Researchers identify deletions in long noncoding RNA that lead to severe neurodevelopmental disorder

Good news! Apparently, these deletions have very severe consequences.

"... scientists reveal the role of CHASERR deletions in disrupting neurodevelopment through increased CHD2 protein expression. ...

All three patients had de novo deletions in the CHASERR gene, distinct from the promoter or coding region of CHD2. The deletions caused overexpression of the CHD2 gene on the same chromosome, leading to increased protein levels. ...

Clinical evaluations showed that the children exhibited severe encephalopathy, unique facial dysmorphisms, cortical atrophy, and cerebral hypomyelination, none of which are typical in patients with CHD2 haploinsufficiency. Brain imaging in the children revealed significant cortical atrophy, a thin corpus callosum by age 4, and generalized hypomyelination of subcortical white matter. ..."

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• 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

..."

From the abstract:

"CHASERR encodes a human long noncoding RNA (lncRNA) adjacent to CHD2, a coding gene in which de novo loss-of-function variants cause developmental and epileptic encephalopathy. Here, we report our findings in three unrelated children with a syndromic, early-onset neurodevelopmental disorder, each of whom had a de novo deletion in the CHASERR locus. The children had severe encephalopathy, shared facial dysmorphisms, cortical atrophy, and cerebral hypomyelination — a phenotype that is distinct from the phenotypes of patients with CHD2 haploinsufficiency. We found that the CHASERR deletion results in increased CHD2 protein abundance in patient-derived cell lines and increased expression of the CHD2 transcript in cis. These findings indicate that CHD2 has bidirectional dosage sensitivity in human disease, and we recommend that other lncRNA-encoding genes be evaluated, particularly those upstream of genes associated with mendelian disorders. ..."

Researchers identify deletions in long noncoding RNA that lead to severe neurodevelopmental disorder "Broad Institute-led research has revealed that deletions in the CHASERR gene cause a distinct neurodevelopmental disorder resulting in severe encephalopathy, cortical atrophy, and cerebral hypomyelination."

Little-studied RNA might be key to regulating genetic disorders like epilepsy, autism (original news release) "Future studies that manipulate this RNA could help treat neurodevelopmental diseases in humans"

Neurodevelopmental Disorder Caused by Deletion of CHASERR, a lncRNA Gene