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.

Developmental and epileptic encephalopathies are genetically complex disorders often caused by loss of function in various genes. Mutations in CHD2, a DNA-binding protein, have been previously linked to seizures, intellectual disability, and developmental delay. Pathogenic variants in CHD2 have been primarily associated with haploinsufficiency, where the loss of one gene copy causes disease.

CHASERR is located next to CHD2 and encodes a long noncoding RNA that has not previously been linked to human disease. These newly discovered CHASERR deletions result in a disorder significantly different from conditions associated with the neighboring CHD2 gene.

In the study, “Neurodevelopmental Disorder Caused by Deletion of CHASERR, a lncRNA Gene,” published in The New England Journal of Medicine, scientists reveal the role of CHASERR deletions in disrupting neurodevelopment through increased CHD2 protein expression.

The research team examined three unrelated children with neurodevelopmental disorders. 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.

Genomic analyses using short-read and long-read sequencing identified deletions in the CHASERR locus. In two patients, the deletions occurred on chromosomes inherited from their fathers.

Detailed RNA and protein expression studies confirmed that these deletions caused an increase in CHD2 transcription and protein levels, particularly in the allele adjacent to the deletion. The findings show that CHD2 has a range of dosage sensitivity where both loss and gain of function can result in disease.

A genome-wide search for other de novo variants in the three patients did not identify any other pathogenic or likely pathogenic SNVs, small insertions or deletions, short-tandem-repeat expansions, or structural variants in the nuclear or mitochondrial genomes.

Based on the results, the study authors suggest a need for reanalysis of genome sequencing data to uncover additional cases of CHASERR deletions in patients with undiagnosed neurodevelopmental disorders.

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