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Whole-exome sequencing to identify causative genes for autism

Joseph Gleeson, M.D.
University of California, San Diego, School of Medicine


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.

Because epilepsy and forms of autism associated with seizures both have high heritability rates, Joseph Gleeson and colleagues at the University of California, San Diego, are investigating whether some forms of autism are more heritable than others.

The researchers have identified several large consanguineous multiplex pedigrees in which autism spectrum disorders are associated with epilepsy. They are using a technique called whole-exome sequencing to identify potentially causative genes because the majority of mutations in recessive diseases are located in exons and result in a loss of function of the proteins they encode.

The investigators suggest that although the genes they identify will most likely display mutations that are relatively rare causes of autism, the mutations are likely to be associated with more heritable forms of autism spectrum disorder. Relatives carrying these mutations will be likely to have autism, epilepsy or both. The genes may also have common polymorphisms associated with autism.

Gleeson’s team plans to validate these newly implicated genes by identifying additional mutations or associations in the Simons Simplex Collection, the Autism Genetic Resource Exchange and other cohorts. The team then plans to use these findings to determine the phenotypic spectrum associated with the genetic alterations.