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Deletions in chromosome 22, one cause of autism?

Genomic research has found a portion of chromosome 22 is missing in some autism spectrum disorders (ASD) and may be associated with many other neuropsychiatric disorders.

Research has identified a gene that appears to play a significant role in some severe types of autism. The chromosomal disorder 22q11.2 deletion syndrome on the gene, RANBP1, may even disrupt brain signaling in a number of different neuropsychiatric conditions. This finding could open new opportunities for treatment of those multiple neurological diseases.

"The gene we investigated may function as an important factor, not only in types of autism, but also in other neuropsychiatric conditions. We have uncovered underlying molecular defects across disease categories, suggesting these biological networks are good targets for future research."

Hakon Hakonarson MD, PhD, Director, Center for Applied Genomics at The Children's Hospital of Philadelphia (CHOP) and study leader.

The paper appears online 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 those 75 children also had ASD. They searched for copy number variations (CNVs) within a molecular pathway called the metabotropic glutamate receptor (mGluR) pathway.

In previous research, Hakonarson's group showed that genes in the mGluR network were more likely to be disturbed in patients with autism spectrum disorder (ASD). They also found this gene family affects patients with attention-deficit hyperactivity disorder (ADHD) and schizophrenia.

Autism is the best known of the ASDs, so the study focused on those ASDs with identifiable genetic disorders — or about 20 percent of patients with signs and symptoms of ASD.  Among patients with diagnosed ASD syndrome, investigators then focused on a missing portion of chromosome 22 — the 22q11.2 deletion. CHOP has one of the world's largest research and clinical centers for this syndrome.

Although 22q11.2 deletion syndrome occurs in an estimated one in 2000 to 4000 individuals, it is rarely recognized by the general public or by many physicians. As a multisystem disorder, it can affect the heart, immune system, face and palate, the gastrointestinal system and neurocognitive functioning.

The study revealed children with ASDs, harboring copy number variationsin genes in their mGluR network, were more likely to have a subtype of ASD. These patients had a 74 percent prevalence of syndromic ASD, compared to 16 percent in those without CNVs in mGluR. 'Non-syndromic autism' is a term used to describe cases where autism is the primary diagnosis – and not secondary to an existing condition caused by a well-known genetic variant, such as Rett syndrome, Fragile X syndrome, tuberous sclerosis, and the Smith-Lemli-Opitz syndrome.

The study team also analyzed a separate group of 75 children with 22q11.2 deletion syndrome, a region containing the mGluR network gene RANBP1. Among those children, 20 percent also had ASD from 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. Numerous environmental studies also support a role for RANBP1 in autism.

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

Hakon Hakonarson MD PhD, director of the Center for Applied Genomics at The Children's Hospital of Philadelphia.

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. We anticipate that these studies will unveil important interactions between genetic and environmental factors that increase a child's risk for developing ASD."

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

Hakon Hakonarson MD PhD

While abnormal signaling mediated through metabotropic glutamate receptor 5 (mGluR5) is involved in the pathophysiology of Autism Spectrum Disorder (ASD), Fragile X Syndrome and Tuberous Sclerosis, the role of other mGluRs and their associated signaling network genes in syndromic ASD is unknown. This study sought to determine whether mGluR Copy Number Variants (CNV’s) were overrepresented in children with syndromic ASD and if mGluR “second hit” confers additional risk for ASD in 22q11.2 Deletion Syndrome (22q11DS). To determine whether mGluR network CNV’S are enriched in syndromic ASD, we examined microarrays from children with ASD (n = 539). Patient categorization (syndromic vs nonsyndromic) was done via blinded medical chart review in mGluR positive and randomly selected mGluR negative cases. 11.5% of ASD had mGluR CNV’s vs. 3.2% in controls (p < 0.001). Syndromic ASD was more prevalent in children with mGluR CNVs (74% vs 16%, p < 0.001). A comparison cohort with 22q11DS (n = 25 with ASD, n = 50 without ASD), all haploinsufficient for mGluR network gene RANBP1, were evaluated for “second mGluR hits”. 20% with 22q11.2DS + ASD had “second hits” in mGluR network genes vs 2% in 22q11.2DS-ASD (p < 0.014). We propose that altered RANBP1 expression may provide a mechanistic link for several seemingly unrelated genetic and environmental forms of ASD.

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.

"The Role of mGluR Copy Number Variation in Genetic and Environmental Forms of Syndromic Autism Spectrum Disorder," Scientific Reports, published online Jan. 19, 2016. http://doi.org/10.1038/srep19372.

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.

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.

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 http://www.chop.edu.

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