Public Release: 

Gene may be important in autism disorders, other neuropsychiatric syndromes

CHOP genomics expert leads study of gene network perturbed in forms of ASD, a chromosome deletion syndrome, other syndromes

Children's Hospital of Philadelphia


IMAGE: Hakon Hakonarson, M.D., Ph.D., is the director of the Center for Applied Genomics at The Children's Hospital of Philadelphia. view more

Credit: The Children's Hospital of Philadelphia

Scientists have identified a gene that appears to play a significant role in raising a person's risk of having more severe subtypes of autism that co-occur with other genetic diseases, such as the chromosomal disorder 22q11.2 deletion syndrome. Variations in this gene, RANBP1, may disrupt brain signaling in different neuropsychiatric conditions--a finding that could open new research opportunities for treatment for multiple neurological diseases.

"The gene we investigated may function as an important factor, not only in forms of autism, but also in other neuropsychiatric conditions," said study leader, Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at The Children's Hospital of Philadelphia (CHOP). "We have uncovered underlying molecular defects across disease categories, suggesting that these biological networks are good targets for future research."

The paper appears online today in Scientific Reports.

The study team compared DNA from 539 children with autism spectrum disorder (ASD) to DNA from 75 children with 22q11.2 deletion syndrome--25 of whom also had ASD. The researchers searched for copy number variations (CNVs) within a particular gene network, the metabotropic glutamate receptor (mGluR) pathway affecting the neurotransmitter glutamate.

In previous research, Hakonarson and colleagues showed that genes on the mGluR network were more likely to be perturbed in patients with ASD. His team also showed that members of this gene family also affected subsets of patients with attention-deficit hyperactivity disorder (ADHD) and schizophrenia.

Autism is the best known of the ASDs, a large group of heritable neuropsychiatric conditions in which patients have impaired social interaction and communication. The current study focused on the 20 percent of patients with syndromic ASD--that associated with identifiable genetic disorders. Among many such syndromes, the investigators focused particularly on 22q11.2 deletion syndrome, in which a portion of chromosome 22 is missing. CHOP has one of the world's largest research and clinical centers in this syndrome, and several leaders from that program co-authored the current study.

Although 22q11.2 deletion syndrome occurs in an estimated one in every 2000 to 4000 individuals, it remains under-recognized by the general public and even by many physicians. A multisystem disorder, it may affect the heart, immune system, face and palate, the gastrointestinal system and neurocognitive functioning. The deleted region of chromosome 22 contains multiple genes, none of which have been identified as causative.

The current study revealed that children with ASDs harboring CNVs in the mGluR network were more likely to have the syndromic subtype of ASD. Those patients had a 74 percent prevalence of syndromic ASD, compared to 16 percent in those without CNVs in mGluR.

The study team also analyzed a separate cohort of 75 children with 22q11.2 deletion syndrome. The deleted region contains the mGluR network gene RANBP1. Among these children, 20 percent of those who also had ASD had a "second hit"--a deletion of an mGluR network gene outside of the 22q11.2 region. In contrast, only 2 percent of children having the deletion syndrome without ASD had a second hit.

"Based on this study, we propose that the RANBP1 gene is a significant genetic factor in both ASD and 22q.11.2 deletion syndrome," said Hakonarson. "Furthermore, when the mGluR network is disrupted at multiple points, it predisposes individuals to a more severe disease." Numerous environmental studies also support a role for RANBP1 in autism.

Other scientists have shown that deactivating the animal version of the RNBP1 gene decreases neurons and disrupts brain circuitry. "Further research," added Hakonarson, "is aimed at uncovering additional gene variations in the mGluR network, and we anticipate that these studies will unveil important interactions among genetic and environmental factors that increase a child's risk of developing ASD."

"The mGluR variants we identified may be important in identifying those patients who are most likely to respond to new treatments," said Hakonarson. "As such, this could be the basis for one of the first examples of a precision medicine focus in drug development for complex disease."


Funds from the National Institutes of Health (grants GM008628, MH089924, HD070454, and MH87636), the Margaret Q. Landenberger Research Foundation, and the Simons Foundation Autism Research Initiative supported this research. In addition to his CHOP position, Hakonarson is on the faculty of the Perelman School of Medicine at the University of Pennsylvania.

Hakonarson's co-authors were Charlly Kao, Donna McDonald-McGinn, Elaine H. Zackai, Alice Bailey, Robert T. Schultz, and Beverly Emanuel, all from CHOP; Tara L. Wenger, formerly of CHOP, now of Seattle Children's Hospital; and Bernice E. Morrow, of Albert Einstein College of Medicine.

Editor's Note: Dr. Hakonarson's current work at CHOP's Center for Applied Genomics is funded in part by Medgenics, Inc. Hakonarson indirectly owns stock in Medgenics. He has an interest in technology related to the reported study; that technology has been licensed by CHOP to Medgenics. CHOP and Hakonarson may benefit financially from their relationships with Medgenics.

"The Role of mGluR Copy Number Variation in Genetic and Environmental Forms of Syndromic Autism Spectrum Disorder," Scientific Reports, published online Jan. 19, 2016.

About The Children's Hospital of Philadelphia: The Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. In addition, its unique family-centered care and public service programs have brought the 535-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit

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