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

dc.contributor.authorMorgan, Thomas M.
dc.contributor.authorPfotenhauer, Jean P.
dc.identifier.citationFountain, 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. L., Patel, A., … Schaaf, C. P. (2019). Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies. Genetics in medicine : official journal of the American College of Medical Genetics, 21(8), 1797–1807.
dc.descriptionmore than 10 authors, only add the Vanderbilt authors and put in comments section: "Only Vanderbilt University affiliated authors are listed on VUIR. For a full list of authors, access the version of record at
dc.description.abstractPurpose: 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 Factin 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.en_US
dc.description.sponsorshipThis study was partially supported by Intellectual and Developmental Disabilities Research Center (IDDRC) grant 1U54HD083092 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development, and by a grant to J.W. from the National Science Centre of Poland, project UMO-2014/15/B/NZ5/03503. Funding was also provided by the German Federal Ministry of Education and Research (BMBF) (CHROMATINNet 01GM1520C to F.J.K.), and the Medical Faculty of the University of Lubeck (J09-2017 to I.P.). We acknowledge HUGODIMS consortium, supported by a grant from the French Ministry of Health and from the Health Regional Agency from Poitou-Charentes (HUGODIMS, 2013, RC14_0107); we are grateful for the support of Frederique Allaire from the Health Regional Agency of Poitou-Charentes. We appreciate the support of Kym Boycott, from the Children's Hospital of Eastern Ontario and the Children's Hospital of Eastern Ontario Research Institute, and Taila Hartley, from the Children's Hospital of Eastern Ontario Research Institute. We are grateful to Charles Minard from Baylor College of Medicine for his discussion and input. The National Institutes of Health (NIH) Common Fund, through the Office of Strategic Coordination/Office of the NIH Director under award numbers U01HG007672 (Duke University) and U01HG007942 (Baylor College of Medicine-Sequencing) also supported this research. The content is solely the responsibility of the authors and does not necessarily represent the NIH's official views. We thank the Undiagnosed Disease Network (UDN) and the iHope Program, supported by Illumina, for each diagnosing a patient reported. UDN members are listed in supplementary materials. Finally, the authors are indebted to the patients and their families for their participation in this study. A Facebook group for affected families can be found at pages for the Foundation for USP7-Related Diseases (USA) and the Association Manger la Vie (France) can be found at and, respectively.en_US
dc.publisherGenetics Medicineen_US
dc.rightsOpen Access This article is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. If you remix, transform, or build upon this article or a part thereof, you must distribute your contributions under the same license as the original. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit
dc.subjectpeech delayen_US
dc.subjectwhite matter paucityen_US
dc.subjectcorpus callosum thinningen_US
dc.titlePathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomaliesen_US

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