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

Maria J Guillen Sacoto¹, Iva A Tchasovnikarova², Erin Torti³, Cara Forster³, E Hallie Andrew⁴, Irina Anselm⁵, Kristin W Baranano⁶, Lauren C Briere⁷, Julie S Cohen⁸, William J Craigen⁹, Cheryl Cytrynbaum¹⁰, Nina Ekhilevitch¹¹, Matthew J Elrick⁶, Ali Fatemi¹², Jamie L Fraser⁴, Renata C Gallagher¹³, Andrea Guerin¹⁴, Devon Haynes¹⁵, Frances A High⁷, Cara N Inglese¹⁶, Courtney Kiss¹⁴, Mary Kay Koenig¹⁷, Joel Krier¹⁸, Kristin Lindstrom¹⁹, Michael Marble²⁰, Hannah Meddaugh²¹, Ellen S Moran²², Chantal F Morel²³, Weiyi Mu²⁴, Eric A Muller 2nd²⁵, Jessica Nance²⁶, Marvin R Natowicz²⁷, Adam L Numis²⁸, Bridget Ostrem²⁹, John Pappas³⁰, Carl E Stafstrom⁶, Haley Streff⁹, David A Sweetser⁷, Marta Szybowska³¹; Undiagnosed Diseases Network; Melissa A Walker³², Wei Wang³, Karin Weiss¹¹, Rosanna Weksberg³³, Patricia G Wheeler¹⁵, Grace Yoon¹⁶, Robert E Kingston², Jane Juusola³

Affiliations

¹ GeneDx, Inc., Gaithersburg, MD 20877, USA. Electronic address: mguillen@genedx.com.
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
PMCID: PMC7413887
DOI: 10.1016/j.ajhg.2020.06.013

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

Maria J Guillen Sacoto et al. Am J Hum Genet. 2020.

. 2020 Aug 6;107(2):352-363.

doi: 10.1016/j.ajhg.2020.06.013. Epub 2020 Jul 20.

Authors

Affiliations

¹ GeneDx, Inc., Gaithersburg, MD 20877, USA. Electronic address: mguillen@genedx.com.
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
PMCID: PMC7413887
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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Conflict of interest statement

M.J.G.S., C.F., E.T., W.W., and J.J. are employees of GeneDx, Inc. J.S.C. is a consultant to Invitae. A.F. is a consultant to Calico Labs and a paid Data and Safety Monitoring Board (DSMB) member of Bluebirdbio, Inc. and Stealth Therapeutics. M.K.K. is a paid member of the DSMB for Modis and is on the Speakers Bureau for Novartis.

Figures

**Figure 1**
Neurodevelopmental Variants Cluster in the ATPase Module of MORC2 Schematic representation of the domain structure of MORC2. MORC2 binds ATP through its GHKL-type ATPase module,^, which consists of a GHKL-type ATPase domain (residues 1–265), a transducer S5-like domain ([S5], residues 266–494), and an 80 amino acid antiparallel coiled-coil insertion within the transducer-like domain (coiled-coil 1 [CC1], residues 282–361) that projects out of the ATPase module. MORC2 also contains two putative chromatin-binding modules, a CW-type zinc finger (CW) and a chromo-like domain (CD), and two additional coiled-coils (CC2 and CC3). All variants described in this paper cluster in the ATPase module of MORC2.

**Figure 2**
Facial Characteristics of Individuals Harboring *MORC2* Variants

**Figure 3**
*MORC2* Mutations Hyperactivate Epigenetic Silencing by the HUSH Complex (A) Schematic representation of the complementation experiment in which the ability of MORC2 variants to restore repression of a HUSH-sensitive GFP reporter in MORC2 knockout cells was assessed. (B and C) MORC2 variants hyperactivate HUSH repression. At day 12 (B), all MORC2 variants exhibit enhanced silencing of the GFP reporter construct (blue histograms) compared to wild-type MORC2 (orange histograms). The full results for the time-course are, which reveal that the c.79G > A (p.Glu27Lys) and c.394C > T (p.Arg132Cys) variants are the most hyperactivating, are shown in (C). The p.Glu236Gly and p.Arg252Trp variants (shown in purple) previously associated with CMT2Z were included as a reference.

See this image and copyright information in PMC

References

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

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