Study Offers New Clues to Autism's Underlying Biology


Over the last decade, autism spectrum disorder has been associated with mutations in a variety of genes, accounting for up to 30% of all cases so far. Most of these variants are de novo mutations, which are not inherited, affect only one copy of a gene, and are relatively easy to find. Timothy Yu, MD, PhD's laboratory at Boston Children's Hospital has chosen a less traveled road, tracking rare recessive mutations in which a child inherits two "bad" copies of a gene.

The study, involving one of the largest cohorts to date, suggests that recessive mutations are more common in autism than previously thought. The results, published on June 17 Genetics of Nature, provide a likely explanation for up to 5 percent of all cases of autism and offer new clues to the biological causes of autism.

"This is the deepest dip of all recessive mutations in autism – but we're not done," says Yu, who led the study with first author Ryan Doan, PhD, at the Division of Genetics and Genomics at Boston Children. "This study provides a glimpse into an interesting piece of the puzzle that we still have to put together."

Double beating

Recessive mutations have been associated with autism in the past, especially in small study populations in areas where marriages between relatives are common. When the parents are genetically related, their offspring are more likely to get "double successes" from genetic variants – most often harmless, but some may be disease-causing.

The new study represented a much larger population: 8,195 individuals in the International Autism Sequencing Consortium, founded by co-author of the Joseph Buxbaum, PhD study at the Icahn School of Medicine at Mount Sinai. The study included 2,343 individuals with autism in the United States, the United Kingdom, Central America, Germany, Sweden, the Middle East and Finland. He examined ex-whole data, comparing DNA sequences to all protein-encoding genes in these individuals with autism, against 5,852 unaffected controls.

The researchers first searched for "loss of function" or "knockout" mutations that completely disabled the gene, such that the proteins they normally encode are truncated and nonfunctional. "The concept is simple, although execution has required a lot of careful work," says Doan, who was the first author of the study.

The team identified function loss mutations that were rare (affecting less than 1% of the cohort) and biallelic (affecting both copies of the gene) in 266 people with autism. Overall, people with autism were 62% more likely than the control group to have disabling mutations in both copies of a gene.

The team also looked for missial biallelic mutations, which involve a change in a single amino acid (a "misspelling"). Missense mutations are more common than function loss mutations, and some of them cause the same damage. Missial biallelic mutations were also significantly more common in the autistic group.

Biological tracks

After excluding genetic variants that were also found in the control group and in a large separate cohort of more than 60,000 individuals without autism, Doan, Yu and his colleagues were left with 41 genes that were deleted only in individuals with autism. Overall, researchers estimate that these genes account for another 3 to 5 percent of all cases of autism (2 percent of function loss mutations and 1 to 3 percent of missense mutations).

Eight of these had already been flagged in previous studies. The remaining 33 have never been linked to autism before, and several have intriguing attributes that require more research.

One gene, SLC1A1, for example, helps to modulate brain neurotransmitter glutamate activity and has been associated with a metabolic disorder associated with intellectual disability and obsessive-compulsive disorder. Another gene lost in two siblings, FEV, is critical for the production of serotonergic neurotransmitters in the brain, further supporting the idea that the dysfunction of serotonin signaling is central to autism.

Many of the double knockouts were found in only one individual and would need to be confirmed in other patients, Yu notes.

Male susceptibility to autism confirmed

Autism rates are higher among men than among women, at a ratio of approximately 4: 1. However, previous studies, mainly looking at mutations again found that boys tend to have milder mutations and girls tend to to have more serious mutations, an apparent contradiction.

One hypothesis is that the female brain is somehow more robust – it has more reserve and is more resistant to autism, so it takes a bigger blow to knock it out. We ask, is the same pattern true for recessive mutations? And we found out that yes – women had a higher rate of complete knockout than males. "

Timothy Yu, MD, PhD, at Children's Hospital Boston

In fact, an astonishing 1 in 10 girls had a biallelic gene knockout caused by loss-of-function mutations or by severe missense mutations. And curiously, a boy with autism lost a gene involved in estrogen signaling, suggesting that something in the estrogen pathway could be a risk factor for autism.


Boston Children's Hospital

Journal Reference:

Yu, T. et al. (2019) Recessive gene breakdowns in autism spectrum disorder. Genetics of Nature.


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