A rapidly increasing number of genes are implicated in autism. While null alleles —those with mutations that eliminate gene function — tightly linked to autism are extremely helpful in identifying causative genes, one can’t predict the in vivo effects of other types of alleles (such as those with mutations that change the function of the gene).

Studies have identified a large number of genes that contribute to autism, and many affect communication between neurons, known as synaptic transmission. However, we do not understand the mechanisms responsible for the genes’ effects on synaptic transmission or how these effects give rise to abnormal behavior. To elucidate these mechanisms, Robert Edwards and his group at the University of California, San Francisco plan to study a protein of known biochemical function that has been implicated in autism and determine its role in synaptic physiology and behavior.

Autism is characterized by profound social impairments. There is little understanding of the origin of these social deficits, and efficient diagnosis and therapeutic options are lacking. Molecular genetic approaches allow for the discovery of specific neural circuits involved in social behavior, facilitating the development of diagnostics and therapeutic approaches specific to social deficits.

Autism is most likely caused by changes in the development of the cerebral cortex, particularly in neural circuits that process social and cognitive information. Under- or over-connectivity in these circuits has been found in the brains of children and adults with autism. It remains unknown how altered development might lead to these disrupted connections. This knowledge is crucial for new diagnostic, preventive and therapeutic approaches in autism.

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.