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

Jul 23, 2020

Contributor: Maria J Guillen Sacoto,Iva A Tchasovnikarova,Erin Torti,Cara Forster,E Hallie Andrew,Irina Anselm,Kristin W Baranano,Lauren C Briere,Julie S Cohen,William J Craigen,Cheryl Cytrynbaum,Nina Ekhilevitch,Matthew J Elrick,Ali Fatemi,Jamie L Fraser,Renata C Gallagher,Andrea Guerin,Devon Haynes,Frances A High,Cara N Inglese,Courtney Kiss,Mary Kay Koenig,Joel Krier,Kristin Lindstrom,Michael Marble,Hannah Meddaugh,Ellen S Moran,Chantal F Morel,Weiyi Mu,Eric A Muller,Jessica Nance,Marvin R Natowicz,Adam L Numis,Bridget Ostrem,John Pappas,Carl E Stafstrom,Haley Streff,David A Sweetser,Marta Szybowska, ,Melissa A Walker,Wei Wang,Karin Weiss,Rosanna Weksberg,Patricia G Wheeler,Grace Yoon,Robert E Kingston,Jane Juusola

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

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.

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Maria J Guillen Sacoto

GeneDx, Inc., Gaithersburg, MD 20877, USA. Electronic address: mguillen@genedx.com.

Iva A Tchasovnikarova

Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.

Erin Torti

GeneDx, Inc., Gaithersburg, MD 20877, USA.

Cara Forster

GeneDx, Inc., Gaithersburg, MD 20877, USA.

E Hallie Andrew

Myelin Disorders Program, Rare Disease Institute, Children’s National Hospital, Washington, DC 20010, USA.

Irina Anselm

Department of Neurology, Boston Children’s Hospital, Boston, MA 02115, USA.

Kristin W Baranano

Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.

Lauren C Briere

Department of Medical Genetics and Metabolism, Massachusetts General Hospital, Boston, MA 02114, USA.

Julie S Cohen

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.

William J Craigen

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

Cheryl Cytrynbaum

Nina Ekhilevitch

The Genetics Institute, Rambam Health Care Campus, Haifa 3109601, Israel.

Matthew J Elrick

Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.

Ali Fatemi

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.

Jamie L Fraser

Myelin Disorders Program, Rare Disease Institute, Children’s National Hospital, Washington, DC 20010, USA.

Renata C Gallagher

Department of Pediatrics, Division of Medical Genetics, University of California, San Francisco, CA 94158, USA.

Andrea Guerin

Division of Medical Genetics, Department of Pediatrics, Queen’s University, Kingston, ON K7L 2V7, Canada.

Devon Haynes

Division of Genetics, Arnold Palmer Hospital for Children, Orlando Health, Orlando, FL 32806, USA.

Frances A High

Department of Medical Genetics and Metabolism, Massachusetts General Hospital, Boston, MA 02114, USA.

Cara N Inglese

Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.

Courtney Kiss

Division of Medical Genetics, Department of Pediatrics, Queen’s University, Kingston, ON K7L 2V7, Canada.

Mary Kay Koenig

Department of Pediatrics, University of Texas McGovern Medical School, Houston, TX 77030, USA.

Joel Krier

Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA.

Kristin Lindstrom

Division of Genetics and Metabolism, Phoenix Children’s Hospital, Phoenix, AZ 85016, USA.

Michael Marble

Department of Pediatrics, Division of Clinical Genetics and Metabolism, LSU Health Sciences Center and Children’s Hospital, New Orleans, LA 70112, USA.

Hannah Meddaugh

Department of Clinical Genetics and Metabolism, Children’s Hospital New Orleans, New Orleans, LA 70118, USA.

Ellen S Moran

Hassenfeld Children’s Hospital at New York University Langone, New York University Langone Orthopedic Hospital, New York, NY 10003, USA.

Chantal F Morel

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.

Weiyi Mu

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Eric A Muller

Clinical Genetics, Stanford Children’s Health, San Francisco, CA 94109, USA.

Jessica Nance

Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; Center for Genetic Muscle Disorders, Kennedy Krieger Institute, Baltimore, MD 21205, USA.

Marvin R Natowicz

Institutes of Pathology and Laboratory Medicine and Genomic Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.

Adam L Numis

Department of Neurology and Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USA.

Bridget Ostrem

Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.

John Pappas

Clinical Genetic Services, Pediatrics, NYU Grossman School of Medicine, New York, NY 10016, USA.

Carl E Stafstrom

Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.

Haley Streff

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

David A Sweetser

Department of Medical Genetics and Metabolism, Massachusetts General Hospital, Boston, MA 02114, USA.

Marta Szybowska

Fred A. Litwin Family Center in Genetic Medicine, University Health Network, Toronto, ON M5T 3L9, Canada.

Melissa A Walker

Department of Neurology, Division of Neurogenetics, Massachusetts General Hospital, Boston, MA 02114, USA.

Wei Wang

GeneDx, Inc., Gaithersburg, MD 20877, USA.

Karin Weiss

The Genetics Institute, Rambam Health Care Campus, Haifa 3109601, Israel.

Rosanna Weksberg

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.

Patricia G Wheeler

Division of Genetics, Arnold Palmer Hospital for Children, Orlando Health, Orlando, FL 32806, USA.

Grace Yoon

Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.

Robert E Kingston

Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.

Jane Juusola

GeneDx, Inc., Gaithersburg, MD 20877, USA.

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

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