A team of researchers led by Tara Wenger, PhD of The Children's Hospital of Philadelphia's Center for Autism Research (CAR) have found that genetic mutations in a specific family of genes – the “metabotropic glutamate receptors” (mGluRs) – play a significant role in a person’s risk for autism spectrum disorder (ASD). One mGluR gene in particular- RANBP1- was the focus of a study published this month in the Nature journal Scientific Reports. The mGluR gene network typically contains two copies of RANBP1; however, in children who were missing one of those RANBP1 genes, the risk of autism increased dramatically.
Previous studies have shown that RANBP1 contributes to “syndromic autism”- a form of ASD caused by genetic mutations that lead to complex medical problems. Syndromic ASD, which includes 22q11.2 Deletion Syndrome, Fragile X Syndrome, and Tuberous Sclerosis, accounts for about 20% of all ASD cases and are frequently more severe forms of ASD.
The new CAR study confirms the important role of mGluR genes in other neuropsychiatric conditions, such as attention-deficit hyperactivity disorder (ADHD), in addition to autism. Moreover, this mGluR family of genes contains hints about how several well-known environmental factors may cause ASD, including prenatal exposure to thalidomide. The scientists say these findings pave the way for developing precision treatments targeted to those who carry this genetic variation.
“This is another step in of a series of genetic findings that shine a spotlight on select aspects of early neurodevelopment that contribute most to ASD,” said Robert Schultz, PhD, Director of the CAR. “At CHOP we are extremely fortunate to be able to convene the resources and expertise of the Center for Applied Genomics (CAG), the 22q and You Center, and CAR in order to examine complex genetic questions – spanning multiple diagnoses- in order to tease out important interactions among genetic and environmental factors that increase a child’s risk of developing ASD, and in turn develop targeted treatments. There are only a few places in the world positioned to do this type of research.”
For this study, scientists analyzed DNA from more than
500 children with ASD. They searched for copy number variations (CNVs) within
the mGluR gene network, since previous studies have shown that CNVs within this
mGluR “gene family” occur more frequently in children with ASD than in other
children. The research team discovered that children with ASD who also had CNVs
within the mGluR network were far more likely to have the syndromic type of
ASD, compared to those without CNVs in mGluR.
The study team also compared the ASD cohort to a separate
set of 75 children with 22q11.2 deletion syndrome, 25 of whom also had ASD. All 75 were already missing RMBP1,
because that gene is contained in the deleted region of their chromosome.
But if they had a “second hit”—either a deletion or a duplication
of another mGluR gene outside that region—they were much more likely to have
autism than children with the deletion syndrome who didn’t have that second
Combining these findings, the research team concluded the RANBP1 gene is a significant genetic factor in some forms of ASD, and the greater number of mGluR genes affected, the greater the chances of the person developing ASD. “The mGluR variants we identified may be important in identifying those patients who are most likely to respond to new treatments,” said Hakon Hakonarson, MD, PhD, Director of the Center for Applied Genomics at CHOP. “As such, this could be the basis for one of the first examples of a precision medicine focus in drug development for complex disease.”
This study, entitled "The Role of mGluR CopyNumber Variation in Genetic and Environmental Forms of Syndromic AutismSpectrum Disorder”, was published January 19th in Scientific Reports. The study was led by Tara Wenger, MD, PhD of CHOP’s Center for Autism Research and Hakon Hakonarson, MD, PhD, director of CHOP’s Center for Applied Genomics. Co-authors included Robert Schultz,PhD, director of CHOP’s Center for Autism Research and Donna McDonald-McGinn, MS, CGC, program director of CHOP’s 22q and You Center. Find more information about these research findings in the accompanying press release.
Wednesday, January 27, 2016
CHOP Researchers Identify Gene That Plays Important Role in Autism & Other Neuropsychiatric Conditions
Switching Lenses: A Shift in Perspective Led Researchers to Unexpected Results About Face-Processing in ASD
Humanity seems to be “hard-wired” to pay attention to faces and facial expressions. Zeroing in on faces (rather than other body parts or objects) and being able to differentiate between people’s identities or expressions is one of the first skills developed during infancy; and differences in social attention appear to be one of the earliest observable signs of autism.
Because reduced attention to and interest in social information is a prevalent symptom of ASD, many studies have focused on comparing two groups - those on the spectrum vs. those with typical development - to search for differences in how they prioritize faces compared with other objects in the environment. However, no one had studied individual differences along the continuum of “face expertise”, without taking diagnostic labels into account. A group of CAR scientists led by Julia Parish-Morris, PhD, and Coralie Chevallier, PhD (now at INSERM), believed that ignoring diagnostic categories in favor of a more “dimensional approach” might improve our understanding of how humans develop their facial recognition skills and might also shed light on how differences in attentional biases or motivation to look at faces might influence the development of social skills.
For their study, the researchers enrolled 110 children between the ages of 6 and 17 (50 typically developing and 60 with ASD). The children participated in a series of scientifically validated tests, including Let’s Face It! to assess their ability to recognize both a person’s identity and perceive differences in facial expressions. They also watched short videos showing faces and objects, while their eye movements were tracked to measure gaze and attention. The team assessed each child’s behavior and social using the Social Communication Questionnaire (SCQ).
“We were surprised to find that, overall, children with ASD and their typically developing peers spent a similar amount of time looking at faces and objects,” explained Dr. Parish-Morris.
Interestingly, children who paid more attention to facial information were better able to differentiate between face identities and facial expressions in the Let’s Face it game, and so did children who performed better on the SCQ.
According to Dr. Parish-Morris, “The connection between attention to faces and face processing skill held regardless of whether or not the participant had autism. This suggests that face processing is truly dimensional and linked to underlying differences in social attention or motivation.” The Social Motivation Theory of autism suggests that while these differences might start small, they could have a snowball effect on face processing skill over developmental time.
Using a dimensional approach to assess social processing in autism is gaining favor across multiple areas of mental health research, and is consistent with a growing trend to think of ASD in terms of neurodiversity. Just as autism displays itself across a wide spectrum of symptoms and characteristics, it can be helpful for researchers to take a spectrum-approach as well, rather than adhering to strict diagnostic categories at the outset.
Shifting the lens through which we study ASD creates the potential for new pathways to understanding the variability that makes the diagnosis so challenging. Parish-Morris and her colleagues are interested in further exploring the relationship between social interest, social motivation, and a person's ability to identify and interpret faces as a potential area of interest for developing effective skill-building tools.