Novel syndromic neurodevelopmental disorder caused by de novo deletion of CHASERR, a long noncoding RNA

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


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Genes encoding long non-coding RNAs (lncRNAs) comprise a large fraction of the human genome, yet haploinsufficiency of a lncRNA has not been shown to cause a Mendelian disease. CHASERR is a highly conserved human lncRNA adjacent to CHD2– a coding gene in which de novo loss-of-function variants cause developmental and epileptic encephalopathy. Here we report three unrelated individuals each harboring an ultra-rare heterozygous de novo deletion in the CHASERR locus. We report similarities in severe developmental delay, facial dysmorphisms, and cerebral dysmyelination in these individuals, distinguishing them from the phenotypic spectrum of CHD2 haploinsufficiency. We demonstrate reduced CHASERR mRNA expression and corresponding increased CHD2 mRNA and protein in whole blood and patient-derived cell lines–specifically increased expression of the CHD2 allele in cis with the CHASERR deletion, as predicted from a prior mouse model of Chaserr haploinsufficiency. We show for the first time that de novo structural variants facilitated by Alu-mediated non-allelic homologous recombination led to deletion of a non-coding element (the lncRNA CHASERR ) to cause a rare syndromic neurodevelopmental disorder. We also demonstrate that CHD2 has bidirectional dosage sensitivity in human disease. This work highlights the need to carefully evaluate other lncRNAs, particularly those upstream of genes associated with Mendelian disorders. ### Competing Interest Statement Anne ODonnell-Luria was a paid advisor of Tome Biosciences, Ono Pharma USA, and is a member of the scientific and community advisory board for the Simons Foundation SPARK for Autism study. Gemma L. Carvill is a scientific advisory board member of Coalition to Cure CHD2, consultant for BridgeBio and previous collaborative research funding from Stoke Therapeutics. Igor Ulitsky is the author of a patent on the use of CHASERR inhibition for CHD2 up-regulation, supervising sponsored research on the use of CHASERR ASOs. Daniel G. MacArthur is a paid advisor to GlaxoSmithKline (GSK), Insitro, Variant Bio and Overtone Therapeutics, and has received research support from AbbVie, Astellas, Biogen, BioMarin, Eisai, Google, Merck, Microsoft, Pfizer, and Sanofi-Genzyme. Brian Broadbent is President of The Coalition to Cure CHD2, a patient advocacy group that funds research, including possible equity investments, into CHD2 and CHASERR. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratories. ### Funding Statement VSG was supported by the Mass General Brigham Training Program in Precision and Genomic Medicine (NHGRI T32 HG10464). KML is supported by NICHD F32 HD101280. EY is supported by T32 GM142604. IU is supported by the European Research Council Consolidator Grant lncIMPACT and by the Nella and Leon Benoziyo Center for Neurological Diseases. GLC is supported by NINDS K99/R00NS089858 and the CURE taking Flight Award. AO-L is supported by the National Human Genome Research Institute (NHGRI) grants UM1HG008900 (with additional support from the National Eye Institute, and the National Heart, Lung and Blood Institute), U01HG011755, and R01HG009141 and in part by Chan Zuckerberg Initiative Donor-Advised Fund at the Silicon Valley Community Foundation 2019-199278 () (funder DOI 10.13039/100014989). We thank the Groupama foundation for funding research on intellectual disability. This research was made possible through access to the data generated by the 2025 French Genomic Medicine Initiative. The Undiagnosed Disease Network (UDN) supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director under Award Numbers U01HG007709, U01HG007530, and U01HG007943. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of Mass General Brigham (MGB, protocol# 2016P001422) gave ethical approval for this work through the Rare Genomes Project at the Broad Institutes of MIT and Harvard (for Individual 1). The IRB of the National Institutes of Health (NIH, protocol #15HG0130) gave ethical approval for this work through the Undiagnosed Diseases Network (UDN) (for Individual 1). The Ethics Committee of Centre Hospitalier Universitaire (CHU) de Nantes (protocol DC-2011-1399) gave ethical approval for this work (for Inviduals 2 and 3). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.
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