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Scientists Start with One Gene in Hunt for Autism Subtype

Marina Sarris
Interactive Autism Network
Date Last Revised: 
October 12, 2015
Date Published: 
August 4, 2014

Photo of people with CDH8 mutation, courtesy of journal CellScientists often make medical discoveries by starting with a set of symptoms and looking for the cause. Recently, however, autism researchers worked in reverse: they began with a mutated gene and then looked for its symptoms.

In so doing, researchers identified a subtype of autism with its own pattern of symptoms.1 This is the first time in which scientists have used the "genetics first" approach with a single gene and found an autism subtype. Families in the Simons Simplex Collection (SSC) research project played a crucial role in this discovery.

People with a mutation to the CHD8 gene share similar features. These include a large head, frequent bouts of constipation followed by loose stools, wide-set eyes that slant downward, a broad nose and forehead, pointed chin, and sleep problems. Interestingly, as in all autism, there is a range of intellectual functioning, with some people having a significant disability while others have average intelligence.

A New Approach to Studying Autism

Although less than one-half of 1 percent of people with autism appear to have the mutation, its discovery highlights a new focus on finding biological differences among people diagnosed with conditions such as autism. It is hoped that one day doctors will be able to find more effective, targeted treatments for autism if they understand what type of autism a person has.

"Discovery of this particular mutation represents the successful application for the first time of a different approach of studying autism," said one of the lead researchers, Raphael Bernier Ph.D., associate professor of psychiatry and behavioral sciences at University of Washington. "We were able to identify a clear subtype of autism by starting with genetics."

Right now autism is still diagnosed based on behavioral characteristics, but that too is changing. For years, doctors tried to distinguish between different types of autism by considering a child's behavior and developmental history, and assigning him one of several related diagnoses: autistic disorder, Asperger's Disorder or Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS or "subthreshold" autism). But even well-trained experts often could not agree on which type of autism a child had based on his or her behavior, according to another study that also involved SSC families.2

The different labels also could be confusing to laypeople. Does autistic disorder mean "severe" and PDD-NOS or Asperger's mean "moderate" or "mild," respectively? Some people with autistic disorder are adept speakers with advanced degrees, such as Colorado State University professor Temple Grandin, Ph.D. How different are they, really, from people with Asperger's or PDD-NOS? Do the same treatments work for all types of autism?

So last year, the manual that American doctors use to diagnose psychiatric conditions officially combined all three autistic diagnoses into one, "autism spectrum disorder" (ASD).

Can Genes Tell Us What Kind of Autism Someone Has?

Photo of Dr. Bernier, a discoverer of an autism gene Scientists are now looking for genetic differences to try to distinguish between different types of autism. The recent discovery by Dr. Bernier and his fellow researchers took that genetics-first approach. The study, published in the journal Cell, involved families in the SSC research project. The SSC includes nearly 2,800 families who each have only one member – a son or daughter – with ASD.

Scientists originally found the mutation when looking at the genes of a small portion of the SSC families. Researchers expanded their search to all children with autism in the SSC. They found a total of eight children with severe CHD8 mutations and a ninth with a mild mutation.

Then, researchers began looking for the mutation in a different group of 3,730 children who have either autism or developmental delay. They found eight additional cases. Importantly, researchers did not find the mutation in almost 8,800 people who don't have autism, including about 2,300 siblings in the SSC project.

An "a ha" Moment: Spotting Similar Facial Features

To complete the study, Dr. Bernier's team evaluated 15 people ages 4 to 41 with the mutation, including three SSC participants. Some of the SSC families with the mutation happened to live relatively near Dr. Bernier's office at University of Washington.

He invited them to meet with him. The first family who visited brought their preteen daughter with autism. She had major sleep and gastrointestinal (GI) problems and a large head with wide-set eyes. "These are subtle facial features, and sleep and GI problems are common in autism," he said. If she were seen in an autism clinic for a routine matter, those characteristics probably would not have piqued a doctor's curiosity.

