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Genetic epilepsy syndromes

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

4 reviews

Helen Lord (Oxford Medical Genetics Laboratories)

I don't know

Chr 16p13.2 deletion syndrome - Hao et al 2015 (26365382) - 6 unrelated children with variable neurodev disorders associated with de novo het microdeletions of 16p13.2 (not recurrent) and 1 patient with a de novo het truncating variant in the USP7 gene - Y143* (MIM616863) 5/7 patients had seizures including the indivdiual with the Y143* variant. Fountain et al, 2019 - 16 newly identified individuals with het de novo USP7 variants also include clinical manifestations of all 23 individuals reported with USP7 variants. In total found 7 deletions, 4 nonsense, 8 missense and 3 splice site. Seizures detected in 10/22 cases (45%) across all types. We woudln't detect the large deletions by WES - which do encompass other genes as well as this one.
Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.
Panel Version: 1.261

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

Alison Callaway (Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust)

I don't know

No phenotype association on OMIM, no obvious epilepsy phenotype on HGMDPro
Created: 23 Aug 2019, 10:24 a.m. | Last Modified: 23 Aug 2019, 10:24 a.m.
Panel Version: 1.256

Rebecca Foulger (Genomics England curator)

I don't know

Kept rating as Amber based on two post-Webex Amber reviews from Helen Lord and Alison Callaway.
Created: 9 Sep 2019, 9:49 a.m. | Last Modified: 9 Sep 2019, 9:49 a.m.
Panel Version: 1.307
Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.
Panel Version: 1.262
Comment on list classification: USP7 was added to the panel and 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, nearly half (10/22) individuals have a seizure phenotype. 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. Rated Amber until there is more evidence that USP7 variants are causative for the seizure phenotype.
Created: 2 Jul 2019, 2:21 p.m. | Last Modified: 2 Jul 2019, 2:21 p.m.
Panel Version: 1.101
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. Seizures are recorded in 10/22 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, 2:19 p.m. | Last Modified: 2 Jul 2019, 2:19 p.m.
Panel Version: 1.100
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. 5/7 individuals had epilepsy, including the female with the Y143X variant. Note that the Tyr143Ter variant described is listed as a VUS in OMIM.
Created: 2 Jul 2019, 2:19 p.m. | Last Modified: 2 Jul 2019, 2:19 p.m.
Panel Version: 1.100

Konstantinos Varvagiannis (Other)

Green List (high evidence)

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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As a result, this gene can be considered for inlusion in this panel as green (or amber).
Sources: Literature
Created: 26 Jan 2019, 11:22 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

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Wessex and West Midlands GLH
  • NHS GMS
  • Expert Review Amber
Phenotypes
  • Intellectual disability, autism, epilepsy, aggressive behaviour, hypotonia, and hypogonadism
OMIM
602519
Clinvar variants
Variants in USP7
Penetrance
unknown
Publications
Panels with this gene

History Filter Activity

17 Sep 2019, Gel status: 2

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to USP7.

17 Sep 2019, Gel status: 2

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to USP7.

9 Sep 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: 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: 0

Set Phenotypes

Rebecca Foulger (Genomics England curator)

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

2 Jul 2019, Gel status: 0

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: USP7 were changed from Global developmental delay; Delayed speech and language development; Intellectual disability; Behavioral abnormality; Seizures; Abnormality of brain morphology; Hypogonadism to Intellectual disability, autism, epilepsy, aggressive behaviour, hypotonia, and hypogonadism

26 Jan 2019, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: USP7 was added gene: USP7 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: USP7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: USP7 were set to 26365382; 19946331 Phenotypes for gene: USP7 were set to Global developmental delay; Delayed speech and language development; Intellectual disability; Behavioral abnormality; Seizures; Abnormality of brain morphology; Hypogonadism Penetrance for gene: USP7 were set to unknown Review for gene: USP7 was set to GREEN