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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.*

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

Genet. Med. 21, 1797-1807 (2019)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Usp7 ; Neurodevelopment ; Speech Delay ; White Matter Paucity ; Corpus Callosum Thinning; Prader-willi-syndrome; Corpus-callosum; Children; Mutations; Abnormalities; Hausp; P53
Sprache
Veröffentlichungsjahr 2019
HGF-Berichtsjahr 2019
ISSN (print) / ISBN 1530-0366
e-ISSN 1098-3600
Zeitschrift Genetics in Medicine
Quellenangaben Band: 21, Heft: 8, Seiten: 1797-1807 Artikelnummer: , Supplement: ,
Verlag Lippincott Williams & Wilkins
Verlagsort Baltimore, Md.
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)
POF Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-500700-001
DOI 10.1038/s41436-019-0433-1
WOS ID WOS:000478784800019
Scopus ID 85060682012
PubMed ID 30679821
Erfassungsdatum 2019-03-12
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