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

Autor: Ganesh VS; Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA., Riquin K; Nantes Université, CHU de Nantes, CNRS, INSERM, L'institut du Thorax, Nantes, France., Chatron N; Institut Neuromyogène, Laboratoire Physiopathologie et Génétique du Neurone et du Muscle, Equipe Métabolisme énergétique et développement neuronal, CNRS UMR 5310, INSERM U1217, Université Lyon 1, Lyon, France.; Service de génétique, Hospices Civils de Lyon, Lyon, France., Lamar KM; Departments of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL., Aziz MC; Departments of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL., Monin P; Service de génétique, Hospices Civils de Lyon, Lyon, France., O'Leary M; Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Goodrich JK; Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Garimella KV; Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., England E; Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Yoon E; Departments of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL., Weisburd B; Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Aguet F; Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Bacino CA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Murdock DR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Dai H; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Rosenfeld JA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Emrick LT; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Ketkar S; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Sarusi Y; Departments of Biological Regulation and Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel., Sanlaville D; Institut Neuromyogène, Laboratoire Physiopathologie et Génétique du Neurone et du Muscle, Equipe Métabolisme énergétique et développement neuronal, CNRS UMR 5310, INSERM U1217, Université Lyon 1, Lyon, France.; Service de génétique, Hospices Civils de Lyon, Lyon, France., Kayani S; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA., Broadbent B; Coalition to Cure CHD2, USA., Isidor B; Nantes Université, CHU de Nantes, CNRS, INSERM, L'institut du Thorax, Nantes, France.; Nantes Université, CHU de Nantes, Service de Génétique médicale, F-44000 Nantes, France., Pengam A; Nantes Université, CHU de Nantes, Service de Génétique médicale, F-44000 Nantes, France., Cogné B; Nantes Université, CHU de Nantes, CNRS, INSERM, L'institut du Thorax, Nantes, France.; Nantes Université, CHU de Nantes, Service de Génétique médicale, F-44000 Nantes, France., MacArthur DG; Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Centre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, Australia.; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Australia., Ulitsky I; Departments of Biological Regulation and Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel., Carvill GL; Departments of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL.; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL., O'Donnell-Luria A; Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA.
Jazyk: angličtina
Zdroj: MedRxiv : the preprint server for health sciences [medRxiv] 2024 Feb 07. Date of Electronic Publication: 2024 Feb 07.
DOI: 10.1101/2024.01.31.24301497
Abstrakt: 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.
Databáze: MEDLINE
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