Human Gene Module / Chromosome 16 / USP7

USP7Ubiquitin specific peptidase 7 (herpes virus-associated)

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
8 / 15
Rare Variants / Common Variants
31 / 0
Aliases
USP7, HAUSP,  TEF1
Associated Syndromes
Hao-Fountain Syndrome, ADHD, DD, ID, Hao-Fountain syndrome, Hao-Fountain syndrome, DD
Chromosome Band
16p13.2
Associated Disorders
ADHD, ASD, EPS
Relevance to Autism

De novo variants (six multigenic deletions, one nonsense variant) affecting the USP7 gene were identified in seven patients presenting with developmental delay/intellectual disability, with five of these cases having an additional diagnosis of ASD (Hao et al., 2015). Subsequent statistical analysis determined that there was a strong correlation between the seven patients having both a de novo USP7 variant and the expressed phenotype that was likely not due to chance (p<0.0001).

Molecular Function

Hydrolase that deubiquitinates target proteins such as FOXO4, p53/TP53, MDM2, ERCC6, DNMT1, UHRF1, PTEN and DAXX. Together with DAXX, prevents MDM2 self-ubiquitination and enhances the E3 ligase activity of MDM2 towards p53/TP53, thereby promoting p53/TP53 ubiquitination and proteasomal degradation. Deubiquitinates p53/TP53 and MDM2 and strongly stabilizes p53/TP53 even in the presence of excess MDM2, and also induces p53/TP53-dependent cell growth repression and apoptosis. In association with DAXX, is involved in the deubiquitination and translocation of PTEN from the nucleus to the cytoplasm. Involved in cell proliferation during early embryonic development.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome Informatics
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to USP7 (15 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Primary USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder Hao YH , et al. (2015) Yes Epilepsy/seizures
4 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
5 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
6 Support A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology Vissers LE , et al. (2017) No -
7 Recent Recommendation Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies Fountain MD , et al. (2019) No ASD, ADHD, epilepsy/seizures
8 Support - Mahjani B et al. (2021) Yes -
9 Support - Qiao H et al. (2022) Yes -
10 Support - Zhou X et al. (2022) Yes -
11 Support - Zheng H et al. (2022) No Autistic behavior
12 Support - Wang J et al. (2023) Yes -
13 Support - Khaled N Itani et al. (2023) No -
14 Support - Moritz Claudius Wimmer et al. (2024) No ASD
15 Support - Mei Sun et al. (2024) No Autistic features
Rare Variants   (31)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 26365382 Hao YH , et al. (2015)
- - copy_number_loss De novo - - 30679821 Fountain MD , et al. (2019)
c.429C>G p.Tyr143Ter stop_gained De novo - - 26365382 Hao YH , et al. (2015)
c.1041T>G p.Tyr347Ter stop_gained Unknown - - 34615535 Mahjani B et al. (2021)
c.1728T>A p.Cys576Ter stop_gained De novo - - 30679821 Fountain MD , et al. (2019)
c.2823G>T p.Leu941%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.2241T>C p.Gly747= missense_variant De novo - - 30679821 Fountain MD , et al. (2019)
c.675G>A p.Met225Ile missense_variant De novo - - 30679821 Fountain MD , et al. (2019)
c.863T>C p.Leu288Ser missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.1243A>G p.Thr415Ala missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.1258A>G p.Lys420Glu missense_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.1033G>A p.Glu345Lys missense_variant De novo - - 30679821 Fountain MD , et al. (2019)
c.1105G>A p.Gly369Ser missense_variant De novo - - 30679821 Fountain MD , et al. (2019)
c.1117C>T p.Leu373Phe missense_variant De novo - - 30679821 Fountain MD , et al. (2019)
c.1384T>G p.Cys462Gly missense_variant De novo - - 30679821 Fountain MD , et al. (2019)
c.2297T>C p.Ile766Thr missense_variant De novo - - 30679821 Fountain MD , et al. (2019)
c.835T>G p.Leu279Val missense_variant De novo - Simplex 36466803 Zheng H et al. (2022)
c.992A>G p.Tyr331Cys missense_variant De novo - Simplex 36466803 Zheng H et al. (2022)
c.3017C>T p.Pro1006Leu missense_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.3238G>A p.Asp1080Asn missense_variant De novo - - 30679821 Fountain MD , et al. (2019)
c.2697A>C p.Leu899Phe missense_variant De novo - Simplex 38229971 Mei Sun et al. (2024)
c.314G>A p.Cys105Tyr splice_site_variant De novo - - 30679821 Fountain MD , et al. (2019)
c.3174G>T p.Arg1058= splice_site_variant De novo - - 30679821 Fountain MD , et al. (2019)
c.715C>T p.Arg239Ter stop_gained Unknown - Unknown 37849578 Khaled N Itani et al. (2023)
c.1969C>G p.Pro657Ala missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2244dup p.Tyr749LeufsTer2 frameshift_variant De novo - - 28333917 Vissers LE , et al. (2017)
c.2140_2141del p.Thr714Ter frameshift_variant De novo - - 30679821 Fountain MD , et al. (2019)
c.2196dup p.Tyr733LeufsTer2 frameshift_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.1708dup p.Glu570GlyfsTer19 frameshift_variant De novo - - 30679821 Fountain MD , et al. (2019)
c.247_250del p.Glu83ArgfsTer18 frameshift_variant De novo - Simplex 36466803 Zheng H et al. (2022)
c.3305A>C p.Asn1102Thr missense_variant Familial Maternal Extended multiplex 38229971 Mei Sun et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

De novo variants (six multigenic deletions, one nonsense variant) affecting the USP7 gene were identified in seven patients presenting with developmental delay/intellectual disability, with five of these cases having an additional diagnosis of ASD (Hao et al., 2015). Subsequent statistical analysis determined that there was a strong correlation between the seven patients having both a de novo USP7 variant and the expressed phenotype that was likely not due to chance (p<0.0001). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Fountain et al., 2019 reported 16 newly identified individuals with de novo USP7 variants, obtained additional clinical information on the seven individuals previously identified in Hao et al., 2015, and found that the clinical phenotypes of these 23 individuals suggested a neurodevelopmental syndrome characterized by speech delay, developmental delay/intellectual disability, dysmorphic facial features, eye abnormalities, and behavioral problems, including ASD (9/17 cases, 53%) and ADHD (6/16 cases, 38%).

Score Delta: Score remained at 2S

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

10/1/2019
2S
icon
2S

Score remained at 2S

New Scoring Scheme
Description

De novo variants (six multigenic deletions, one nonsense variant) affecting the USP7 gene were identified in seven patients presenting with developmental delay/intellectual disability, with five of these cases having an additional diagnosis of ASD (Hao et al., 2015). Subsequent statistical analysis determined that there was a strong correlation between the seven patients having both a de novo USP7 variant and the expressed phenotype that was likely not due to chance (p<0.0001). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Fountain et al., 2019 reported 16 newly identified individuals with de novo USP7 variants, obtained additional clinical information on the seven individuals previously identified in Hao et al., 2015, and found that the clinical phenotypes of these 23 individuals suggested a neurodevelopmental syndrome characterized by speech delay, developmental delay/intellectual disability, dysmorphic facial features, eye abnormalities, and behavioral problems, including ASD (9/17 cases, 53%) and ADHD (6/16 cases, 38%).

Reports Added
[New Scoring Scheme]
1/1/2019
2
icon
2S

Score remained at 2S

Description

De novo variants (six multigenic deletions, one nonsense variant) affecting the USP7 gene were identified in seven patients presenting with developmental delay/intellectual disability, with five of these cases having an additional diagnosis of ASD (Hao et al., 2015). Subsequent statistical analysis determined that there was a strong correlation between the seven patients having both a de novo USP7 variant and the expressed phenotype that was likely not due to chance (p<0.0001). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Fountain et al., 2019 reported 16 newly identified individuals with de novo USP7 variants, obtained additional clinical information on the seven individuals previously identified in Hao et al., 2015, and found that the clinical phenotypes of these 23 individuals suggested a neurodevelopmental syndrome characterized by speech delay, developmental delay/intellectual disability, dysmorphic facial features, eye abnormalities, and behavioral problems, including ASD (9/17 cases, 53%) and ADHD (6/16 cases, 38%).

Reports Added
[Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies.2019]
4/1/2017
2
icon
2

Score remained at 2

Description

De novo variants (six multigenic deletions, one nonsense variant) affecting the USP7 gene were identified in seven patients presenting with developmental delay/intellectual disability, with five of these cases having an additional diagnosis of ASD (Hao et al., 2015). Subsequent statistical analysis determined that there was a strong correlation between the seven patients having both a de novo USP7 variant and the expressed phenotype that was likely not due to chance (p<0.0001). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology.2017]
7/1/2016
2
icon
2

Score remained at 2

Description

De novo variants (six multigenic deletions, one nonsense variant) affecting the USP7 gene were identified in seven patients presenting with developmental delay/intellectual disability, with five of these cases having an additional diagnosis of ASD (Hao et al., 2015). Subsequent statistical analysis determined that there was a strong correlation between the seven patients having both a de novo USP7 variant and the expressed phenotype that was likely not due to chance (p<0.0001). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016]
10/1/2015
icon
2

Increased from to 2

Description

De novo variants (six multigenic deletions, one nonsense variant) affecting the USP7 gene were identified in seven patients presenting with developmental delay/intellectual disability, with five of these cases having an additional diagnosis of ASD (Hao et al., 2015). Subsequent statistical analysis determined that there was a strong correlation between the seven patients having both a de novo USP7 variant and the expressed phenotype that was likely not due to chance (p<0.0001). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Krishnan Probability Score

Score 0.56845914221644

Ranking 1115/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99999999841186

Ranking 107/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Iossifov Probability Score

Score 0.933

Ranking 106/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.94240824810298

Ranking 15295/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.34919320753624

Ranking 2019/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
ACD Adrenocortical dysplasia protein homolog Human Protein Binding 65057 Q96AP0
ARHGEF6 Rho guanine nucleotide exchange factor 6 Human Protein Binding 9459 Q15052-2
ARL6IP4 ADP-ribosylation factor-like protein 6-interacting protein 4 Human Protein Binding 51329 Q66PJ3-2
C14ORF179 Intraflagellar transport protein 43 homolog Human Protein Binding 112752 Q96FT9-2
FAM170A Protein FAM170A Human Protein Binding 340069 A1A519-2
PHF7 PHD finger protein 7 Human Protein Binding 51533 Q9BWX1
POTEB POTE ankyrin domain family member B Human Protein Binding 102724631 Q6S5H4
POTEC POTE ankyrin domain family member C Human Protein Binding 388468 B2RU33-2
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