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
  • 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. [email protected].
  • 41. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. [email protected].
  • 42. Institute of Human Genetics, University Hospital Cologne, Cologne, Germany. [email protected].
  • 43. Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany. [email protected].
  • 44. Center for Rare Diseases, University Hospital Cologne, Cologne, Germany. [email protected].
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.