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

Abstract

PurposeHaploinsufficiency 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.MethodsWe 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.ResultsThe 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.ConclusionThe 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.

USP7 Is a Master Regulator of Genome Stability

“…This includes its significant role in genome stability, where USP7 regulates the well-characterized p53/Mdm2 signaling axis ( Li et al, 2004 ), along with many other factors that will be addressed in detail in this review. USP7 is an essential enzyme; its homozygous knockout in mice results is early embryonic lethality ( Kon et al, 2010 ) and no human individuals have been identified who are USP7 homozygous-null ( Fountain et al, 2019 ). Heterozygous loss-of-function USP7 mutations have, however, been identified in 23 individuals, all of whom have experienced neurodevelopmental disorders – characterized by developmental delay/intellectual disability (DD/ID), speech delay, behavioral anomalies and autism spectrum disorder – as well as physical characteristics that include dysmorphic facial features ( Hao et al, 2015 ; Fountain et al, 2019 ).…”

“…USP7 is an essential enzyme; its homozygous knockout in mice results is early embryonic lethality ( Kon et al, 2010 ) and no human individuals have been identified who are USP7 homozygous-null ( Fountain et al, 2019 ). Heterozygous loss-of-function USP7 mutations have, however, been identified in 23 individuals, all of whom have experienced neurodevelopmental disorders – characterized by developmental delay/intellectual disability (DD/ID), speech delay, behavioral anomalies and autism spectrum disorder – as well as physical characteristics that include dysmorphic facial features ( Hao et al, 2015 ; Fountain et al, 2019 ). While diseases caused by pathogenic somatic mutations of USP7 are rare, the aberrant expression of USP7 is much more frequent, resulting in deregulation of numerous pathways and contributing to disease states that include non-small cell lung cancer ( Masuya et al, 2006 ) and prostate cancer ( Song et al, 2008a ).…”

Early Detection and Management of Prader-Willi Syndrome in Egyptian Patients

“…Partial ankyloglossia and median grooved tongue could be congenital defects linked to breast feeding difficulties of those patients. [22][23][24] All studied PWS patients had infantile hypotonia and at least two PWS facial features during neonatal and early childhood period, while sixteen patients (94.1%) had feeding difficulties. At the time of examination all studied patients presented with hypotonia.…”

DUBs Activating the Hedgehog Signaling Pathway: A Promising Therapeutic Target in Cancer

“…Usp7 localizes in both cytoplasm and nucleus and counteracts respectively SCF Slimb and Hib-Cul3-mediated Ci degradation ( Figure 5A) [106]. In mouse Usp7 knockout is lethal [103,104], while in human its mutations and deletions have been recently identified in children suffering from neurodevelopmental disorders [105]. ligases Similarly, USP7 binds all GLI factors in mammals, and these interactions are favored by HH and hindered by SUFU [106].…”

“…In mouse Usp7 knockout is lethal [103,104], while in human its mutations and deletions have been recently identified in children suffering from neurodevelopmental disorders [105]. ligases function to maintain the HH pathway activity [106].…”