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

Michael D. Fountain, David S. Oleson, Megan E. Rech, Lara Segebrecht, Jill V. Hunter, John M. McCarthy, Philip J. Lupo, Manuel Holtgrewe, Rocio Moran, Jill A. Rosenfeld, Bertrand Isidor, C. dric le Caignec, Margarita S. Saenz, Robert C. Pedersen, Thomas M. Morgan, Jean P. Pfotenhauer, Fan Xia, Weimin Bi, Sung-Hae L. Kang, Ankita Patel & 36 others Ian D. Krantz, Sarah E. Raible, Wendy Smith, Ingrid Cristian, Erin Torti, Jane Juusola, Francisca Millan, Ingrid M. Wentzensen, Richard E. Person, S. bastien Küry, Stéphane Bézieau, K. vin Uguen, Claude Férec, Arnold Munnich, Mieke van Haelst, Klaske D. Lichtenbelt, Koen van Gassen, Tanner Hagelstrom, Aditi Chawla, Denise L. Perry, Ryan J. Taft, Marilyn Jones, Diane Masser-Frye, David Dyment, Sunita Venkateswaran, Chumei Li, Luis F. Escobar, Denise Horn, Rebecca C. Spillmann, Loren Peña, Jolanta Wierzba, Tim M. Strom, Ilaria Parenti, Frank J. Kaiser, Nadja Ehmke, Christian P. Schaaf

Research output: Contribution to journalArticleAcademicpeer-review

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. 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.
Original languageEnglish
JournalGenetics in Medicine
DOIs
Publication statusE-pub ahead of print - 2019

Cite this

Fountain, Michael D. ; Oleson, David S. ; Rech, Megan E. ; Segebrecht, Lara ; Hunter, Jill V. ; McCarthy, John M. ; Lupo, Philip J. ; Holtgrewe, Manuel ; Moran, Rocio ; Rosenfeld, Jill A. ; Isidor, Bertrand ; le Caignec, C. dric ; 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 ; Millan, Francisca ; Wentzensen, Ingrid M. ; Person, Richard E. ; Küry, S. bastien ; Bézieau, Stéphane ; Uguen, K. vin ; Férec, 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. ; Peña, Loren ; Wierzba, Jolanta ; Strom, Tim M. ; Parenti, Ilaria ; Kaiser, Frank J. ; Ehmke, Nadja ; Schaaf, Christian P. / Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies. In: Genetics in Medicine. 2019.
@article{c4760739e7204b208dd180b90cf6cf68,
title = "Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies",
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. 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.",
author = "Fountain, {Michael D.} and Oleson, {David S.} and Rech, {Megan E.} and Lara Segebrecht and Hunter, {Jill V.} and McCarthy, {John M.} and Lupo, {Philip J.} and Manuel Holtgrewe and Rocio Moran and Rosenfeld, {Jill A.} and Bertrand Isidor and {le Caignec}, {C. dric} and Saenz, {Margarita S.} and Pedersen, {Robert C.} and Morgan, {Thomas M.} and Pfotenhauer, {Jean P.} and Fan Xia and Weimin Bi and Kang, {Sung-Hae L.} and Ankita Patel and Krantz, {Ian D.} and Raible, {Sarah E.} and Wendy Smith and Ingrid Cristian and Erin Torti and Jane Juusola and Francisca Millan and Wentzensen, {Ingrid M.} and Person, {Richard E.} and K{\"u}ry, {S. bastien} and St{\'e}phane B{\'e}zieau and Uguen, {K. vin} and Claude F{\'e}rec and Arnold Munnich and {van Haelst}, Mieke and Lichtenbelt, {Klaske D.} and {van Gassen}, Koen and Tanner Hagelstrom and Aditi Chawla and Perry, {Denise L.} and Taft, {Ryan J.} and Marilyn Jones and Diane Masser-Frye and David Dyment and Sunita Venkateswaran and Chumei Li and Escobar, {Luis F.} and Denise Horn and Spillmann, {Rebecca C.} and Loren Pe{\~n}a and Jolanta Wierzba and Strom, {Tim M.} and Ilaria Parenti and Kaiser, {Frank J.} and Nadja Ehmke and Schaaf, {Christian P.}",
year = "2019",
doi = "10.1038/s41436-019-0433-1",
language = "English",
journal = "Genetics in Medicine",
issn = "1098-3600",
publisher = "Lippincott Williams and Wilkins",

