Journal Article

Neurodevelopmental Disorder Caused by Deletion of CHASERR, a lncRNA Gene

O’Donnell-Luria, Anne, Carvill, Gemma L., O’Leary, Melanie C., Bacino, Carlos A., Murdock, David R., Yoon, Esther, Kayani, Saima, Bezieau, Stéphane, Lamar, Kay-Marie, Garimella, Kiran V., Weisburd, Ben, Dai, Hongzheng, Aziz, Miriam C., Broadbent, Brian, Isidor, Bertrand, Sarusi, Yael, Goodrich, Julia K., England, Eleina, Riquin, Kevin, Ulitsky, Igor, Chatron, Nicolas, Pengam, Alisée, Rosenfeld, Jill A., Monin, Pauline, Cogné, Benjamin, Sanlaville, Damien, Aguet, François, Emrick, Lisa T., Ganesh, Vijay S., Ketkar, Shamika, MacArthur, Daniel G.

2024

Overview

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. (Funded by the National Human Genome Research Institute and others.) Deletions in a gene ( CHASERR ) that encodes a long noncoding RNA cause severe developmental delay and an increase in expression of a neighboring gene, CHD2 .

• Publisher: Massachusetts Medical Society
• Subject: Age / Atrophy / Brain - diagnostic imaging / Brain - metabolism / Brain - pathology / Cell lines / Child development / Child, Preschool / Chromosomes / Clonal deletion / Convulsions & seizures / Disease / DNA-Binding Proteins - analysis / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Electroencephalography / Encephalopathy / Epilepsy / Families & family life / Female / Gene Deletion / Gene expression / Genetics / Genetics General / Genomes / Growth and Development / Haploinsufficiency / Humans / Infant / Intellectual disabilities / Magnetic resonance imaging / Male / Neurodevelopmental disorders / Neurodevelopmental Disorders - diagnosis / Neurodevelopmental Disorders - genetics / Neurodevelopmental Disorders - pathology / Neurology / Neuroscience / Neurosurgery / Neurosurgery General / Non-coding RNA / Pediatrics / Pediatrics General / Phenotype / Phenotypes / Proteins / Review boards / RNA, Long Noncoding - genetics / Sensitivity analysis / Sequence Deletion / Stem cells