Then, a week later, the second SSC family visited with an 8-year-old son with autism. Dr. Bernier had an "a ha" moment when he spied this boy: "I thought he could be a sibling of this young girl" from the week before, he said. Because he saw the two children right after each other, he was able to spot and begin cataloging the similarities among people with a CHD8 mutation.

Among the 15 people who were studied extensively, 13 have autism and one has attention deficit hyperactivity disorder and "borderline" intelligence. The fifteenth, an adult who lives in an institution in Italy, has a suspected psychotic disorder and intellectual disability.

The autism prevalence is significant. Although CHD8 is not the first genetic mutation linked to autism, it's the first one that seems so strongly linked to autism, he said. So far, almost all of the people found to have a CHD8 mutation also have autism.

By contrast, the genetic mutation in Fragile X syndrome causes autism in only 15 to 33 percent of the people who have it.3 Similarly, only about 23% of the people with a different genetic anomaly, a copy number variation on Chromosome 16 called 16p11.2, actually has autism, Dr. Bernier said. Copy number variation means a person has an unusual number of copies of one or more sections of DNA.

Using Fish to Test a Genetic Theory

To confirm the findings, the researchers worked with scientists at Duke University to see what would happen if they deliberately modified the CHD8 gene in zebra fish early in development. The genetic change resulted in fish with large heads and wide set eyes. The mutation apparently caused on overgrowth of the forebrain/midbrain region, which led to the head differences. The researchers also fed the fish fluorescent food pellets to track their digestion; those fish were more likely to be constipated.1

The CHD8 gene, located on Chromosome 14, is a regulator gene involved in the growth and proliferation of cells in the central nervous system (such as the brain) and the enteric nervous system (including the colon), Dr. Bernier said.

Parents interested in having their children tested for the mutation should talk to their doctor or a geneticist. The test may not be covered by insurance, Dr. Bernier said. He said it's too soon to predict whether a CHD8 test will become a routine part of the process for diagnosing autism. Research on CHD8 is still in an early stage, and the mutation is believed to be very rare. "It's not going to impact a huge portion of the individuals with autism," he said.

Nonetheless, the approach used to uncover the link to CHD8 represents an important step in autism research, one that possibly may lead to targeted treatments in the future.

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  1. Bernier, R., Golzio, C., Xiong, B., Stessman, H.A., Coe, B.P., Penn, O., Witherspoon, K., Gerdts, J., Baker, C., Vulto-van Silfhout, A.T., Schuurs-Hoeijmakers, J.H., Fichera, M., Bosco, P., Buono, S., Alberti, A., Failla, P., Peeters, H., Steyaert, J., Vissers, L.E., Francescatto, L., Mefford, H.C., Rosenfeld, J.A., Bakken, T., O'Roak, B.J., Pawlus, M., Moon, R., Shendure, J., Amaral, D.G., Lein, E., Rankin, J., Romano, C., de Vries, B.B., Katsanis, N. & Eichler, E.E. (2014). Disruptive CHD8 Mutations Define a Subtype of Autism Early in Development. Cell. 2014 Jul 3. pii: S0092-8674(14)00749-1. doi: 10.1016/j.cell.2014.06.017. View abstract.
  2. Lord, C., Petkova, E., Hus, V., Gan, W., Lu, F., Martin, D.M., Ousley, O., Guy, L., Bernier, R. et. al. (2012) A multisite study of the clinical diagnosis of different autism spectrum disorders. Arch Gen Psychiatry. 2012 Mar;69(3):306-13. doi: 10.1001/archgenpsychiatry.2011.148. View abstract.
  3. National Fragile X Foundation. Autism and Fragile X Syndrome. Retrieved on July 15, 2014, from

Photo gallery reprinted with permission of Cell. Photo of Dr. Bernier reprinted with permission of Dr. Bernier and University of Washington.