Autism spectrum disorders represent a challenge for geneticists because of the heterogeneity of causes. Still, in a subset of people with autism, certain deleterious gene mutations have been identified, and most are involved in the formation of synapses — the points of contact between neurons. At first, these mutations alone were thought to be sufficient to cause autism, but studies suggest that the inheritance of ‘modifier genes,’ which alter the expression of other genes, might contribute to the wide behavioral variability observed in individuals with autism.

Autism has strong genetic origins, but neither common nor rare gene variants explain the majority of cases. This suggests that less-studied portions of the genome may contribute significantly to the disorder.

Chromosomal microarray (CMA) analysis to detect copy number variations (CNVs) —duplication or deletion of chromosomal regions — is the recommended first-tier diagnostic screen for autism, and studies of structural variation (SV) to date have largely focused on CNV detection and interpretation. Copy-neutral SVs, or balanced chromosomal abnormalities (BCAs), have not been systematically surveyed in autism, suggesting that these rearrangements could represent a potent class of loss-of-function mutations that have not yet been characterized in autism.

Growing evidence links errors in genetic control to autism. However, an emerging theme in the pathobiology of human neurologic disorders is that such errors are often found in the regulation of RNA rather than DNA. This fascinating set of observations suggests that whole-genome analysis may be complemented by new technologies that can be used to study RNA regulation. Robert Darnell and his colleagues at The Rockefeller University in New York plan to do just that.

Motor stereotypies, a core feature of autism, are involuntary, repetitive movements that are often associated with self-injury. Treatments for these behaviors are limited and often inadequate, owing to a poor understanding of the underlying biological mechanisms.

Despite the high heritability of autism, the genetic risk factors are still poorly understood. In the absence of reliable and feasible biomarkers, autism spectrum disorders are still diagnosed exclusively according to behavioral criteria. Novel therapeutic approaches are urgently needed, yet genome‐wide association studies have not met the need for a better understanding of the etiology of autism.

There is definitive evidence that rare mutations, including spontaneous, or de novo, structural variations, contribute to autism spectrum disorders. However, recent findings highlight important remaining areas for investigation.

Genotyping, gene expression and genetic sequencing methods are generating large amounts of data that are potentially relevant to autism research. Collaborative efforts and a searchable, web-based repository would maximally harness this unprecedented load of information. Giovanni Coppola’s team at the University of California, Los Angeles, has created a database of about 800,000 DNA sequence variants from roughly 900 individuals in the Simons Simplex Collection (SSC), which includes data and biospecimens from 2,700 families affected by autism. The database of sequence variants is intended for browsing and data mining by autism researchers worldwide.

The Simons Simplex Collection (SSC) is a rigorously characterized set of data drawn from 2,700 families, designed to enrich the discovery of rare and de novo events in autism spectrum disorders. Twelve clinical sites in North America provided data from families who have one child between 4 and 18 years of age with an autism spectrum disorder. Data from each family also include information about unaffected siblings and unaffected biological parents.

Douglas Wallace and his colleagues at the Children’s Hospital of Philadelphia tested the hypothesis that partial defects in mitochondrial bioenergetics are important factors in the etiology of autism. The mitochondria are assembled from genes coded by the maternally inherited, thousand-copy mitochondrial DNA (mtDNA) in addition to the one to two thousand nuclear DNA (nDNA) coded genes that affect mitochondrial structure and function. In addition to generating most of cellular energy by oxidative phosphorylation (OXPHOS), the mitochondria regulate cellular oxidation-reduction status, calcium ion levels, apoptosis, intermediary metabolism and, through high-energy mitochondrial intermediates, the cellular signal transduction pathways and the epigenome.