Technological advances in whole-genome sequencing (WGS) to study complex genetic disorders have outpaced innovations in the analysis of large genetic datasets. An ever-increasing amount of genetic data is being acquired, at a higher resolution, from patient populations numbering in the thousands. While this has led to the identification of many genes and genetic variants associated with increased risk for disorders, such as autism spectrum disorder (ASD), novel biological insight from these datasets has lagged behind.

Genetics plays a central role in autism spectrum disorder (ASD), yet much remains unknown about how DNA sequence variation predisposes individuals to ASD. Rare mutations have emerged as critical in ASD, and there is great hope that whole-genome sequencing will reveal many more causal mutations and lead to a better understanding of genetics and pathogenesis in ASD. This presumes that we will be able to identify which DNA mutations predispose individuals to ASD against the background of the millions of benign or unrelated DNA mutations present in every human genome. For mutations that disrupt proteins, such causal relationships have been successfully demonstrated, leading to significant new insights into the etiology of ASD. However, the majority of the human genome does not code for proteins, and predicting which mutations are pathogenic in noncoding regions is much more challenging. Enhancers — regulatory DNA sequences within our genomes that control when genes are activated — have emerged as critically important to human health and development. It is likely that noncoding mutations that disrupt enhancers also contribute to the pathogenesis of ASD.

Amniotic fluid (AF) and cerebrospinal fluid (CSF) are routinely sampled for biomarkers of diseases, including autism spectrum disorder (ASD). The cerebral cortex, which governs higher cognitive functions, initially develops from neural stem cells that interface with CSF-filled ventricles. Surprisingly little is known about how fluid-borne signals are distributed across the developing brain, or about the mechanisms by which changes in fluid composition actively instruct brain development.

It is well established that homeostatic signaling systems interface with the mechanisms of developmental and learning-related plasticity to achieve stable yet flexible neural function and animal behavior. Experimental evidence from organisms as diverse as Drosophila, mice and humans demonstrates that homeostatic signaling systems stabilize neural function through the modulation of synaptic transmission, ion channel abundance and neurotransmitter receptor trafficking. At a fundamental level, if homeostatic plasticity is compromised, then the nervous system will be less robust to perturbation. As such, it is widely speculated that defective or maladaptive homeostatic plasticity will be relevant to the cause or severity of autism. However, clear molecular or genetic links between autism and homeostatic plasticity have yet to be defined in any organism.

Between 55 and 70 percent of children with autism spectrum disorders (ASDs) experience sensory over-responsivity (SOR), a severe and negative response to, or avoidance of, sensory stimuli such as noisy environments, unexpected loud noises, scratchy clothing or being touched. Children with ASD and SOR have more anxiety, greater functional impairment and poorer social outcomes than those without it. Because SOR has only recently been considered in the diagnostic criteria for ASD, it has not yet been well studied and little is known about brain mechanisms of SOR or how to treat it.

Recent studies have provided compelling evidence that loss-of-function mutations in the CHD8 gene, which encodes an ATP-dependent chromatin-remodeling factor, are associated with an autism subtype characterized by macrocephaly, specific craniofacial features and gut immobility. The CHD8 protein modifies the structure of chromatin in the cell nucleus, and in vitro studies have suggested that CHD8 might function as a regulator of the developmentally important Wnt and PTEN signaling pathways. Tight control of both of these pathways is critical for normal brain development, and mutations that affect their activity have been strongly associated with autism and brain size. It is therefore important to test whether CHD8 functions as a regulator of these pathways during brain development.

Autism spectrum disorders (ASDs) and related neuropsychiatric diseases, such as schizophrenia, are thought to involve alterations in neural circuitry in different brain regions, including the hippocampus, an area critical for memory formation. Most studies on the role of the hippocampus in learning and memory have focused on information flow through the hippocampal CA3, CA1 and dentate gyrus subregions. Much less is known about the hippocampal CA2 region, a relatively small area that is altered in individuals with schizophrenia and bipolar disorder. The CA2 region is of particular interest in ASD because it has high levels of receptors for the social hormones oxytocin and vasopressin, which have been implicated in ASD.

Medications for treating the core symptoms of autism spectrum disorder (ASD) continue to be an unmet need. The only medications approved by the U.S. Food and Drug Administration (FDA) for the treatment of individuals with ASD are effective in treating irritability and associated aggressive behaviors, but these medications can also cause severe long-term side effects such as diabetes and involuntary motor movements. Effective medications with more tolerable side effect profiles are highly desirable.