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Intellectual disability

Gene: USP7

Amber List (moderate evidence)

USP7 (ubiquitin specific peptidase 7)
EnsemblGeneIds (GRCh38): ENSG00000187555
EnsemblGeneIds (GRCh37): ENSG00000187555
OMIM: 602519, Gene2Phenotype
USP7 is in 4 panels

3 reviews

Zornitza Stark (Australian Genomics)

Green List (high evidence)

The number of individuals with de novo variants in this gene is large, even if those with microdeletions +/- ?second diagnostic findings are completely discounted. I am not sure who has assessed the Tyr143Ter variant as a VOUS and what their reasoning was: it is de novo and absent from gnomad, and easily meets criteria for pathogenicity if gene-disease association is considered established. I also note the almost complete absence of LoF variants in this gene in gnomad.
Created: 2 Mar 2020, 5:20 a.m. | Last Modified: 2 Mar 2020, 5:20 a.m.
Panel Version: 3.3

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
ID; Autism

Publications

Variants in this GENE are reported as part of current diagnostic practice

Rebecca Foulger (Genomics England curator)

Comment on list classification: USP7 was rated Green by Konstantinos Varvagiannis. Not currently associated with a disorder in OMIM, but has a 'possible' Disease confidence in Gene2Phenotype for the disorder: Intellectual disability, autism, epilepsy, aggressive behaviour, hypotonia, and hypogonadism (based on PMID:26365382). There is now a 2019 paper in addition to PMID:26365382 (PMID:30679821). In total, 22/23 individuals have an ID/DD phenotype, and 23/23 have speech delay. However, the Tyr143Ter variant described by both PMID:26365382 and PMID:30679821 is a VUS, and the microdeletions in other patients cover additional genes (PMID:26365382, Figure 5). Plus three patients in PMID:30679821 harbour variants in additional genes. Therefore although the phenotype is relevant, I have updated the rating from Red to Amber until there is more evidence that USP7 variants are causative.
Created: 2 Jul 2019, 2:26 p.m. | Last Modified: 2 Jul 2019, 2:26 p.m.
Panel Version: 2.935
PMID:30679821: Fountain et al., 2019 report on the clinical and genetic spectrum of 16 new and 7 previously reported (by PMID:26365382) individuals with USP7 heterozygous de novo variants.
The variants include 2 deletions, 3 nonsense, 3 splice site variants and 8 missense variants. Speech delay was seen in 23/23 patients, and ID/DD was seen in 22/23 patients. Note that Patients 18 and 20 harbor additional variants in TMEM106B and SLC2A1, Patient 19 also has a de novo heterozygous 102.5-kb mosaic loss of uncertain significance at 10q21.1.
Created: 2 Jul 2019, 2:21 p.m. | Last Modified: 2 Jul 2019, 2:21 p.m.
Panel Version: 2.933
PMID:26365382: Hao et al., 2015 queried clinical databases to identify 6 cases with de novo heterozygous chromosomal microdeletions (varying from 267kb - 4.74Mb), and one case with a heterozygous nonsense variant in USP7. DD/ID was seen in 7/7 patients. Note that the Tyr143Ter variant described is listed as a VUS in OMIM.
Created: 2 Jul 2019, 2:21 p.m. | Last Modified: 2 Jul 2019, 2:21 p.m.
Panel Version: 2.933

Konstantinos Varvagiannis (Other)

Green List (high evidence)

This gene was previously included in the current panel, rated red, though with no reviews (Source : Victorian Clinical Genetics Services).
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Fountain et al. (2019 - doi.org/10.1038/s41436-019-0433-1 - PMID: NA) report on 23 individuals, all of whom harbored pathogenic de novo variants affecting USP7.

Variants included 8 deletions spanning USP7 (and other proximal genes - the gene is located at 16p13.2), 4 nonsense, 8 missense and 3 splice site mutations.

Haploinsufficiency appears to be the underlying mechanism (as suggested by the type of variants reported).

The common phenotype consisted of DD/ID (almost universal feature - 22/23) with prominent speech delay (23/23). Other features included seizures (10/22 - seen in all categories of USP7 variants), variable behavioral anomalies (incl. aggressive behavior, temper tantrums, ASD, ADHD), brain MRI abnormalities, as well as hypogonadism in some.

7 of these (23) individuals (6 with deletions, 1 with nonsense variant) were previously reported by the same group (2015 - Hao et al. - PMID: 26365382). In this study, the authors provided evidence that USP7 encodes a deubiquitinating enzyme, component of the MAGEL2/TRIM27 ubiquitin ligase complex. USP7 is involved in fine-tuning of the WASH activity - a protein involved in endosomal actin assembly and protein recycling - by promoting or limiting WASH ubiquitination (the former achieved by preventing TRIM27 autoubiquitination and degradation and the latter by direct WASH deubiquitination).

Overlap to some extent of the USP7-related phenotype with Schaaf-Yang syndrome (due to MAGEL2 mutations - MIM615547) is suggested.

In mice, Usp7 (or Hausp - herpesvirus-associated ubiquitin-specific protease) conditional knockout in brain results in neonatal lethality (PMID cited: 19946331).
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USP7 is not associated with any phenotype in OMIM.
This gene is part of the DD panel of G2P, associated with "Intellectual disability, autism, epilepsy, aggressive behaviour, hypotonia, and hypogonadism" (Disease confidence: possible).
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USP7 is included in gene panels for ID offered by diagnostic laboratories (incl. also Radboudumc).
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As a result, this gene can be considered for upgrade to green.
Created: 26 Jan 2019, 11:18 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Global developmental delay; Delayed speech and language development; Intellectual disability; Behavioral abnormality; Seizures; Abnormality of brain morphology; Hypogonadism

Publications

Variants in this GENE are reported as part of current diagnostic practice

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
Phenotypes
  • Intellectual disability, autism, epilepsy, aggressive behaviour, hypotonia, and hypogonadism
OMIM
602519
Clinvar variants
Variants in USP7
Penetrance
None
Publications
Panels with this gene

History Filter Activity

2 Jul 2019, Gel status: 2

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: USP7 were changed from to Intellectual disability, autism, epilepsy, aggressive behaviour, hypotonia, and hypogonadism

2 Jul 2019, Gel status: 2

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: usp7 has been classified as Amber List (Moderate Evidence).

2 Jul 2019, Gel status: 1

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: usp7 has been classified as Red List (Low Evidence).

2 Jul 2019, Gel status: 1

Set mode of inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for gene: USP7 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

10 Jun 2019, Gel status: 1

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: USP7 were set to

29 Sep 2018, Gel status: 1

Created, Added New Source, Set mode of inheritance

Louise Daugherty (Genomics England Curator)

gene: USP7 was added gene: USP7 was added to Intellectual disability. Sources: Victorian Clinical Genetics Services Mode of inheritance for gene: USP7 was set to