Autism spectrum disorder continues to be a mystery. No link to vaccines has been found, but over the past 20 years studies have identified more than 100 genes with rare mutations linked to it.

If autism can be caused by mutations in different genes, why is it that people with autism often share common signs and symptoms? One theory is that they may share a common developmental path.

Gene mutations associated with autism may affect early brain development, when these genes are most active.

A team led by researchers at the University of California at Los Angeles and Stanford University developed a model to show how gene mutations associated with autism may affect early brain development, when these genes are most active.

The model gives researchers a way to understand how and why different types of autism may have the same biological features. “This work demonstrates how stem cell models can help us understand neurodevelopmental conditions during periods most relevant to disease origins,” the senior author on the study, Daniel Geschwind, said in a statement.

The researchers grew clusters of brain cells, organoids, in the lab using human stem cells. These stem cells came from people with three different genetic makeups, or signatures: those with eight mutations known to be associated with autism; those with idiopathic autism, or autism with no known genetic cause; and neurotypical controls who did not have autism.

To see how genetic changes affected early brain development, researchers monitored gene expression in the organoids for 100 days. Though each genetic signature affected different biological processes early on, the genetic mutations began to affect similar processes as they matured.

“Think of it as different routes leading to similar destinations,” said Geschwind, the Gordon and Virginia MacDonald distinguished professor of Human Genetics, Neurology and Psychiatry at UCLA. The mutations may affect different parts of brain development at first, but they go on to affect other, overlapping developmental pathways as a child's brain development continues.

Though each genetic signature affected different biological processes early on, the genetic mutations began to affect similar processes as they matured.

The researchers identified a gene network that regulated gene expression and chromatin remodeling, the process by which DNA is packaged so the genetic information it carries can be read. This network appears to determine why overlapping pathways are affected in later stages of brain development.

Using CRISPR gene editing technology, the researchers reduced the activity of these regulatory genes in brain cells. They confirmed that many of these gene-controlled pathways linked to autism downstream, or later. This regulatory network may have potential targets for future treatments.

The UCLA and Stanford scientists found few consistent molecular changes in organoids derived from people with idiopathic autism. This inconsistency may be the result of complex genetic processes that lead to this type of autism, the researchers said. It also highlights the need for much larger studies to better understand these processes, which involve multiple genes.

The study is published in Nature.