Human Gene Module / Chromosome X / USP27X

USP27Xubiquitin specific peptidase 27 X-linked

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
4 / 6
Rare Variants / Common Variants
15 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
Xp11.23
Associated Disorders
-
Relevance to Autism

Koch et al., 2024 reported 10 affected males from 9 unrelated families carrying variants in the USP27X gene and presenting with an X-linked neurodevelopmental disorder characterized by intellectual disability and/or speech delay, motor delay, autism spectrum disorder, and ADHD; functional characterization of disease-associated missense variants in this gene demonstrated effects on developmentally-relevant protein-protein interactions and/or deubiquitylating activity. Maternally-inherited variants in this gene had previously been identified in affected males from two unrelated families presenting with borderline to moderate intellectual disability, variable absent or poor speech and behavioral problems (Hu et al., 2016). Rare variants in the USP27X gene, including a de novo loss-of-function variant, have also been identified in ASD probands (Satterstrom et al., 2020; Hu et al., 2022; Zhou et al., 2022; Wang et al., 2023).

Molecular Function

This gene encodes a member of the peptidase protein family. The encoded protein functions as a deubiquitinase that is involved in upregulation of the pro-apoptotic Bim protein. This protein may act as a tumor suppressor by increasing levels of Bim to counteract anti-apoptotic signals in cancer cells. Mutations in this gene have been associated with X-linked cognitive disability.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to USP27X (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes Hu H et al. (2016) No -
2 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
3 Support - Hu C et al. (2022) Yes -
4 Support - Zhou X et al. (2022) Yes -
5 Support - Wang J et al. (2023) Yes -
6 Primary - Intisar Koch et al. (2024) No ASD, ADHD
Rare Variants   (15)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.905T>C p.Leu302Ser missense_variant Unknown - - 35741772 Hu C et al. (2022)
c.75A>G p.Leu25= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.106C>T p.Gln36Ter stop_gained Unknown - Simplex 38182161 Intisar Koch et al. (2024)
G>GCCCCCCCCCCCCCCC - 2KB_upstream_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.431A>G p.Tyr144Cys missense_variant Familial Maternal - 38182161 Intisar Koch et al. (2024)
c.1211G>A p.Ser404Asn missense_variant Familial Maternal - 38182161 Intisar Koch et al. (2024)
c.1141T>C p.Tyr381His missense_variant Familial Maternal Multiplex 25644381 Hu H et al. (2016)
c.394G>T p.Glu132Ter stop_gained Unknown - Extended multiplex 38182161 Intisar Koch et al. (2024)
c.1171_1172del p.Gln391ValfsTer5 frameshift_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.226G>A p.Gly76Ser missense_variant Familial Maternal Simplex 38182161 Intisar Koch et al. (2024)
c.541A>G p.Lys181Glu missense_variant Familial Maternal Simplex 38182161 Intisar Koch et al. (2024)
c.937T>G p.Phe313Val missense_variant Familial Maternal Simplex 38182161 Intisar Koch et al. (2024)
c.1211G>A p.Ser404Asn missense_variant Familial Maternal Simplex 38182161 Intisar Koch et al. (2024)
c.1205dup p.Ala403GlyfsTer4 frameshift_variant Familial Maternal Simplex 38182161 Intisar Koch et al. (2024)
c.1026_1030del p.Ser342ArgfsTer14 frameshift_variant Familial Maternal Extended multiplex 25644381 Hu H et al. (2016)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

4/1/2024
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.48704026954266

Ranking 7071/25841 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 0.59278499949072

Ranking 5028/18225 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
Sanders TADA Score

Score 0.92393054208332

Ranking 9881/18665 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 0.4086496698952

Ranking 1363/20870 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
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