}

Fountain, MD, Oleson, DS, Rech, ME, Segebrecht, L, Hunter, JV, McCarthy, JM, Lupo, PJ, Holtgrewe, M, Moran, R, Rosenfeld, JA, Isidor, B, le Caignec, CD, Saenz, MS, Pedersen, RC, Morgan, TM, Pfotenhauer, JP, Xia, F, Bi, W, Kang, S-HL, Patel, A, Krantz, ID, Raible, SE, Smith, W, Cristian, I, Torti, E, Juusola, J, Millan, F, Wentzensen, IM, Person, RE, Küry, SB, Bézieau, S, Uguen, KV, Férec, C, Munnich, A, van Haelst, M, Lichtenbelt, KD, van Gassen, K, Hagelstrom, T, Chawla, A, Perry, DL, Taft, RJ, Jones, M, Masser-Frye, D, Dyment, D, Venkateswaran, S, Li, C, Escobar, LF, Horn, D, Spillmann, RC, Peña, L, Wierzba, J, Strom, TM, Parenti, I, Kaiser, FJ, Ehmke, N & Schaaf, CP 2019, 'Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies' Genetics in Medicine. https://doi.org/10.1038/s41436-019-0433-1

Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies. / Fountain, Michael D.; Oleson, David S.; Rech, Megan E.; Segebrecht, Lara; Hunter, Jill V.; McCarthy, John M.; Lupo, Philip J.; Holtgrewe, Manuel; Moran, Rocio; Rosenfeld, Jill A.; Isidor, Bertrand; le Caignec, C. dric; 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; Millan, Francisca; Wentzensen, Ingrid M.; Person, Richard E.; Küry, S. bastien; Bézieau, Stéphane; Uguen, K. vin; Férec, 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.; Peña, Loren; Wierzba, Jolanta; Strom, Tim M.; Parenti, Ilaria; Kaiser, Frank J.; Ehmke, Nadja; Schaaf, Christian P.

In: Genetics in Medicine, 2019.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies

AU - Fountain, Michael D.

AU - Oleson, David S.

AU - Rech, Megan E.

AU - Segebrecht, Lara

AU - Hunter, Jill V.

AU - McCarthy, John M.

AU - Lupo, Philip J.

AU - Holtgrewe, Manuel

AU - Moran, Rocio

AU - Rosenfeld, Jill A.

AU - Isidor, Bertrand

AU - le Caignec, C. dric

AU - Saenz, Margarita S.

AU - Pedersen, Robert C.

AU - Morgan, Thomas M.

AU - Pfotenhauer, Jean P.

AU - Xia, Fan

AU - Bi, Weimin

AU - Kang, Sung-Hae L.

AU - Patel, Ankita

AU - Krantz, Ian D.

AU - Raible, Sarah E.

AU - Smith, Wendy

AU - Cristian, Ingrid

AU - Torti, Erin

AU - Juusola, Jane

AU - Millan, Francisca

AU - Wentzensen, Ingrid M.

AU - Person, Richard E.

AU - Küry, S. bastien

AU - Bézieau, Stéphane

AU - Uguen, K. vin

AU - Férec, Claude

AU - Munnich, Arnold

AU - van Haelst, Mieke

AU - Lichtenbelt, Klaske D.

AU - van Gassen, Koen

AU - Hagelstrom, Tanner

AU - Chawla, Aditi

AU - Perry, Denise L.

AU - Taft, Ryan J.

AU - Jones, Marilyn

AU - Masser-Frye, Diane

AU - Dyment, David

AU - Venkateswaran, Sunita

AU - Li, Chumei

AU - Escobar, Luis F.

AU - Horn, Denise

AU - Spillmann, Rebecca C.

AU - Peña, Loren

AU - Wierzba, Jolanta

AU - Strom, Tim M.

AU - Parenti, Ilaria

AU - Kaiser, Frank J.

AU - Ehmke, Nadja

AU - Schaaf, Christian P.

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/30679821

U2 - 10.1038/s41436-019-0433-1

DO - 10.1038/s41436-019-0433-1

M3 - Article

JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

ER -