De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism.

Autor:	Guillen Sacoto MJ; GeneDx, Inc., Gaithersburg, MD 20877, USA. Electronic address: mguillen@genedx.com., Tchasovnikarova IA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA., Torti E; GeneDx, Inc., Gaithersburg, MD 20877, USA., Forster C; GeneDx, Inc., Gaithersburg, MD 20877, USA., Andrew EH; Myelin Disorders Program, Rare Disease Institute, Children's National Hospital, Washington, DC 20010, USA., Anselm I; Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA., Baranano KW; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA., Briere LC; Department of Medical Genetics and Metabolism, Massachusetts General Hospital, Boston, MA 02114, USA., Cohen JS; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; Department of Neurology and Developmental Medicine, Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD 21205, USA; Center for Genetic Muscle Disorders, Kennedy Krieger Institute, Baltimore, MD 21205, USA., Craigen WJ; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Cytrynbaum C; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada., Ekhilevitch N; The Genetics Institute, Rambam Health Care Campus, Haifa 3109601, Israel., Elrick MJ; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA., Fatemi A; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; Department of Neurology and Developmental Medicine, Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD 21205, USA; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Fraser JL; Myelin Disorders Program, Rare Disease Institute, Children's National Hospital, Washington, DC 20010, USA., Gallagher RC; Department of Pediatrics, Division of Medical Genetics, University of California, San Francisco, CA 94158, USA., Guerin A; Division of Medical Genetics, Department of Pediatrics, Queen's University, Kingston, ON K7L 2V7, Canada., Haynes D; Division of Genetics, Arnold Palmer Hospital for Children, Orlando Health, Orlando, FL 32806, USA., High FA; Department of Medical Genetics and Metabolism, Massachusetts General Hospital, Boston, MA 02114, USA., Inglese CN; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada., Kiss C; Division of Medical Genetics, Department of Pediatrics, Queen's University, Kingston, ON K7L 2V7, Canada., Koenig MK; Department of Pediatrics, University of Texas McGovern Medical School, Houston, TX 77030, USA., Krier J; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA., Lindstrom K; Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ 85016, USA., Marble M; Department of Pediatrics, Division of Clinical Genetics and Metabolism, LSU Health Sciences Center and Children's Hospital, New Orleans, LA 70112, USA., Meddaugh H; Department of Clinical Genetics and Metabolism, Children's Hospital New Orleans, New Orleans, LA 70118, USA., Moran ES; Hassenfeld Children's Hospital at New York University Langone, New York University Langone Orthopedic Hospital, New York, NY 10003, USA., Morel CF; Fred A. Litwin Family Center in Genetic Medicine, University Health Network, Toronto, ON M5T 3L9, Canada; Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada., Mu W; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Muller EA 2nd; Clinical Genetics, Stanford Children's Health, San Francisco, CA 94109, USA., Nance J; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; Center for Genetic Muscle Disorders, Kennedy Krieger Institute, Baltimore, MD 21205, USA., Natowicz MR; Institutes of Pathology and Laboratory Medicine and Genomic Medicine, Cleveland Clinic, Cleveland, OH 44195, USA., Numis AL; Department of Neurology and Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USA., Ostrem B; Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA., Pappas J; Clinical Genetic Services, Pediatrics, NYU Grossman School of Medicine, New York, NY 10016, USA., Stafstrom CE; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA., Streff H; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Sweetser DA; Department of Medical Genetics and Metabolism, Massachusetts General Hospital, Boston, MA 02114, USA., Szybowska M; Fred A. Litwin Family Center in Genetic Medicine, University Health Network, Toronto, ON M5T 3L9, Canada., Walker MA; Department of Neurology, Division of Neurogenetics, Massachusetts General Hospital, Boston, MA 02114, USA., Wang W; GeneDx, Inc., Gaithersburg, MD 20877, USA., Weiss K; The Genetics Institute, Rambam Health Care Campus, Haifa 3109601, Israel., Weksberg R; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Pediatrics and Institute of Medical Science, University of Toronto, Toronto, ON M5G 1X8, Canada., Wheeler PG; Division of Genetics, Arnold Palmer Hospital for Children, Orlando Health, Orlando, FL 32806, USA., Yoon G; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada., Kingston RE; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA., Juusola J; GeneDx, Inc., Gaithersburg, MD 20877, USA.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2020 Aug 06; Vol. 107 (2), pp. 352-363. Date of Electronic Publication: 2020 Jul 20.
DOI:	10.1016/j.ajhg.2020.06.013
Abstrakt:	MORC2 encodes an ATPase that plays a role in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous variants in MORC2 have been reported in individuals with autosomal-dominant Charcot-Marie-Tooth disease type 2Z and spinal muscular atrophy, and the onset of symptoms ranges from infancy to the second decade of life. Here, we present a cohort of 20 individuals referred for exome sequencing who harbor pathogenic variants in the ATPase module of MORC2. Individuals presented with a similar phenotype consisting of developmental delay, intellectual disability, growth retardation, microcephaly, and variable craniofacial dysmorphism. Weakness, hyporeflexia, and electrophysiologic abnormalities suggestive of neuropathy were frequently observed but were not the predominant feature. Five of 18 individuals for whom brain imaging was available had lesions reminiscent of those observed in Leigh syndrome, and five of six individuals who had dilated eye exams had retinal pigmentary abnormalities. Functional assays revealed that these MORC2 variants result in hyperactivation of epigenetic silencing by the HUSH complex, supporting their pathogenicity. The described set of morphological, growth, developmental, and neurological findings and medical concerns expands the spectrum of genetic disorders resulting from pathogenic variants in MORC2. (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu