The most consistent finding of autism research lies in the revelation that the disorders are incredibly complex. Two new studies in the January 23 issue of the Cell Press journal Neuron that add to the growing appreciation of this complexity focus on identifying inherited genetic mutations linked with autism spectrum disorders. The mutations—which are distinct from the spontaneous mutations that have been the focus of previous studies—may provide valuable insights into the causes of autism.
"It's long been known that autism is a heritable condition and that some cases appear to run in families. Our studies are among the first to begin to address this heritable component," says Dr. Christopher Walsh of Boston Children's Hospital, who is the senior author of one of the papers.
Both groups sequenced the portion of the genome that codes for proteins, also known as the exome, in individuals with autism, their relatives, and controls. In one study, investigators focused on rare mutations that completely abolish the function of particular genes—and therefore the expression of a protein. "We utilized new genome-sequencing technologies to discover a component of autism that can be traced to recessive inheritance—that is, when a child inherits two broken copies of the same gene, one from each parent who is a carrier," explains senior author Dr. Mark Daly of Massachusetts General Hospital and the Broad Institute. "There were twice as many autism cases as control individuals that were apparently missing an important protein somewhere in the genome," he adds. Their findings suggest that 5% of autism risk is linked to inherited mutations that completely disrupt the functions of genes.
Like Dr. Daly and his colleagues, Dr. Walsh and his team identified and characterized cases of autism due to the inheritance of two gene mutations, one from each parent. In this work, though, the researchers found that the partial loss of a gene's function—not only complete absence of function—is linked to autism spectrum disorders. They identified several genes—such as those involved in neurometabolic pathways—that were not previously associated with autism risk, and they revealed a striking variability of autism severity despite inheritance of similar genetic mutations.
"These two studies firmly establish that recessive mutations contribute importantly to autism, not just in specialized populations but in the population at large," says first author Dr. Timothy Yu, of Boston Children's Hospital.
With follow-up work, identifying the various genes that are silent or partially disabled in autism cases can provide key clues to understanding the underlying biology of autism spectrum disorders and potentially help generate new therapies.