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

Michael D. Fountain, David S. Oleson, Megan E. Rech, Lara Segebrecht, Jill V. Hunter, John M. McCarthy, Philip J. Lupo, Manuel Holtgrewe, Rocio Moran, Jill A. Rosenfeld, Bertrand Isidor, Cédric Le Caignec, Margarita S. Saenz, Robert C. Pedersen, Thomas M. Morgan, Jean P. Pfotenhauer, Fan Xia, Weimin Bi, Sung Hae L. Kang, Ankita PatelIan D. Krantz, Sarah E. Raible, Wendy Smith, Ingrid Cristian, Erin Torti, Jane Juusola, Francisca Millan, Ingrid M. Wentzensen, Richard E. Person, Sébastien Küry, Stéphane Bézieau, Kévin Uguen, Claude Férec, Arnold Munnich, Mieke van Haelst, Klaske D. Lichtenbelt, Koen van Gassen, Tanner Hagelstrom, Aditi Chawla, Denise L. Perry, Ryan J. Taft, Marilyn Jones, Diane Masser-Frye, David Dyment, Sunita Venkateswaran, Chumei Li, Luis F. Escobar, Denise Horn, Rebecca C. Spillmann, Loren Peña, Jolanta Wierzba, Tim M. Strom, Ilaria Parenti, Frank J. Kaiser, Nadja Ehmke, Christian P. Schaaf*

*Corresponding author for this work
1 Citation (Scopus)


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.

Original languageEnglish
JournalGenetics in Medicine
Issue number8
Pages (from-to)1797-1807
Number of pages11
Publication statusPublished - 01.08.2019

Research Areas and Centers

  • Research Area: Medical Genetics


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