Researchers have discovered that people diagnosed with autism spectrum disorder (ASD) were more likely to have gene deletions than people without the disorder.
That means those individuals — 7 percent of the study group — had one copy of one or more genes when they should have had two, noted researchers from the Icahn School of Medicine at Mount Sinai in New York City.
“This is the first finding that small deletions impacting one or two genes appear to be common in autism, and that these deletions contribute to risk of development of the disorder,” said the study’s lead investigator, Joseph D. Buxbaum, Ph.D., a professor of Psychiatry, Genetics and Genomic Sciences and Neuroscience.
“This conclusion needs to be expanded in other independent samples of ASD so that we can truly understand how the risk manifests.”
That process is now ongoing, according to Buxbaum. The Autism Sequencing Consortium, made up of more than 25 institutions, was awarded a $7 million grant from the National Institutes of Health to continue analyzing the genomes of thousands of ASD individuals at Mount Sinai.
Autism, which affects about 1 percent of the population, is a developmental disorder thought to be caused by a complex interplay between genetic and environmental factors. Although the disorder can be inherited, the majority of autism cases cannot be attributed to known inherited causes, according to Buxbaum.
While research has indicated that there might be as many as 1,000 genes or genomic regions that contribute to autism, most studies have looked for either single point mutations — a change in a single letter of DNA on a gene — or for large areas of the genome, encompassing many genes, that is altered.
For their study, the researchers scanned the genome of hundreds of individuals using gene sequencing technology. They looked for small copy number variation — the deletion or duplication of genes — between individuals with autism and a control group of people without the disorder.
To conduct the study, they used exome sequencing to look at all 22,000 human genes in the sample set. They then analyzed that data using the eXome Hidden Markov Model (XHMM) program. Together, the tools are the first that can find single gene-sized deletions or additions in the genome, according to the researchers.
“This gives us the power, for the first time, to run one test from a blood sample and compare it to a reference genome to search for mutations and small copy number variation in patients,” Buxbaum explained.
The researchers analyzed a database consisting of 431 autism cases and 379 matched controls, totaling 811 individuals. They found 803 gene deletions in the autistic group and 583 deletions in the control group. They also found that those with autism had a greater likelihood of having multiple small deletions.
“It is now known that imperfect gene copy number is one of the major sources of variability between people,” Buxbaum said.
“One of the reasons we are different from each other is because of gene additions or deletions, which are often inherited. But of the extra deletions we see in ASD, not all are due to genetic inheritance. Some occur during the development of the egg or sperm, and deletions that develop in this way tend to be associated with the disorder.”
The researchers found that a significant proportion of gene deletions in those with autism were related to autophagy, a process that keeps cells healthy by replacing membranes and organelles.
“There is a good reason to believe that autophagy is really important for brain development because the brain produces many more synapses than it needs, and the excess needs to be pruned back,” Buxbaum said. “Too many, or too few, synapses have the same effect of not making communication work very well. It could mean that some synaptic connections come in too late and may not solidify properly.”
The researchers say they believe the findings, published in the American Journal of Human Genetics, will have clinical significance.
“Key copy number variations — those that consistently appear in an autistic population — can impact genetic testing,” Buxbaum concluded.