Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies.
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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.
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No human individuals have been identified who are USP7 homozygous-null.
“no human individuals have been identified who are USP7 homozygous-null (Fountain et al., 2019)”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Fountain et al., 2019
Heterozygous loss-of-function USP7 mutations have been identified in 23 individuals, all of whom have neurodevelopmental disorders and physical characteristics including dysmorphic facial features.
“Heterozygous loss-of-function USP7 mutations have, however, been identified in 23 individuals, all of whom have experienced neurodevelopmental disorders – characterized by developmental delay/intellectual disability (DD/ID), speech delay, behavioral anomalies and autism spectrum disorder – as well as physical characteristics that include dysmorphic facial features (Hao et al., 2015; Fountain et al”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Fountain et al., 2019
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A Rare Case of Hao-Fountain Syndrome Mimicking Fragile X Syndrome
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- Authors
- Fountain, M. D., Oleson, D. S., Rech, M. E., Segebrecht, L., Hunter, J. V., McCarthy, J. M., Lupo, P. J., Holtgrewe, M., Moran, R., Rosenfeld, J. A., Isidor, B., Le Caignec, C., Saenz, M. S., Pedersen, R. C., Morgan, T. M., Pfotenhauer, J. P., Xia, F., Bi, W., Kang, S.-H. L., Patel, A., Krantz, I. D., Raible, S. E., Smith, W., Cristian, I., Torti, E., Juusola, J., Millan, F., Wentzensen, I. M., Person, R. E., Küry, S., Bézieau, S., Uguen, K., Férec, C., Munnich, A., van Haelst, M., Lichtenbelt, K. D., van Gassen, K., Hagelstrom, T., Chawla, A., Perry, D. L., Taft, R. J., Jones, M., Masser-Frye, D., Dyment, D., Venkateswaran, S., Li, C., Escobar, L. F., Horn, D., Spillmann, R. C., Peña, L., Wierzba, J., Strom, T. M., Parenti, I., Kaiser, F. J., Ehmke, N., & Schaaf, C. P.
- Affiliations
- Baylor College of Medicine (US)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Texas Children's Hospital (US)
- Cleveland Clinic (US)
- Centre National de la Recherche Scientifique (FR)
- Children's Hospital Colorado (US)
- Tripler Army Medical Center (US)
- Vanderbilt University (US)
- University of California, Los Angeles (US)
- Baylor Genetics (US)
- Children's Hospital of Philadelphia (US)
- Maine Medical Center (US)
- Arnold Palmer Hospital for Children (US)
- Inserm (FR)
- University Medical Center Utrecht (NL)
- Illumina (United States) (US)
- University of California San Diego (US)
- University of Ottawa (CA)
- McMaster University (CA)
- St Vincent Hospital (US)
- Charité – Universitätsmedizin Berlin (DE)
- Duke University (US)
- Cincinnati Children's Hospital Medical Center (US)
- Gdańsk Medical University (PL)
- Helmholtz Munich (DE)
- University of Lübeck (DE)
- University of Cologne (DE)
- Corresponding author
- Schaaf, Christian P.
- ORCID
- Fountain, Michael D.
- Rech, Megan E.
- Segebrecht, Lara
- Hunter, Jill V.
- Lupo, Philip J.
- Holtgrewe, Manuel
- Rosenfeld, Jill A.
- Isidor, Bertrand
- Saenz, Margarita S.
- Morgan, Thomas M.
- Xia, Fan
- Bi, Weimin
- Patel, Ankita
- Krantz, Ian D.
- Smith, Wendy
- Torti, Erin
- Juusola, Jane
- Millan, Francisca
- Wentzensen, Ingrid M.
- Person, Richard E.
- Küry, Sébastien
- Uguen, Kévin
- Férec, Claude
- Lichtenbelt, Klaske D.
- Taft, Ryan J.
- Jones, Marilyn
- Dyment, David
- Li, Chumei
- Escobar, Luis F.
- Horn, Denise
- Spillmann, Rebecca C.
- Peña, Loren
- Wierzba, Jolanta
- Parenti, Ilaria
- Ehmke, Nadja
- Schaaf, Christian P.
- Venue
- Genetics in Medicine
- Publisher
- Elsevier BV
- Published
- 2019-08
- Volume
- 21
- Issue
- 8
- Pages
- 1797-1807
- ISSN
- 1098-3600 (ISSN-L)
- PMC
- PMC6752677
- OpenAlex
- W2914144747
- Cited by
- 80
- References
- 27
- Citations by year
- 2026: 15 · 2025: 18 · 2024: 9 · 2023: 5 · 2022: 17 · 2021: 5 · 2020: 9 · 2019: 2
- FWCI
- 4.96
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Genetics in Medicine (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by-nc-sa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
- mediaTUM (Technical University of Munich) (submittedVersion, other-oa)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Site cant be reached (submittedVersion, cc-by-nc-sa)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Bundesministerium für Bildung und Forschung (01GM1520C)
- Universität zu Lübeck
- National Institutes of Health
- Intellectual and Developmental Disabilities Research Center (1 U54 HD083092)
- National Human Genome Research Institute (U01HG007942, U01HG007672)
- NIH Office of the Director (U01HG007672, U01HG007942)
- Office of Strategic Coordination (U01HG007942, U01HG007672)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083092)
- Common Fund (U01HG007672, U01HG007942)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- USP7, haploinsufficiency, neurodevelopmental disorders, developmental delay, intellectual disability, autism spectrum disorder, speech delay, hypotonia, ocular abnormalities, feeding difficulties, GERD, white matter abnormalities, de novo mutations, protein recycling
- MeSH terms
- Problem Behavior, Autism Spectrum Disorder, Tripartite Motif Proteins, Exome Sequencing, Adolescent, Child, Child, Preschool, Chromosome Deletion, DNA-Binding Proteins, Humans, Infant, Infant, Newborn, Language Development Disorders, Intellectual Disability, Nuclear Proteins, Phenotype, Proteins, Genome, Human, Intracellular Signaling Peptides and Proteins, Haploinsufficiency, Intrinsically Disordered Proteins, Neurodevelopmental Disorders
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