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.

Four independent studies have uncovered different autism-associated variants in the gene contactin­associated protein-like 2 (CNTNAP2), making this gene the first to have multiple variants associated with autism. The striking pervasiveness and diversity of the variants suggest that CNTNAP2 plays a crucial role in autism, leading Aravinda Chakravarti and his colleagues to embark on a detailed study of the gene.

Copy-number variations (CNVs) are losses or gains of genetic material, such as a deletion or duplication of a chromosomal region. There is growing evidence that CNVs play a major role in causing autism spectrum disorders and other brain disorders. Christa Lese Martin and her colleagues at Emory University in Baltimore, along with David Ledbetter at Geisinger Health System, propose to map the genes linked to autism and schizophrenia.

Copy number variants (CNVs) are segments of DNA that vary in copy number between different individuals. CNVs confer significant risk of neuropsychiatric disorders, including autism and schizophrenia. Notably, there appears to be a reciprocal relationship between copy number and brain size for certain genetic loci. For example, deletions of the genomic region 16p11.2 tend to be associated with autism and increased head circumference, whereas duplications of the same segment tend to be associated with schizophrenia and smaller head circumference. The contrasting clinical phenotypes that are associated with reciprocal changes in gene dosage could represent opposite extremes of the same neurodevelopmental process.