CHOP Researchers Identify Gene That Plays Important Role in Autism & Other Neuropsychiatric Conditions


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 hit.
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