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.

Copy number variations (CNVs), or altered numbers of certain stretches of DNA, have been implicated as a genetic cause of autism. Alea Mills and her colleagues at Cold Spring Harbor Laboratory in New York set out to determine whether CNVs in the chromosomal region 16p11.2 cause autism-like phenotypes. They used chromosome engineering to generate mice with a deletion corresponding to 16p11.2 — one of the most prevalent genomic lesions associated with autism — as well as mice with reciprocal duplication of this region.

One copy of 22q11.2, a segment of chromosome 22 that includes several genes, is missing in 1 of every 4,000 individuals. This non-inherited genetic abnormality results in some physical abnormalities, most of which can be repaired surgically early in life. But the most pernicious deficits associated with this microdeletion are cognitive, including severe learning disabilities and a high risk for mental illness, such as autism and schizophrenia. An improved understanding of the mechanisms that contribute to these psychiatric and cognitive symptoms is essential for providing better treatments.

About 15 to 30 percent of children with autism are at risk of epilepsy, which is roughly ten times higher than the general population. Additionally, a significant proportion of individuals with autism who don’t have clinically evident seizures show abnormalities in electroencephalography — a measure of electrical activity in the brain. Some genes implicated in epilepsy, such as the contactin gene family, are also risk factors for autism. And finally, preliminary data suggest that anticonvulsant drugs may be useful for treating some autism spectrum features.

At least 100 different genes have been implicated in autism spectrum disorders. Although certain genetic variations do correlate with autism, other factors must be involved, as not all individuals with these genetic variations develop an autism spectrum disorder.

Christopher Walsh and his colleagues at Boston Children’s Hospital have been studying the genetics of autism by analyzing inherited recessive mutations in consanguineous families — those in which the parents are related to each other (e.g., as cousins).