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

Autor:	Fountain MD; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Oleson DS; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Rech ME; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Segebrecht L; Institut für Medizinische Genetik und Humangenetik, Charité-Universitätsmedizin Berlin, Berlin, Germany.; Berlin Institute of Health (BIH), Berlin, Germany., Hunter JV; Department of Radiology, Texas Children's Hospital, Houston, TX, USA., McCarthy JM; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Lupo PJ; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA., Holtgrewe M; Core Unit Bioinformatics, Berlin Institute of Health, Berlin, Germany., Moran R; Department of Genetics, Cleveland Clinic Children's, Cleveland, OH, USA., Rosenfeld JA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Isidor B; CHU Nantes, Service de Génétique Médicale, Nantes, France.; l'institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France., Le Caignec C; CHU Nantes, Service de Génétique Médicale, Nantes, France., Saenz MS; Clinical Genetics and Metabolism, Children's Hospital Colorado, Aurora, CO, USA., Pedersen RC; Department of Pediatrics, Tripler Army Medical Center, Honolulu, HI, USA., Morgan TM; Department of Pediatrics, Division of Medical Genetics and Genomic Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA., Pfotenhauer JP; Department of Pediatrics, Division of Medical Genetics and Genomic Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA., Xia F; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Bi W; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Kang SL; Department of Pathology & Laboratory Medicine, University of California Los Angeles, Los Angeles, CA, USA., Patel A; Baylor Genetics, Houston, TX, USA., Krantz ID; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Raible SE; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Smith W; Department of Pediatrics, The Barbara Bush Children's Hospital, Maine Medical Center, Portland, ME, USA., Cristian I; Division of Genetics, Department of Pediatrics, Arnold Palmer Hospital, Orlando, FL, USA., Torti E; GeneDx, Gaithersburg, MD, USA., Juusola J; GeneDx, Gaithersburg, MD, USA., Millan F; GeneDx, Gaithersburg, MD, USA., Wentzensen IM; GeneDx, Gaithersburg, MD, USA., Person RE; GeneDx, Gaithersburg, MD, USA., Küry S; CHU Nantes, Service de Génétique Médicale, Nantes, France.; l'institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France., Bézieau S; CHU Nantes, Service de Génétique Médicale, Nantes, France.; l'institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France., Uguen K; Service de Génétique Médicale, CHRU de Brest, INSERM, Brest, France., Férec C; Service de Génétique Médicale, CHRU de Brest, INSERM, Brest, France., Munnich A; UMR1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France., van Haelst M; Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.; Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands., Lichtenbelt KD; Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands., van Gassen K; Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands., Hagelstrom T; Illumina Clinical Services Laboratory, Illumina, San Diego, CA, USA., Chawla A; Illumina Clinical Services Laboratory, Illumina, San Diego, CA, USA., Perry DL; Illumina Clinical Services Laboratory, Illumina, San Diego, CA, USA., Taft RJ; Illumina Clinical Services Laboratory, Illumina, San Diego, CA, USA., Jones M; Division of Genetics, Department of Pediatrics, UC San Diego School of Medicine, Rady Children's Hospital, San Diego, CA, USA., Masser-Frye D; Division of Genetics, Department of Pediatrics, UC San Diego School of Medicine, Rady Children's Hospital, San Diego, CA, USA., Dyment D; Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada., Venkateswaran S; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.; Division of Neurology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada., Li C; McMaster University Medical Center, Hamilton, ON, Canada., Escobar LF; Medical Genetics and Neurodevelopment Center, St Vincent Children's Hospital, Indianapolis, IN, USA., Horn D; Charité-Universtitätsmedizin Berlin, Institute for Medical Genetics and Human Genetics, Berlin, Germany., Spillmann RC; Department of Pediatrics, Division of Medical Genetics, Duke University School of Medicine, Durham, NC, USA., Peña L; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Wierzba J; Department of General Nursery, Medical University of Gdańsk, Gdańsk, Poland., Strom TM; Institute of Human Genetics, Technische Universität München, Munich, Germany.; Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany., Parenti I; Section for Functional Genetics, Institute for Human Genetics, University of Lübeck, Lübeck, Germany., Kaiser FJ; Section for Functional Genetics, Institute for Human Genetics, University of Lübeck, Lübeck, Germany., Ehmke N; Institut für Medizinische Genetik und Humangenetik, Charité-Universitätsmedizin Berlin, Berlin, Germany.; Berlin Institute of Health (BIH), Berlin, Germany., Schaaf CP; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA. schaaf@bcm.edu.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. schaaf@bcm.edu.; Institute of Human Genetics, University Hospital Cologne, Cologne, Germany. schaaf@bcm.edu.; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany. schaaf@bcm.edu.; Center for Rare Diseases, University Hospital Cologne, Cologne, Germany. schaaf@bcm.edu.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2019 Aug; Vol. 21 (8), pp. 1797-1807. Date of Electronic Publication: 2019 Jan 25.
DOI:	10.1038/s41436-019-0433-1
Abstrakt:	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.
Databáze:	MEDLINE
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