From the Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge (V.S.G., M.C.O., J.K.G., K.V.G., E.E., B.W., F.A., D.G.M., A.O.-L.), and the Department of Neurology, Brigham and Women's Hospital (V.S.G.), the Division of Genetics and Genomics, Boston Children's Hospital (V.S.G., A.O.-L.), and Harvard Medical School (V.S.G., A.O.-L.), Boston - all in Massachusetts; L'institut du Thorax (K.R., B.I., S.B., B.C.), Service de Radiopediatrie (A.P.), and Service de Génétique Médicale (B.I., S.B., B.C.), Nantes Université, Centre Hospitalier Universitaire (CHU) de Nantes, Centre National de la Recherche Scientifique (CNRS), INSERM, Nantes, and Institut Neuromyogène, Laboratoire Physiopathologie et Génétique du Neurone et du Muscle, CNRS, INSERM (N.C., D.S.), and Service de Génétique, Hospices Civils de Lyon (N.C., P.M., D.S.), Lyon - all in France; the Departments of Neurology (E.Y., K.-M.L., M.C.A., G.L.C.) and Pharmacology (G.L.C.), Northwestern University Feinberg School of Medicine, Chicago; the Undiagnosed Diseases Network and the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston (C.A.B., D.R.M., H.D., J.A.R., L.T.E., S. Ketkar), and the Department of Pediatrics, University of Texas Southwestern Medical Center (S. Kayani), and Coalition to Cure CHD2 (B.B.), Dallas; the Departments of Immunology and Regenerative Biology and Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel (Y.S., I.U.); and the Centre for Population Genomics, Garvan Institute of Medical Research and University of New South Wales Sydney, Sydney (D.G.M.), and the Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC (D.G.M.) - both in Australia.
N Engl J Med. 2024 Oct 24;391(16):1511-1518. doi: 10.1056/NEJMoa2400718.
encodes a human long noncoding RNA (lncRNA) adjacent to , 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 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 haploinsufficiency. We found that the deletion results in increased CHD2 protein abundance in patient-derived cell lines and increased expression of the transcript in . These findings indicate that 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.).
编码一个人类长链非编码 RNA（lncRNA），该 RNA 与编码基因相邻，该基因中的从头失活功能变异导致发育性和癫痫性脑病。在这里，我们报告了在三个无关联的患有综合征性、早发性神经发育障碍的儿童中发现的结果，他们每个人都在 基因座上发生了新生缺失。这些儿童患有严重的脑病，具有共享的面部畸形、皮质萎缩和脑少突胶质发育不良-这种表型与 CHD8 基因功能不全患者的表型不同。我们发现， 缺失导致患者来源的细胞系中 CHD2 蛋白丰度增加， 转录本在 中表达增加。这些发现表明 在人类疾病中具有双向剂量敏感性，我们建议评估其他编码 lncRNA 的基因，特别是那些与孟德尔疾病相关基因上游的基因。（由国家人类基因组研究所等资助）。
