First Cases of New Neurology Syndrome Identified

Three unrelated children with deletions of CHASERR, a long non-coding RNA, had a severe neurological disorder not previously identified.

The CHASERR deletions and the resulting increased expression of a nearby coding gene — CHD2 — caused an unnamed, early-onset syndrome of severe encephalopathy with cortical atrophy, cerebral hypomyelination, and facial dysmorphism, reported Gemma Carvill, PhD, of Northwestern University Feinberg School of Medicine in Chicago, and co-authors in a New England Journal of Medicine brief report.

The three children with CHASERR deletions had greater impairment than even the most severely affected persons with CHD2 haploinsufficiency, the researchers said. This presents a “Goldilocks” problem because too little CHD2 is bad — and too much also is bad, they noted.

Emma Broadbent is the patient in whom Carvill and colleagues first identified the CHASERR deletion that was not present in either of her parents. She is wheelchair-bound, non-verbal, uses a feeding tube, and has severe intellectual delays.

“Because of Emma’s very profound neurological presentation, her physicians suspected there was a genetic cause,” Carvill told MedPage Today. “Typically, in patients who present like Emma, our first genetic test would be to do an exome, looking for a de novo mutation. Because her physicians were pretty convinced she had something genetic, they did a follow-up genome — not just looking at the exome, but the overwhelming majority of the genome — sequencing the 1% coding, as well as the 99% non-coding.”

Only 1% of the human genome codes for proteins. Long non-coding RNAs don’t make proteins but are needed to regulate gene expression.

CHASERR lies immediately upstream of CHD2, a coding gene in which de novo loss-of-function variants cause developmental and epileptic encephalopathy. The deletion of CHASERR resulted in a corresponding increase in CHD2 transcription and protein abundance that were specifically due to the upregulation of the CHD2 allele, Carvill and colleagues wrote.

“With one patient, it was very difficult to make any sweeping conclusions,” Carvill said. “We spent the last 3 or 4 years looking for more patients.” They found them through word-of-mouth, including one patient through a group of French researchers they met at a poster presentation during a conference.

“With three patients, we were able to finally classify this as a new disorder,” noted co-author Anne O’Donnell-Luria, MD, PhD, of Boston Children’s Hospital. The mechanism in this study suggests there are more long non-coding RNAs underlying rare genetic disorders still to be found, she added.

“We really should be looking at the non-coding genome, the other 3.6 billion base pairs in the genome,” Carvill said. “We need to start building new tools to understand what the other 99% of the genome actually does, and which parts are important for human disease.”

The present study suggests that CHASERR acts like a brake to control how much or how little CHD2 protein is produced, Carvill observed.

“For the longest time, we didn’t know what CHASERR did,” she said. “There was some evidence in mice that it affected how much CHD2 protein was made but we didn’t know if the same thing happened in humans.”

About 40% of long non-coding RNAs that have been identified are expressed in the brain, and there’s some support that at least a few of them contribute to neuronal disease, noted Ling-Ling Chen, PhD, of the Chinese Academy of Sciences in Shanghai, in an accompanying essay. “For example, BACE1-AS was shown to facilitate amyloid-beta plaque formation, and its expression is elevated in persons with Alzheimer’s disease,” she wrote.

Researchers have reported dysregulated long non-coding RNAs in schizophrenia, autism spectrum disorder, and Parkinson’s disease, she pointed out.

“However, because of the poor conservation of long non-coding RNAs across species — only approximately 20% of human long non-coding RNAs have homologues in mice — evaluating their pathophysiological roles in vivo has been challenging,” Chen noted.