2. Academic Validation
  3. Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies

Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies

  • Genet Med. 2019 Aug;21(8):1797-1807. doi: 10.1038/s41436-019-0433-1.
Michael D Fountain 1 2,  David S Oleson 2,  Megan E Rech 1 2,  Lara Segebrecht 3 4,  Jill V Hunter 5,  John M McCarthy 1 2,  Philip J Lupo 6,  Manuel Holtgrewe 7,  Rocio Moran 8,  Jill A Rosenfeld 2,  Bertrand Isidor 9 10,  Cédric Le Caignec 9,  Margarita S Saenz 11,  Robert C Pedersen 12,  Thomas M Morgan 13,  Jean P Pfotenhauer 13,  Fan Xia 2,  Weimin Bi 2,  Sung-Hae L Kang 14,  Ankita Patel 15,  Ian D Krantz 16 17,  Sarah E Raible 16,  Wendy Smith 18,  Ingrid Cristian 19,  Erin Torti 20,  Jane Juusola 20,  Francisca Millan 20,  Ingrid M Wentzensen 20,  Richard E Person 20,  Sébastien Küry 9 10,  Stéphane Bézieau 9 10,  Kévin Uguen 21,  Claude Férec 21,  Arnold Munnich 22,  Mieke van Haelst 23 24,  Klaske D Lichtenbelt 25,  Koen van Gassen 25,  Tanner Hagelstrom 26,  Aditi Chawla 26,  Denise L Perry 26,  Ryan J Taft 26,  Marilyn Jones 27,  Diane Masser-Frye 27,  David Dyment 28 29,  Sunita Venkateswaran 29 30,  Chumei Li 31,  Luis F Escobar 32,  Denise Horn 33,  Rebecca C Spillmann 34,  Loren Peña 35,  Jolanta Wierzba 36,  Tim M Strom 37 38,  Ilaria Parenti 39,  Frank J Kaiser 39,  Nadja Ehmke 3 4,  Christian P Schaaf 40 41 42 43 44
Affiliations

Affiliations

  • 1 Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA.
  • 2 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • 3 Institut für Medizinische Genetik und Humangenetik, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • 4 Berlin Institute of Health (BIH), Berlin, Germany.
  • 5 Department of Radiology, Texas Children's Hospital, Houston, TX, USA.
  • 6 Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
  • 7 Core Unit Bioinformatics, Berlin Institute of Health, Berlin, Germany.
  • 8 Department of Genetics, Cleveland Clinic Children's, Cleveland, OH, USA.
  • 9 CHU Nantes, Service de Génétique Médicale, Nantes, France.
  • 10 l'institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France.
  • 11 Clinical Genetics and Metabolism, Children's Hospital Colorado, Aurora, CO, USA.
  • 12 Department of Pediatrics, Tripler Army Medical Center, Honolulu, HI, USA.
  • 13 Department of Pediatrics, Division of Medical Genetics and Genomic Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • 14 Department of Pathology & Laboratory Medicine, University of California Los Angeles, Los Angeles, CA, USA.
  • 15 Baylor Genetics, Houston, TX, USA.
  • 16 Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 17 Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 18 Department of Pediatrics, The Barbara Bush Children's Hospital, Maine Medical Center, Portland, ME, USA.
  • 19 Division of Genetics, Department of Pediatrics, Arnold Palmer Hospital, Orlando, FL, USA.
  • 20 GeneDx, Gaithersburg, MD, USA.
  • 21 Service de Génétique Médicale, CHRU de Brest, INSERM, Brest, France.
  • 22 UMR1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France.
  • 23 Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
  • 24 Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
  • 25 Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
  • 26 Illumina Clinical Services Laboratory, Illumina, San Diego, CA, USA.
  • 27 Division of Genetics, Department of Pediatrics, UC San Diego School of Medicine, Rady Children's Hospital, San Diego, CA, USA.
  • 28 Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
  • 29 Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.
  • 30 Division of Neurology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
  • 31 McMaster University Medical Center, Hamilton, ON, Canada.
  • 32 Medical Genetics and Neurodevelopment Center, St Vincent Children's Hospital, Indianapolis, IN, USA.
  • 33 Charité-Universtitätsmedizin Berlin, Institute for Medical Genetics and Human Genetics, Berlin, Germany.
  • 34 Department of Pediatrics, Division of Medical Genetics, Duke University School of Medicine, Durham, NC, USA.
  • 35 Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • 36 Department of General Nursery, Medical University of Gdańsk, Gdańsk, Poland.
  • 37 Institute of Human Genetics, Technische Universität München, Munich, Germany.
  • 38 Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
  • 39 Section for Functional Genetics, Institute for Human Genetics, University of Lübeck, Lübeck, Germany.
  • 40 Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA. schaaf@bcm.edu.
  • 41 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. schaaf@bcm.edu.
  • 42 Institute of Human Genetics, University Hospital Cologne, Cologne, Germany. schaaf@bcm.edu.
  • 43 Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany. schaaf@bcm.edu.
  • 44 Center for Rare Diseases, University Hospital Cologne, Cologne, Germany. schaaf@bcm.edu.
PMID: 30679821 DOI: 10.1038/s41436-019-0433-1
Abstract

Purpose: Haploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal F-actin polymerization and dysregulated protein recycling.

Methods: We report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome Sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency.

Results: The clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies,feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination.

Conclusion: The consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers.

Keywords

USP7; corpus callosum thinning; neurodevelopment; speech delay; white matter paucity.

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