Neurodevelopmental Disorder Caused by Deletion of CHASERR, a lncRNA Gene

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

Research output: Contribution to journalArticlepeer-review

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. (Funded by the National Human Genome Research Institute and others.).

Original languageEnglish
Pages (from-to)1511-1518
Number of pages8
JournalThe New England journal of medicine
Volume391
Issue number16
DOIs
StatePublished - 24 Oct 2024
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Medicine

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