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SPARK Finds New Class of Genes that Cause Autism

A photo of SPARK's scientific director, Pam Feliciano, PhD

Marina Sarris

Date Published: August 18, 2022

A study using SPARK data has uncovered a new class of genes that may expand what we know about autism and the way the brain works. Variations in these genes have a less severe effect on the brain, and cause milder forms of autism, than previously identified autism genes.

These moderate-effect genes may be more important long-term to understanding brain functioning. And studying them may also provide clues about how we can best support people on the spectrum, some researchers say.

Until now, researchers have mostly uncovered variations to genes that cause a severe effect on early brain development. People with those major variants are more likely to have intellectual disability and autism than people with the newly identified variants.

In this study, researchers analyzed the DNA of almost 43,000 people with autism, including 35,000 participants in the SPARK autism research project. Researchers discovered that differences in one gene, called NAV3, were mostly inherited from parents who do not have autism. Differences in three other genes may be either inherited, or newly occurring (also called de novo) in the child.

SPARK Scientific Director Pamela Feliciano, Ph.D., is one of the authors of this study, which was published in the scientific journal Nature Genetics in August 2022.1 She answered questions about its findings, below.

Q: Why is this new research so important to our understanding of the role genes play in the development of autism?

A: We have identified genes that cause autism in a different way. We have known for a long time, since studies of twins in the 1970s, that autism is highly heritable. That is, we’ve known that inherited genetic factors are a major cause of autism. About 15 years ago, we first started to appreciate how de novo variants in a gene — variations that were not inherited from parents — can lead to autism. Since then researchers have discovered variants in almost 200 genes, most of which are de novo, that lead to autism. But these variants explain just a fraction of autism cases. These newly identified genes show us a different way that genetic differences can cause autism.

Q: People who have differences in the genes identified in this new study have a moderate chance of having autism. What does that mean?

A: It means that these genes increase someone’s chance of having autism, but not everyone with these variants has autism. By comparison, genetic variants with larger effects cause autism or intellectual disability in almost everyone who has that genetic variant.

Q: What did you learn about the characteristics of people with variations in these moderate-effect genes, some of which are inherited? How does that compare to the characteristics of people with variations to genes that cause major effects on the brain?

A: There were two main findings. First, the people with de novo or major-effect genetic variants are much more likely to have intellectual disability than people in SPARK as a whole. About 70 to 80 percent of the people with major effect variants in autism genes have intellectual disability, compared to about a third of people in SPARK overall.

In our study, we identified approximately 100 people who have inherited genetic variants in the four new moderate-effect genes. They resemble SPARK participants as a whole. They are much less likely to have intellectual disability and seizures than the people who have de novo, or major-effect, variants.

Secondly, in autism in general, and in the SPARK study, we see a 4 to 1 ratio of males to females. In this statement, I’m referring to the sex a person was assigned at birth. We see a similar male-to-female ratio in the people with moderate-effect genetic variants.

That ratio is different from what we found previously in people who have major-effect genetic variants. In that group, there are about two males for every female. We’re not sure if that is because females are more likely to have a genetic cause of autism, or if it’s because females with milder autism are less likely to be diagnosed with autism. But the difference in sex ratio in people with autism with de novo genetic changes (2 males to 1 female) and inherited genetic changes (4 males to 1 female) is very interesting and something for researchers to investigate in the future.

Q: How can parents pass along a moderate-effect autism variant, but not have autism themselves?

A: It is important to remember that genes do not always express themselves the same way in all people. Our data show us that these kind of genetic differences are more likely to be found in people with autism than in people who don’t have autism. But other genetic factors or environmental factors have an impact on whether a particular genetic difference leads to autism. (Environmental factors, for example, may include conditions such being born prematurely or a mother having a high fever or infection during pregnancy.)

Another example is identical twins. They have the same genes, but the behavior and many features of twins are not exactly the same. When one identical twin has autism, the majority of the time the other twin has autism, too, but usually their manifestations of autism are somewhat different.

In the same way, the presence of a moderate-effect genetic variant in both parent and child may increase their chances of having autism, but it does not mean they will 100 percent of the time.

Q: Some families have more than one member with autism. Are they more likely to have an inherited, moderate-effect autism variant, such as the ones that SPARK found?

A: We don’t have enough data to say that, but I suspect that may be the case.

Q: This study included 42,607 people with autism, and researchers estimate that they will need almost three times that number to find more moderate-effect genetic variants. Why do you need so many people? Are moderate-effect variants harder to find because they do not always cause autism?

A: The type of genetic variations that were identified before this study were easier to identify because they have a strong effect on the people who have them. Strong de novo changes that occur in genes such as CHD8 or SCN2A can increase the chance that someone has autism by 20 to 50 times compared to someone who does not have that variant. That means that almost everyone with those genetic variants has autism. It’s easier to establish the statistical link between that type of genetic variant, and autism in these cases.

By comparison, if you have a variant in one of the moderate-effect genes we studied, you may be three to five times more likely to have autism than someone who doesn’t have that variant. That means some people with the same genetic variant do not have autism. The variant has a weaker effect. You need to find even larger numbers of people with autism with those genetic variants to be able to establish a link, statistically, between the genetic variant and autism.

So genetic differences with a weaker effect, that don’t always cause autism, are more difficult to find without sequencing genes from very large numbers of people.

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  1. Zhou X. et al. Nat. Genet. (2022) Article