Little-studied RNA might be key to regulating genetic disorders like epilepsy, autism

• Study focused on ‘Goldilocks Gene’ CHD2 that causes autism and epilepsy
• Deletion of long non-coding RNA CHASERR produces too much CHD2 protein in the cell, leaving patients non-ambulatory, nonverbal and with intellectual delays
• Patient’s dad from study: ‘We intuitively understood this was a lot bigger than just Emma’
• ‘It is mind-boggling that we only know what 1% of the human genome does’

CHICAGO --- When a gene produces too much protein, it can have devastating consequences on brain development and function. Patients with an overproduction of protein from the chromodomain helicase DNA binding (CHD2) gene can develop a rare and severe neurodevelopmental disorder that renders them non-ambulatory, nonverbal and with profound intellectual delays.

Now, scientists at Northwestern Medicine and the Broad Institute of MIT and Harvard have discovered an RNA that acts like the brake in one’s car to control how much or how little protein is produced by a gene. In patients with this rare disorder, a long non-coding RNA called CHASERR (CHD2 adjacent, suppressive regulatory RNA) is deleted — the “foot” is taken off the “brake” — and CHD2 protein production goes into overdrive, reports a new Northwestern Medicine study.

The study was published Oct. 23 in the New England Journal of Medicine.

While most RNAs make proteins, long non-coding RNAs don't make proteins but are crucial for regulating gene activity. Long non-coding RNAs exist in the so-called “Wild West” (99%) of the human genome that is currently understudied.

Not only does this finding have treatment implications for patients with neurodevelopmental disorders such as epilepsy and autism, the study also underscores the need to explore understudied non-coding regions within the human genome.

“There are thousands of long non-coding RNAs, but, until this study, we didn’t know what they did,” said Gemma Carvill, the study’s corresponding author. “One of the things we learned in this study is that the deletion of a specific long non-coding RNA changes the expression of a particular gene called CHD2. We call CHD2 a ‘Goldilocks Gene,’ because both too little is bad and too much is also bad. There's no reason at all to think that this is an isolated case, but more likely that these long non-coding RNAs and non-coding regions are implicated more broadly across human disorders.”

Carvill is an assistant professor of neurology, pharmacology and pediatrics at Northwestern University Feinberg School of Medicine.

Like taking the foot off the brake

The study specifically focused on the CHD2 gene, which causes autism and epilepsy. In 2013, Carvill and colleagues found that in a subset of patients with epilepsy and autism, the CHD2 gene produces too little protein.

This new study, however, examined three patients whose CHD2 gene produced too much protein. The common thread among all three patients was a deletion of the long non-coding RNA CHASERR.

Carvill said future studies that attempt to manipulate CHASERR might have success in controlling the amount of CHD2 protein that is produced, thereby leading to more effective treatments for patients.

Although previous studies in mice by Igor Ulitsky at the Weizmann Institute have found a link between a CHASERR deletion and how much CHD2 protein is produced, this is the first study to find this link in humans. Ulitsky, an expert in the biology of long non-coding RNAs, also is an author on the paper.

“With three patients, we were able to finally classify this as a new disorder,” said co-senior author Anne O'Donnell-Luria, co-director of the Broad Center for Mendelian Genomics and an institute member at the Broad, clinical genetics physician at Boston Children’s Hospital, and an assistant professor of pediatrics at Harvard Medical School. “The unique mechanism we’ve identified here suggests that there are more long non-coding RNAs underlying rare genetic disorders still to be found, which could potentially bring answers for some of the many families still waiting for a rare-disease diagnosis.”

Emma’s story

Emma Broadbent, 8, was the first of the three patients identified for this study. She uses a wheelchair, is non-verbal, uses a feeding tube and has severe intellectual delays. When her dad, Brian Broadbent, learned of Emma’s deletion of CHASERR through her genome sequencing, he began scouring the internet for anyone researching CHD2. He eventually connected with Carvill and other scientists globally, and the resulting research team was able to identify the other two patients with the CHASERR deletion.

“Emma suffers a lot, and this adds purpose to her life because she’s helping science,” said Brian, who is a co-author on the study. “We felt we had a responsibility to push this as forward as much as we can because it's going to impact future children. This is just scratching the surface of something that could be really important. We intuitively understood that this was a lot bigger than just Emma.”

Sequencing the ‘Wild West’ of the human genome

Today, when someone undergoes genetic testing to identify variants or changes that might be linked to genetic disorders or diseases, they first receive gene panels or exome sequencing — which focuses on only 1% of the human genome that codes for proteins.

“It is mind-boggling that we only know what 1% of the human genome does, and we have very little idea what the other 99% does,” Carvill said. “We ignore it, and our study highlights why we shouldn't.”

If scientists don’t find genetic disorders or diseases after exome testing, then they can perform genome testing. But so little is known about the function of the full genome that interpreting the findings can be challenging.

“Everything we currently we know about disease is rooted in a genetic variant in a gene, and that is because that genetic variant either destroys the function of the protein or it alters the function of the protein, but it's all protein based, and that's mostly because we've been doing exome sequencing,” Carvill said. “But we know we're still missing things because there are still a significant percentage of kids in pediatric epilepsies and other disorders as well where we suspect they have a genetic basis, but we just haven't found it yet.”

Implications for future treatments

Currently, patients with epilepsy are treated with antiseizure medications, but this is treating the symptom of the disorder and not the root cause. Additionally, 30% of patients with epilepsy do not respond to current medications. Ideally, Carvill and her team would like to treat patients with epilepsy and other seizure-related disorders with gene-targeting therapies to correct the root cause: the genetic change. Identification of non-coding regions that control gene expression, like CHASERR, is one way her team is thinking about using their knowledge of the human genome to design gene-targeting therapies.

Funding for the study, “Neurodevelopmental Disorder Caused by De Novo Deletions in lncRNA Gene,” was provided by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant K23AR083505); the National Human Genome Research Institute (grants T32HG10464 and UM1HG008900); the National Institute of Child Health and Development (grant F32HD101280); the National Institute of General Medical Sciences (grant T32GM142604); the National Health and Medical Research Counsel (Australia) (grant 2009982); the European Research Council Consolidator Grant lncIMPACT; the Nella and Leon Benoziyo Center for Neurological Diseases; the National Institute of Neurologic Disorders and Stroke (grant K99/R00NS089858); the CURE taking Flight Award; the National Eye Institute (grant U01HG011755); the National Heart, Lung and Blood Institute (grant R01HG009141); and in part by Chan Zuckerberg Initiative Donor-Advised Fund at the Silicon Valley Community Foundation 2019-199278.