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Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies.
- Source :
-
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. - Publication Year :
- 2019
-
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.<br />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.<br />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.<br />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.
- Subjects :
- Adolescent
Autism Spectrum Disorder genetics
Autism Spectrum Disorder physiopathology
Child
Child, Preschool
Chromosome Deletion
DNA-Binding Proteins genetics
Genome, Human genetics
Haploinsufficiency genetics
Humans
Infant
Infant, Newborn
Intellectual Disability physiopathology
Language Development Disorders physiopathology
Neurodevelopmental Disorders physiopathology
Nuclear Proteins genetics
Phenotype
Proteins genetics
Exome Sequencing
Intellectual Disability genetics
Language Development Disorders genetics
Neurodevelopmental Disorders genetics
Problem Behavior
Subjects
Details
- Language :
- English
- ISSN :
- 1530-0366
- Volume :
- 21
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Genetics in medicine : official journal of the American College of Medical Genetics
- Publication Type :
- Academic Journal
- Accession number :
- 30679821
- Full Text :
- https://doi.org/10.1038/s41436-019-0433-1