene discovery.

Keywords: Autism Spectrum Disorder; Genetics/Genomics; Neurodevelopmental Disorders.

FIGURE 1.. Gene discovery in ASD simplex families identifies risk genes that converge on specific biological processes and suggest multiple models to account for sex differences in ASD pathology^a

^aThe diagram in panel A illustrates a simplex autism pedigree, including an affected proband and unaffected parents and siblings (affected status is represented by the purple color). Multiple studies of de novo mutations in ASD leveraged the Simons Simplex Collection (24), in which the majority of pedigrees were “quartets” as shown here, comprising a parent-proband trio and at least one unaffected sibling. This structure is ideal for genetic studies of spontaneous mutations, as it allows for the evaluation of spontaneous germline mutation rates within families, comparing affected to unaffected siblings. In panel B, functional annotations of ASD-associated genes highlight the putative role of synaptic structure and function and the regulation of gene expression, particularly enriched for chromatin structure and dynamics. Genes that reached the highest statistical threshold in references or are included in the diagram, placed according to their commonly annotated functional role and cellular location. Panel C depicts several models of the possible intersections of ASD pathobiology (green) and sexual differentiation of the brain (pink and blue): at right, ASD pathogenesis may affect cortical development in regions that interact with subcortical structures (arrows) that show differences between males and females to produce sex-biased phenotypes. At left, sex differences and ASD pathogenesis may converge in regions of the cortex, in populations of cells that remain to be identified, to produce sex differences in ASD. At center, sexual differentiation and ASD pathogenesis may disrupt sex-typical patterns of development and activity in cortical and subcortical structures to produce sex biases in ASD.