Autism is a sex-biased, complex disorder in which the recurrence risk for siblings of girls with autism is 7 percent, compared with 3.2 percent for siblings of boys with autism. In multiplex families — those in which more than one individual has autism — the sex difference in sibling recurrence risk is far higher: 39 percent in families containing two or more females with autism, and 19 percent in families containing two or more males with autism.

Evan Eichler and his colleagues are investigating the genetics underlying the variability of disease associated with deletion or duplication of chromosomal region 16p11.2. They plan to look for high-impact risk factors for autism in participants with variants both within and outside the 16p11.2 region.

Epidemiological and clinical studies show that children with autism have a ten-fold higher risk of epilepsy compared with the general population. In addition, most mouse models of autism display spontaneous epileptic tendencies, altered brain activity or synaptic deficits. The disrupted genes in mouse models of autism include BCKDK, CNTNAP2, FMR1, SYN1, CDKL5 and SCN1A. Joseph Gleeson and his colleagues at the University of California, San Diego and The Rockefeller University are studying the genetic basis of the connection between autism and epilepsy in order to gain insight into the mechanisms of these diseases, which may point to more targeted therapies.

The search for genetic risk factors for autism has revealed rare mutations in many genes. A critical step toward understanding autism is finding a common theme among the genes implicated in the disorder.

Human genomes differ from one another in many respects. Some people harbor more or fewer than the typical number (two copies, one from each parent) of certain genome segments. These differences are known as copy number variations (CNVs). CNVs play an important role in determining the phenotype, or observable characteristics, of each individual.

Major progress has been made in understanding the genetic basis of autism spectrum disorders. Rare or de novo mutations throughout the genome are now known to be important factors. These include copy number variations (CNVs) and point mutations that disrupt the protein-coding sequences of genes.

Several loci, or stretches of chromosomal DNA, have been shown to be defective in individuals with autism. These loci each contain more than one gene, so the next step is to identify the specific genes that are disrupted.

Among the many interesting findings emerging from studies of de novo mutations in the Simons Simplex Collection has been the extreme degree of genetic heterogeneity that underlies autism spectrum disorders. In addition, one mutation may be associated with a wide range of distinct psychiatric and neurodevelopmental outcomes. Many of the genes that contribute to autism also demonstrate considerable pleiotropy, playing diverse biological roles at different points in brain development. These factors present important obstacles to translating the rapidly growing understanding of autism genomics into a deeper understanding of autism pathophysiology.

The diverse genetic variations associated with autism are thought to affect molecular networks, which have yet to be identified. Dennis Vitkup and his colleagues at Columbia University in New York have developed an algorithm called NETBAG to search for clusters of genes perturbed by autism-associated genetic variations.