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Boys with autism inherit mutations from unaffected mothers

by  /  1 June 2015

In the family: Mothers who are not on the spectrum can still pass a risk of autism to their sons.

Rare inherited mutations contribute to autism in about 10 percent of boys with the disorder, suggests a study published 11 May in Nature Genetics1. These genetic glitches are primarily passed down from unaffected mothers, consistent with the idea that women are somehow protected from the disorder.

Genes are thought to account for more than half the risk of autism. But most studies aimed at identifying particular candidate genes focus on rare spontaneous mutations that are relatively easy to detect — the ‘low-hanging fruit’ among mutations.

The new study looks at rare inherited mutations, which are harder to link to autism because every person carries hundreds of them. “I am excited by this work because it sheds light on another class of mutations important in autism,” says lead researcher Evan Eichler, professor of genome sciences at the University of Washington in Seattle.

Eichler and his team found that boys with autism are more likely than their unaffected siblings to have inherited rare mutations in genes that are conserved, or seldom mutated, in the general population.

The study represents a step toward understanding the inherited component of autism risk, says Jacob Vorstman, assistant professor of child psychiatry and genetics at the University Medical Center Utrecht’s Brain Center Rudolf Magnus in the Netherlands, who was not involved in the work. It’s “one of the first to make a successful attempt at gathering the not-so-low hanging fruit.”

Family ties:

Eichler and his colleagues analyzed sequences from 2,377 people with autism and their unaffected parents and siblings. The families are part of the Simons Simplex Collection (SSC), a repository of data and samples from families that have one child with autism and unaffected parents and siblings. (The collection is funded by the Simons Foundation,’s parent organization.) The researchers focused on the swaths of the genome that encode proteins, called the exomes.

The researchers excluded common genetic variants, which appear in at least 5 percent of the general population. They then homed in on rare single-letter typos in DNA, called single nucleotide variants (SNVs), that disrupt the function of a gene.

“I am excited by this work because it sheds light on another class of mutations important in autism.”

People with autism inherit just as many SNVs as their unaffected siblings do, the study found. However, when the researchers restricted their analysis to conserved genes, they found that people with autism are about 14 percent more likely than their siblings to have so-called ‘private’ SNVs — variants so rare that they have so far been observed in only a single family.

These differences appear to track with symptom severity. Private SNVs are enriched in individuals with severe autism and lower-than-average intelligence quotients (IQs) relative to their unaffected siblings.

Variants passed from unaffected mothers to sons account for most of the increased frequency of private SNVs in people with autism. Those passed from mothers to daughters and from fathers to either sons or daughters make minimal contributions.

Because each variant is so rare, it is difficult to definitively link any one of them to autism. The researchers identified one gene called RIMS1 that carries rare inherited mutations more frequently in people with autism than in unaffected siblings. Studies have identified spontaneous mutations in RIMS1 in people with autism2,3.

Finding a heritable contribution to autism in this population is surprising, because the individuals with autism in the SSC do not have a family history of the disorder, says Tychele Turner, a postdoctoral fellow in Eichler’s lab. Most studies of the SSC have focused on trying to find spontaneous mutations linked to autism, she says.

The researchers estimate that rare inherited SNVs contribute to autism in 7 percent of people with the disorder. Ivan Iossifov, assistant professor at Cold Spring Harbor Laboratory in New York, says he and his colleagues came up with a similar estimate in an unpublished analysis of the SSC.

A 2013 study by a third group estimated that rare inherited variants account for 5 percent of autism cases. However, the investigators examined only mutations that affect both copies of a gene.

The new study also looked at large DNA deletions or duplications, called copy number variations (CNVs). The researchers found that people with autism are more likely than their unaffected siblings to carry relatively small (shorter than 100 kilobases) duplications that include at least one conserved gene. These small duplications contribute to autism in an estimated 3 percent of autism cases. Intriguingly, they often disrupt genes regulated by CHD8 — one of the strongest candidate autism genes identified to date.

