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.

Autism spectrum disorders (ASD) are frequently associated with immune dysregulation. Peripheral immune responses and microglial function have been the major focus in the field. However, recent studies have suggested that neurons are also able to use their own innate immune receptors, including toll-like receptors (TLRs), to detect the danger signals derived from both endogenous cells and pathogens.

Chromosomal copy number variations (CNVs) are common genetic abnormalities in autism spectrum disorder (ASD) and have been identified in approximately 10 percent of individuals with ASD. Currently, there is a knowledge gap in the understanding of the molecular and synaptic mechanisms underlying CNV-associated ASD.

Williams syndrome (WS) is a neurodevelopmental disorder caused by deletions in the 7q11.23 chromosomal region. Individuals with WS show developmental delays, learning disabilities and excessively social behavior. Interestingly, individuals with duplications of this same chromosomal region display a symmetrically opposite phenotype with regard to social behavior. This genomic segment therefore offers a unique opportunity to understand the molecular underpinnings of social behaviors.

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.