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

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

  • Am J Hum Genet. 2020 Aug 6;107(2):352-363. doi: 10.1016/j.ajhg.2020.06.013.
Maria J Guillen Sacoto 1,  Iva A Tchasovnikarova 2,  Erin Torti 3,  Cara Forster 3,  E Hallie Andrew 4,  Irina Anselm 5,  Kristin W Baranano 6,  Lauren C Briere 7,  Julie S Cohen 8,  William J Craigen 9,  Cheryl Cytrynbaum 10,  Nina Ekhilevitch 11,  Matthew J Elrick 6,  Ali Fatemi 12,  Jamie L Fraser 4,  Renata C Gallagher 13,  Andrea Guerin 14,  Devon Haynes 15,  Frances A High 7,  Cara N Inglese 16,  Courtney Kiss 14,  Mary Kay Koenig 17,  Joel Krier 18,  Kristin Lindstrom 19,  Michael Marble 20,  Hannah Meddaugh 21,  Ellen S Moran 22,  Chantal F Morel 23,  Weiyi Mu 24,  Eric A Muller 2nd 25,  Jessica Nance 26,  Marvin R Natowicz 27,  Adam L Numis 28,  Bridget Ostrem 29,  John Pappas 30,  Carl E Stafstrom 6,  Haley Streff 9,  David A Sweetser 7,  Marta Szybowska 31,  Undiagnosed Diseases Network,  Melissa A Walker 32,  Wei Wang 3,  Karin Weiss 11,  Rosanna Weksberg 33,  Patricia G Wheeler 15,  Grace Yoon 16,  Robert E Kingston 2,  Jane Juusola 3
Affiliations

Affiliations

  • 1 GeneDx, Inc., Gaithersburg, MD 20877, USA. Electronic address: [email protected].
  • 2 Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
  • 3 GeneDx, Inc., Gaithersburg, MD 20877, USA.
  • 4 Myelin Disorders Program, Rare Disease Institute, Children's National Hospital, Washington, DC 20010, USA.
  • 5 Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
  • 6 Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
  • 7 Department of Medical Genetics and Metabolism, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 8 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.
  • 9 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 10 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.
  • 11 The Genetics Institute, Rambam Health Care Campus, Haifa 3109601, Israel.
  • 12 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.
  • 13 Department of Pediatrics, Division of Medical Genetics, University of California, San Francisco, CA 94158, USA.
  • 14 Division of Medical Genetics, Department of Pediatrics, Queen's University, Kingston, ON K7L 2V7, Canada.
  • 15 Division of Genetics, Arnold Palmer Hospital for Children, Orlando Health, Orlando, FL 32806, USA.
  • 16 Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • 17 Department of Pediatrics, University of Texas McGovern Medical School, Houston, TX 77030, USA.
  • 18 Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • 19 Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.
  • 20 Department of Pediatrics, Division of Clinical Genetics and Metabolism, LSU Health Sciences Center and Children's Hospital, New Orleans, LA 70112, USA.
  • 21 Department of Clinical Genetics and Metabolism, Children's Hospital New Orleans, New Orleans, LA 70118, USA.
  • 22 Hassenfeld Children's Hospital at New York University Langone, New York University Langone Orthopedic Hospital, New York, NY 10003, USA.
  • 23 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.
  • 24 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • 25 Clinical Genetics, Stanford Children's Health, San Francisco, CA 94109, USA.
  • 26 Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; Center for Genetic Muscle Disorders, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
  • 27 Institutes of Pathology and Laboratory Medicine and Genomic Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 28 Department of Neurology and Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 29 Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 30 Clinical Genetic Services, Pediatrics, NYU Grossman School of Medicine, New York, NY 10016, USA.
  • 31 Fred A. Litwin Family Center in Genetic Medicine, University Health Network, Toronto, ON M5T 3L9, Canada.
  • 32 Department of Neurology, Division of Neurogenetics, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 33 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.
PMID: 32693025 DOI: 10.1016/j.ajhg.2020.06.013
Abstract

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.

Keywords

CMT2Z; Leigh-like disease; MORC2; developmental delay; intellectual disability; microcephaly.

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