Neurodevelopmental Disorder Caused by Deletion of <i>CHASERR</i>, a lncRNA Gene.

Abstract

<i>CHASERR</i> encodes a human long noncoding RNA (lncRNA) adjacent to <i>CHD2</i>, 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 <i>CHASERR</i> 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 <i>CHD2</i> haploinsufficiency. We found that the <i>CHASERR</i> deletion results in increased CHD2 protein abundance in patient-derived cell lines and increased expression of the <i>CHD2</i> transcript in <i>cis</i>. These findings indicate that <i>CHD2</i> 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. (Funded by the National Human Genome Research Institute and others.).