Fountain, Michael D., Oleson, David S., Rech, Megan E., Segebrecht, Lara ORCID: 0000-0002-0939-3213, Hunter, Jill, V, McCarthy, John M., Lupo, Philip J., Holtgrewe, Manuel, Moran, Rocio, Rosenfeld, Jill A., Isidor, Bertrand, Le Caignec, Cedric, Saenz, Margarita S., Pedersen, Robert C., Morgan, Thomas M., Pfotenhauer, Jean P., Xia, Fan, Bi, Weimin, Kang, Sung-Hae L., Patel, Ankita, Krantz, Ian D., Raible, Sarah E., Smith, Wendy, Cristian, Ingrid, Torti, Erin, Juusola, Jane, Milian, Francisca, Wentzensen, Ingrid M., Person, Richard E., Kury, Sebastien, Bezieau, Stephane, Uguen, Kevin, Ferec, Claude, Munnich, Arnold, van Haelst, Mieke, Lichtenbelt, Klaske D., van Gassen, Koen, Hagelstrom, Tanner, Chawla, Aditi, Perry, Denise L., Taft, Ryan J., Jones, Marilyn, Masser-Frye, Diane, Dyment, David, Venkateswaran, Sunita, Li, Chumei, Escobar, Luis F., Horn, Denise, Spillmann, Rebecca C., Pena, Loren, Wierzba, Jolanta, Strom, Tim M., Parenti, Ilaria, Kaiser, Frank J., Ehmke, Nadja and Schaaf, Christian P. (2019). Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies. Genet. Med., 21 (8). S. 1797 - 1808. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1530-0366

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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 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Fountain, Michael D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oleson, David S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rech, Megan E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Segebrecht, LaraUNSPECIFIEDorcid.org/0000-0002-0939-3213UNSPECIFIED
Hunter, Jill, VUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McCarthy, John M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lupo, Philip J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holtgrewe, ManuelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moran, RocioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosenfeld, Jill A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Isidor, BertrandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Le Caignec, CedricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saenz, Margarita S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pedersen, Robert C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morgan, Thomas M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pfotenhauer, Jean P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Xia, FanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bi, WeiminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kang, Sung-Hae L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Patel, AnkitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krantz, Ian D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Raible, Sarah E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smith, WendyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cristian, IngridUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Torti, ErinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Juusola, JaneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Milian, FranciscaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wentzensen, Ingrid M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Person, Richard E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kury, SebastienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bezieau, StephaneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Uguen, KevinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ferec, ClaudeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Munnich, ArnoldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Haelst, MiekeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lichtenbelt, Klaske D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Gassen, KoenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hagelstrom, TannerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chawla, AditiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perry, Denise L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Taft, Ryan J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jones, MarilynUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Masser-Frye, DianeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dyment, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Venkateswaran, SunitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, ChumeiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Escobar, Luis F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Horn, DeniseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spillmann, Rebecca C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pena, LorenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wierzba, JolantaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Strom, Tim M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Parenti, IlariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaiser, Frank J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ehmke, NadjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaaf, Christian P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-145952
DOI: 10.1038/s41436-019-0433-1
Journal or Publication Title: Genet. Med.
Volume: 21
Number: 8
Page Range: S. 1797 - 1808
Date: 2019
Publisher: NATURE PUBLISHING GROUP
Place of Publication: NEW YORK
ISSN: 1530-0366
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PRADER-WILLI-SYNDROME; CORPUS-CALLOSUM; CHILDREN; MUTATIONS; ABNORMALITIES; HAUSP; P53Multiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/14595

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