De Novo Mutations and Autism

Rates of autism have risen to extraordinary levels over the last several decades. Whereas 50 years ago an autism diagnosis was made for 1 in 360 children, today, autism spectrum disorder affects 1 in every 66 boys. Some of this increase can be attributed to changes in the timing and nature of diagnoses, but even accounting for these factors the rates have risen dramatically and continue to rise. Autism is a difficult disease to study because it is not likely to have a single functional cause. The disease onset is in children and it affects a core human characteristic: it impairs social communication. In trying to identify causal factors that lead to autism, researchers have been focused on environmental agents that interact with heritable traits as possible causes for the disease. The results of these studies have not yet shown a single pathway or mechanism. Researchers are also trying to define distinct mechanisms for different sub-groups with the goal of accounting for the heterogeneous aspects of the disease.

A new study used modern genetic techniques to examine unique properties of autistic children’s DNA that might be associated with the disorder. The authors searched for point mutations that occur spontaneously or what are called “de novo mutations.” These are mutations in the child that are not present in the parents. Researchers at the University of Washington selectively sequenced the exomes (protein coding regions) of 20 families with autistic children by what they called trio-based exome sequencing (TBES). In contrast to relatively coarse micro-array studies, TBES can look with high resolution at individual point mutations in patients.

The study reports that the de novo mutation rate in autistic children does not differ from the rate in controls. However, the de novo mutations in the autistic children were located in crucial places in the genome, and that such de novo mutations do not occur at similar places in controls. The study estimates that the new technique may identify up to 40-50 percent of the genetic causes of the disease.

In several children they found mutations they believed were causative to their diagnosis. The four genes implicated were FOXP1, GRIN2B, SCN1A, and LAMC3. LAMC3 was not previously implicated in autism, but the gene does have some association with the limbic system and frontal cortex; these are brain regions that researchers believe are abnormal in some autistic brains. Looking at the specific mutations that arise spontaneously in autism is an innovative approach to studying autism. As whole genome sequencing becomes more accessible and less expensive, more data can be collected to find all of the genes implicated in autism.

O’Roak et al, “Exome Sequencing In Sporadic Autism Spectrum Disorders Identifies Severe de Novo Mutations”. Nature Genetics. Online May 15, 2011.

Gray L. “Sporadic Mutations Idenitified in Children with Autsim Spectrum Disorders.” University of Washington Press Release. May 16th, 2011.