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Results from CHOP Study, Licensed to Medgenics, Link mGluR Pathway CNVs to Risk of Syndromic Autism

NEW YORK (GenomeWeb) – Researchers led by the Children's Hospital of Philadelphia have linked alterations in the gene RANBP1 to an individual's risk for developing severe subtypes of autism that tend to co-occur with other genetic diseases.

The team, led by Hakon Hakonarson, director of the Center for Applied Genomics at CHOP, published its results this week in Scientific Reports. CHOP has been collaborating with Medgenics to develop new treatments for rare pediatric genetic diseases.

In the study, Hakonarson and colleagues analyzed DNA from 539 children with autism spectrum disorder and 75 other children with 22q11.2 deletion syndrome, 25 of whom also had a concurrent diagnosis of ASD that was obtained using SNP microarrays.

Following previous research in which they had shown that genes involved in the mGluR pathway were more likely to be perturbed in patients with ASD, the CHOP investigators looked for copy number variations in those genes in their subjects..

The results revealed that children with ASD who harbored CNVs in the mGluR network were more likely to have the so-called "syndromic" subtype of ASD, in which patients display symptoms apart from behavioral differences, such as birth defects, which imply that their autism is related to a separate genetic disorder.

Amongst 62 children in the study who did have a CNV in an mGluR-related gene, 74 percent had syndromic ASD, compared to only 16 percent amongst the 100 subjects without such markers, the authors reported.

The study team also analyzed a separate cohort of 75 children with 22q11.2 deletions, which include the deletion of a gene, RANBP1, that is involved in the mGluR network. 25 of the children also had a concurrent ASD diagnosis along with their 22q11.2 deletion.

Based on the results, the researchers concluded that the presence of an alteration or "hit" in a second mGluR network gene other than RANBP1 was a strong predictor of developing ASD, in addition to the symptoms of a 22q11.2 deletion.

Twenty percent of the kids who had both diagnoses had one of these second hits, while only two percent of those without a double-diagnosis had two genetic alterations to the mGluR pathway.

"Based on this study, we propose that the RANBP1 gene is a significant genetic factor in both ASD and 22q.11.2 deletion syndrome," Hakonarson said in a statement.

"Furthermore, when the mGluR network is disrupted at multiple points, it predisposes individuals to a more severe disease," he said.

According to the authors, mGluR signaling has also recently been implicated in the development of ASD in patients afflicted with two other diseases, fragile X syndrome and tuberous sclerosis.

In mouse models of these syndromes, other researchers have been able to reverse abnormal learning and atypical behavior by breeding mice to restore normal mGluR signaling, and by treating animals with an mGluR antagonist, suggesting a promising avenue for pharmacological treatment not just for these, but also for other disorders, including potentially syndromic ASD, the team wrote.

With much future research and development, it's possible that the mGluR variants the CHOP team identified could play a role in identifying patients who are most likely to respond to new treatments targeting the pathway, Hakonarson said in his statement.

Hakonarson, receives funding for his work on the genetics of rare diseases by Medgenics, which in late 2014 announced a collaboration with CHOP, under which it gained access to the biobank at CHOP's Center for Applied Genomics.

At the time, Medgenics agreed to pay CHOP $5 million in exchange for exclusive rights to use the rare and orphan disease samples at the CAG biobank to develop and commercialize therapeutic treatments and diagnostic targets. The agreement also involves milestone payments to CHOP and low single-digit royalties on future sales from products developed from the agreement, as well as research funding for rare and orphan disease studies.

Hakonarson disclosed in the newly published study that he owns stock in Medgenics, and that technology specifically related to the new results has also been licensed to the company.

Last year, Medgenics also acquired an LLC founded by Hakonarson, called neuroFix Therapeutics, which developed NFC-1, a non-stimulant mGluR neuromodulator entering Phase 2/3 trials for the treatment of mGluR network mutation-positive attention deficit hyperactivity disorder, as well as for the symptoms resulting from 22q11.2 deletion syndrome.