News The latest developments in autism research.

Rare mutations linked to severity of autism symptoms

by  /  3 November 2014

Boys with autism who carry rare, spontaneous mutations have lower intelligence quotients (IQs) and more severe symptoms than do those who may have inherited the disorder. The finding, published 21 October in the Proceedings of the National Academy of Sciences1, hints at two classes of autism risk with varying severity.

“Understanding how the genetic heterogeneity is actually leading to phenotypic heterogeneity is a very exciting time in our research,” says lead researcher Mark Daly, associate professor of medicine at Harvard University.

The researchers looked at harmful mutations present in 618 boys with autism but not in their parents or unaffected siblings.

The researchers initially included 152 girls with autism in their study. This number turned out to be too low to spot any meaningful trends between spontaneous mutations and IQ.

However, these girls have double the rate of harmful mutations compared with the boys. This is in line with the finding that girls need a bigger genetic hit to develop autism than boys do.

Boys with IQs below 100, the population average, have a high rate of spontaneous, or de novo, mutations, the study found. They also have more severe symptoms than boys with higher IQs. This suggests that harmful mutations track with both IQ and autism severity.

By contrast, boys with autism who have IQs higher than 100 have the same number of de novo mutations as do people without autism. This suggests that themutations do not contribute to autism in these boys.

The boys with higher IQs also tend to have a family history of psychiatric disorders, suggesting that inherited milder mutations may have combined to cause their autism.

“It seems as if the higher-IQ boys [have] a different class of genetic mechanism,” says Michael Wigler, professor at Cold Spring Harbor Laboratory in New York. Wigler was not involved in this study, but has found similar results.

In a study published last week, he and his colleagues reported that de novo mutations are present predominantly in children with low IQs. One harmful de novo mutation in an autism gene can lower IQ by about 5 points, and two mutations by about 20 points, they found.

New risk:

Wigler’s study also found that de novo mutations may account for just under one-third of the risk for autism. This is the latest in a string of results suggesting an important role for de novo mutations in autism risk.

Much of the search for harmful de novo mutations so far has focused on families that have only one member with autism. For example, the new study and Wiger’s report last week both drew samples from the Simons Simplex Collection (SSC) — a database of children with autism whose parents and siblings do not have the disorder2. (The SSC is funded by the Simons Foundation,’s parent organization.)

By comparing the exomes — the protein-coding regions of the genome — of these family members, researchers have tried to pinpoint de novo mutations in the child with autism.

Looking instead at boys with autism who have low IQs may be “markedly more productive,” says Elise Robinson, instructor in medicine at Harvard University and one of the researchers on the new study.

Boys who were unable to complete an IQ test also have an elevated rate of de novo mutations, the study found. These boys have the most severe behavioral problems, further reinforcing the link between de novo mutations and autism severity.

Not everyone with a de novo mutation in an autism gene has severe symptoms, however. And many people with the disorder may carry both de novo and inherited risk factors.

 “We shouldn’t set up a situation where we say only the kids who have severe de novo mutations are the ones who are going to be severely affected,” says Brian O’Roak, assistant professor of molecular and medical genetics at Oregon Health and Science University, who was not involved in the new study. “You can have the same high-risk genetic mutation in kids who have an IQ above 100 and on the other side have a kid who is basically on the low IQ end.”

As a proxy for inherited mutations, the researchers looked at the children’s family history — up to first cousins — of depression, bipolar disorder and schizophrenia. This is “clever,” says Kathryn Roeder, professor of statistics
at Carnegie Mellon University in Pittsburgh, who was not involved in the study. “It’s a good insight. You see that the people with a family history [of psychiatric disorders] still have autism, but they are high functioning.”

The milder symptoms, which may be the result of common variants found throughout the population, may shed light on important aspects of autism, she says.

 “Studying the impact of the common variants will give us greater insight into how we develop into social beings,” Roeder says. “They’re going to get us to the subtle symptoms, which are the pretty interesting part of autism.”


1: Robinson E.B. et al. Proc. Natl. Acad. Sci. USA 111, 15161-15165 (2014) PubMed

2: Iossifov I. et al. Nature Epub ahead of print (2014) Abstract

10 responses to “Rare mutations linked to severity of autism symptoms”

  1. SAM says:

    Another genetic study, not too convincing of being anything fruitfull or hopefull. Even neurotypical children have denovo mutations but no autism. Why the professor explain why children during fever and infections their autism diminishes. Why the sleep cycle is normal during infection and during fever as when not sick their autism is uncontrollable. I am not a Harvard scientist but seems like immune system in the brain is eating the brain, only not when it has something else to play with (Infection or disease)
    Simple questions, tools are available, but these dear researchers are trying to reach sun surface when everybody knows that it is impossible.

    Moderator dont delete the comments which are at the heart of autism cure

  2. Shah Aftab says:

    During fever the sleep patterns return and autistic traits decrease because body is in a fight mode and starts fighting with the disease and the chemicals in the body.
    Immune system is not eating the brain. It is saving the brain from the toxic chemicals that are roaming in the body and the brain. Think of it like brain closing itself to avoid a much worse situation because of the chemicals that the body is unable to expel.
    I may recommend you to read Adeerus Ghayan’s books on Autism. He is of the belief that chemicals in the food chain and the air are contributing to ASD and if the autistic children are given farm fresh organic foods only, then their autistic traits start decreasing.

  3. Dianne says:

    My son has had the most comprehensive genetic testing available and there were NO abnormalities. Yet, he has severe autism ???

  4. autism mom says:

    I wonder what do they mean when they say girls need “a bigger genetic hit’. A hit of what exactly?? an insult to their immune system that could trigger a dysfunction? Are they referring to environmental exposure??? more prone genes? its just an odd way of saying that some girls carry more mutations if that is what they mean

    from the above article. “However, these girls have double the rate of harmful mutations compared with the boys. This is in line with the finding that girls need a bigger genetic hit to develop autism than boys do”

    • wendychung says:

      Girls are more likely to have a single gene as the cause of their autism, and these single genes tend to have a significant impact.

  5. ASD says:

    The title is misleading. Severity of autism is hard to define. These rare mutations lead to low IQ. Those with lower IQ aren’t necessarily more socially impaired.

  6. Mimi says:

    Our son has “severe” autism; aggressive and disruptive behavior, low IQ, his sibling is typical. We had our 4 exomes sequenced so we could look and see what’s different. What we see is many, many small changes in our son’s DNA. Some he inherited from his dad, and some from me, some rare, a few de novo. He has WAY more small changes than any of us. I’m guessing most DNA tests would come up with nothing causative like Dianne’s child above, so it may just be the combination of the large # of changes combined with rare and de novo variants.

  7. michael crosby says:

    functioning labels are pretty much useless because they mean different things to different people. they don`t have anything to do with iq, for instance. they`re a subjective interpretation of what a person can do. many “low functioning” people recently have shown that they can communicate just like you or me when given the appropriate kind of communication tool that works for them. we`re currently going through a similar realisation with autism as there was with deaf, blind and mutes like helen keller. autistics are much more capable of “functioning” than people have given them credit for in the past. assuming no other especially disabling comorbids like intellectual disability exist.

    also, typical iq evaluations and quantifying systems do not work for autistics. autistics have a variety of iq levels in different areas so a single number doesn`t really reflect how smart they are or could be.

  8. John Demick says:

    Why are autistics with normal IQs look like the general populace in terms of De Novo deletions and duplications? What is going on with them? I would like to know.

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