Based on their analysis, the researchers estimate that each private SNV increases autism risk by about 11 percent, and each rare inherited CNV boosts the odds by 23 percent. Most of the autism-linked SNVs and CNVs were passed from unaffected mothers to sons who have autism.

The next step — figuring out which inherited variants contribute to autism — is a challenge because each one is so rare. “It’s very sobering,” says Stephan Sanders, associate professor of psychiatry at the University of California, San Francisco, who was not involved in the study. “It shows just how difficult it is to identify new autism risk genes as you go away from the de novo variants.”


1. Krumm N. et al. Nat. Genet. Epub ahead of print (2015) PubMed

2. Iossifov I. et al. Neuron 74, 285-299 (2012) PubMed

3. Dong S. et al. Cell Rep. 9, 16-23 (2014) PubMed

6 responses to “Boys with autism inherit mutations from unaffected mothers”

  1. Gerry F. says:

    Despite the first sentence in this article, this unfortunate headline recalls the bad old days of Bruno Bettleheim and his acusation that autism was caused by cold “refrigerator mothers”. That clearly is not the case. Moreover, the true percentage of genetic variants passed on from mothers or fathers that are penetrant enough to enhance the risk of autism is not yet known with any certainty. Such “private” variants are extremely rare.

    • Matt Carey says:

      ” this unfortunate headline recalls the bad old days of Bruno Bettleheim”

      No, it doesn’t.

      Why is it that people often try to discount genetic studies as somehow blaming the mother (or father)?

  2. RA Jensen says:

    This study is irrelevant and meaningless to my family. Michael Rutter has opined that behavioral and molecular geneticists consider the environment as an irritant to be ignored. The Simon Simplex Collection is among those who consider the environment as an irritant to be ignored. The Simon Simple Collection and the Autism Simplex Collection (TASC). The exclusionary criteria for the Simon Simplex Collection is similar to the Autism Simplex Collection TASC exclusionary criteria for inclusion into the group:

    The exclusionary criteria in the major genetic consortium projects are irrelevant and misleading for my family. My daughter would have been excluded from participating in the Simons Simplex Collection (SCC) or the Autism Simplex Collection (TASC). The exclusionary criteria for TASC is:

    ‘Individuals with known medical or genetic causes of autism or a history consistent with Childhood Disintegrative Disorder were excluded. Other exclusion criteria included: extreme prematurity (< 1,000 grams or less than 32 weeks) prematurity with associated neurological complications; birth trauma with associated early neo-natal complications; significant brain injury; in utero exposure to medication known to be associated with autism, for example. retinoic acid, sodium valproate'. The data published by Simons Simplex Collection only applies to the subgroup included and can never be extrapolated beyond that highly selective group, but too often is.

  3. UnifyingTheories says:

    There are two articles that put this work in context:

    The first predicted (nearly 10 years ago!) and the next provided further support for a pattern of de novo mutation in simplex families that would result in these very rare mutations which are transmitted almost exclusively from mothers to sons. This isn’t a new class of mutation for ASD – it’s just finding what was expected, now that the sample sizes and technology enable it. You’ve got to hand it to quantitative modeling by Michael Wigler’s group – very nice work!

  4. UnifyingTheories says:

    Of course hats off to the Eichler group, too – inherited variants are the next frontier, and an intimidating one! This study is the first high quality rare inherited variant study to find something real in ASD.

  5. RA Jensen says:

    The Autism Simplex Collection (TASK) excludes any family with a proband with a known genetic cause. Where do these mutations come from and does the environment play any role in the production of de novo gene mutations? Klinefelter syndrome (KS) is along with Down syndrome the most common cause of developmental disability, including high rates of ASD. KS occurs in 1 in 500 to 1,000 live male births. KS and Mosaic KS are not inherited, they are caused by reproductive errors in sperm or egg before conception. The C-BASS (Chinese Benzene Sperm Study Goup) discovered that increased exposure to Benzene in manufacturing plants produced increased rates of XY sperm and at conception produces 47,XXY the de novo mutation that is responsible for KS:

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