Brian J. O’Roak’s team at Oregon Health and Science University in Portland has been exploring genetic mutations that are difficult to identify using conventional means, and what role these mutations might play in neurodevelopmental disorders. In a previous study, O’Roak and his colleagues sequenced the protein-coding regions of the genome, or ‘exomes,’ in more than 200 families that have a single child affected with autism.

Mutations in hundreds of genes may predispose individuals to autism, but no common feature characterizes these genes, little is known about the functions of many of them and it remains unclear how mutations in these genes promote autism pathogenesis. Multiple autism-associated mutations have been identified in genes encoding neuroligins — cell-adhesion molecules that are essential for the organization of synapses, or the junctions between neurons, and for synapse property specification, during which neuroligins contribute to organizing synapse properties.

Nearly 90 percent of children with autism are estimated to suffer from sensory abnormalities, often hypersensitivities, to stimuli that a neurotypical individual could ignore. These hypersensitivities can, in principle, be caused by abnormally acute sensory capabilities. However, empirical data contradict this possibility; individuals with autism do not differ systematically from neurotypical controls in their sensory acuity. Pawan Sinha and his colleagues at the Massachusetts Institute of Technology plan to consider an alternative account of hypersensitivities in autism.

Biological networks provide a natural framework for integrating the diverse genetic variations associated with complex and multifactorial disorders. The main challenge in the analysis of rare genetic variations, such as de novo single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) — duplications or deletions of stretches of DNA — is precisely their rarity. With currently available sample sizes, a vast majority of the observed genetic events are either unique or show only limited recurrency.

We are beginning to identify many genetic alterations, environmental factors and developmental processes that contribute to autism, but we do not yet understand how various molecular perturbations add up to cause the disorder. Vikaas Sohal and his colleagues at the University of California, San Francisco aim to identify possible alterations in the function of circuits in the prefrontal cortex that could contribute to autism.

Efforts to find genetic causes of autism have identified hundreds of rare mutations in individuals with the disorder, and this list is anticipated to grow steadily in the next few years. A pressing question is which of the mutations are responsible for conferring a disease risk. A small number of the mutations appear likely to disrupt the function of the affected genes, and individuals with autism have a higher burden of these mutations, suggesting a causative link to the disorder. However, the majority of mutations change only a single amino acid of the protein product or are ‘silent’ according to the genetic code. These mutations occur at similar frequencies in individuals with autism and unaffected siblings, implying that most of them are probably benign.

A major goal of autism research is to understand the relationships among genetic etiology, altered developmental trajectory, aberrant neural circuits and behavioral symptoms characteristic of this disorder. Understanding how the functional activity of neural circuits is altered with cell-type resolution is likely to lead to more effective and targeted therapies. Among the neural circuits implicated in autism are ones involving the striatum, a structure buried deep within the brain that contributes to the evaluation and selection of behavior. Additionally, one gene associated with autism is SHANK3, which is important for the connections between neurons, including those within the striatum.

A large number of susceptibility genes for autism and schizophrenia have been identified, although the function of many of these risk factors in regulating neuronal development is not well understood. Copy number variations (CNVs), structural rearrangements of the genome in which entire chromosomal regions may be either deleted or duplicated, produce variability in the expression level of affected genes.

The etiology of autism is complex and mysterious. Autism has a strong genetic basis but there is remarkable diversity and heterogeneity in genes that are associated with the disorder. Despite this heterogeneity, a convergence of evidence suggests that disruptions in synapse function, neuronal activity and circuit formation are the origin of behaviors associated with autism.