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.

Comprehensive studies of the human genome using high-speed DNA sequencing have identified new genes whose mutations appear to contribute to autism. One class of autism genes consists of regulators of the way that cells, including neurons in the brain, compact their DNA so that it can fit into the nucleus of the cell, while also being available for the selective production of proteins required for brain function. These genes, called chromatin regulators, appear to be among the most frequently mutated genes in individuals with autism. It seems that chromatin regulators control the production of proteins necessary for the development of neural circuits, and perhaps transmission of electrical impulses in the brain.

Individuals with autism frequently display accelerated brain growth during infancy and a larger brain size that is also associated with increased symptom severity. Given the widely documented heritability suggesting that autism is predominantly a genetic condition, and the well-established link between autism and abnormally accelerated brain-growth patterns, genes involved in brain growth are excellent candidates for better understanding autism.

Autism genetics has made demonstrable progress in the past few years with the recognition of the role of de novo, or spontaneous, copy number variants (CNVs), loss-of-function point mutations and common inherited DNA variants. Although landmark studies have proved the important role of genetics, the common and robust finding is twofold: Hundreds of genes contribute to autism pathogenesis, but owing to limitations of statistical power and sample size, only a tiny fraction of them can be conclusively identified.

The goal of Evan Eichler’s project is to define high-impact genes and mutations associated with sporadic autism. Using molecular inversion probe (MIP) technology, Eichler and his colleagues plan to resequence the protein-coding sequence of 200 autism candidate genes in 8,588 participants who have autism or intellectual disabilities, from eight diagnostic centers worldwide.

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.