USP27X

protein-coding

ubiquitin specific peptidase 27 X-linked, the group of Ubiquitin specific peptidases

Gene summary

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. [provided by RefSeq, Dec 2016]

MANE transcript

NM_001145073.3

Inheritance

ClinVar variants

P:11U:62B:17

Top phenotype

Intellectual developmental disorder, X-linked 105

Max pathogenic AF

—

Genomic locus

chrX:49,879,484-49,882,558

External References & Databases

Ensembl (ENSG00000273820)

Transcript & Mutation Effects

hg38 • Region Span ~3.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, X-linked 105STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010510

Submitter: Labcorp Genetics (formerly Invitae)

non-syndromic X-linked intellectual disabilitySUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019181

Submitter: Orphanet

intellectual developmental disorder, X-linked 105STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010510

Submitter: G2P

X-linked complex neurodevelopmental disorderMODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0100148

Submitter: ClinGen

*USP27X* is located on chromosome Xp11.23 and encodes a deubiquitinase that is highly expressed in the brain and plays a role in cell proliferation and neural development. *USP27X* was first reported in relation to X-linked complex neurodevelopmental disorder in 2016 (Hu et al., PMID: 25644381). Clinical features in affected males include developmental delay affecting language more frequently than motor skills, intellectual disability, and behavioral disorders including autism spectrum disorder and ADHD. Some individuals may also present with additional features such as variable dysmorphic features and ophthalmologic abnormalities. Female carriers are typically unaffected but some may exhibit mild cognitive impairment. Thirteen variants (7 missense, 4 frameshift, 2 nonsense) that have been reported in 14 probands in 5 publications (PMIDs: 25644381, 31316545, 38182161, 39007861, 40596734) are included in this curation. In all cases where parental DNA was available, the variants were maternally inherited, consistent with X-linked recessive inheritance. Variants in this gene segregated with disease in 5 additional family members. *USP27X* is a single-exon gene and truncating variants are expected to escape nonsense-mediated decay and lead to the production of a truncated protein. *USP27X* is constrained for both loss-of-function (pLI = 0.92, LOEUF = 0.36, gnomAD v2.1.1) and missense variants (Z score = 3.18). The mechanism of pathogenicity is reported to be loss of function. Missense variants alter protein function via distinct mechanisms, including reduced deubiquitylating activity, impaired ubiquitin recognition, protein instability, and changes in protein-protein interaction (PMIDs: 38182161, 40596734). This gene-disease relationship is also supported by biochemical function and protein interaction. Two other genes encoding ubiquitin specific peptidases, *USP7* and *USP9X*, are also involved in neurodevelopmental disorders. USP27X binds to a complex containing ATXN7L3 to catalyze histone H2B deubiquitylation; *ATXN7L3* is implicated in a neurodevelopmental disorder with syndromic features. In summary, there is moderate evidence to support the relationship between *USP27X* and X-linked complex neurodevelopmental disorder. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 1, 2023. It was reevaluated on August 26, 2026 (SOP Version 12). As a result of this reevaluation, the classification increased from Limited to Moderate with the addition of new patients and functional evidence (PMIDs: 38182161, 39007861, 40596734).

intellectual developmental disorder, X-linked 105STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010510

Submitter: PanelApp Australia

intellectual developmental disorder, X-linked 105STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010510

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked 105XL

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 25644381

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to USP27X variants in ClinVar

8 Conditions Cataloged

not providedTotal: 46

Intellectual disability, X-linked 105Total: 22

Inborn genetic diseasesTotal: 22

not specifiedTotal: 8

USP27X-related disorderTotal: 3

Neurodevelopmental disorderTotal: 1

Paediatric disordersTotal: 1

Intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001145073.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				12 clinvar	2 clinvar	14
missense	1 clinvar	1 clinvar	60 clinvar	2 clinvar	1 clinvar	65
nonsense		3 clinvar	1 clinvar			4
start loss						0
frameshift	2 clinvar	4 clinvar	1 clinvar			7
splice donor/acceptor (+/-2bp)						0
Total	3	8	62	14	3	90

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001145073.3	RefSeq	NP_001138545.1	1	MANE Select
ENST00000621775.2	Ensembl	ENSP00000483631.1	1	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

ubiquitin-dependent protein catabolic process
protein deubiquitination
positive regulation of apoptotic process
protein stabilization
protein K63-linked deubiquitination

Molecular Function

thiol-dependent ubiquitin-specific protease activity
Lys63-specific deubiquitinase activity
Lys48-specific deubiquitinase activity

Cellular Component

nucleus
cytosol

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Deubiquitinase that can reduce the levels of BCL2L11/BIM ubiquitination and stabilize BCL2L11 in response to the RAF-MAPK- degradation signal. By acting on BCL2L11 levels, may counteract the anti-apoptotic effects of MAPK activity. {ECO:0000250|UniProtKB:Q8CEG8}.;
Disease: DISEASE: Mental retardation, X-linked 105 (MRX105) [MIM:300984]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations. {ECO:0000269|PubMed:25644381}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.110

Essentials

Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.539

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium