New technique reveals another piece of spectrum's genetic architecture

There is little argument among experts that autism spectrum disorders (ASD), complex developmental disabilities that vary widely in their severity, are caused by both genetic and environmental factors. Advances in genome sequencing now permit scientists to uncover specific mutations in DNA that are associated with ASD at unprecedented resolution. Such data are vital to understanding the genetic basis of the disorder.

A new study co-authored by UCLA researchers has led to a better understanding of the genetic contribution to autism using this new approach. By comparing siblings with and without ASD, the researchers have discovered a single instance in the affected siblings in which two independent mutations disrupt a gene called SCN2A.

Reporting in the April 4 edition of the journal Nature, Dr. Daniel Geschwind, a UCLA professor of neurology and psychiatry, and colleagues from Yale University, Carnegie Mellon University and the University of Pittsburgh completed "whole-exome sequencing" of 238 parent-child quartets. A quartet is defined as two parents and one child without ASD and one child with ASD.

Instead of the time-consuming process of searching the entire genome of an individual, the researchers turned to the newer technology of whole-exome sequencing, which searches only the protein-coding regions of the genome to pinpoint the mutation that causes a particular disorder.

The researchers compared mutation rates between unaffected individuals and those with ASD within a family, then compared the ASD mutations to the entire cohort. They found multiple variations between the unaffected and affected groups. Specifically, among a total of 279 coding mutations, they identified a single instance in individual children with ASD - and not in siblings - in which two independent mutations disrupt the gene SCN2A. That same mutation was found in all the unrelated children with ASD, confirming its importance.

In addition, the researchers found many other genes with similar mutations occurring only once - these also make promising new candidates for autism susceptibility. Finally, they were able to estimate that there are likely about 1,000 or more genes that contribute to autism risk.

"This work demonstrates that autism, in most cases, has a contribution from several genes, as the average risk imparted by one mutation is typically not sufficient," said Geschwind, who holds UCLA's Gordon and Virginia MacDonald Distinguished Chair in Human Genetics and directs the UCLA Center for Autism Research and Treatment. "Overall, these results substantially clarify the genomic architecture of ASD, and this is an important step in attempting to better understand the genetic basis of these disorders."

A complete list of contributing authors and institutions is available in the Nature paper. Funding was provided by the Simons Foundation.

Autism is a complex brain disorder that strikes in early childhood. The condition disrupts a child's ability to communicate and develop social relationships and is often accompanied by acute behavioral challenges. Autism spectrum disorders are diagnosed in one in 110 children in the United States, affecting four times as many boys as girls. Diagnoses have expanded tenfold in the last decade.