USP9X

protein-coding

ubiquitin specific peptidase 9 X-linked, the group of Ubiquitin specific peptidases|Armadillo like helical domain containing

Gene summary

This gene is a member of the peptidase C19 family and encodes a protein that is similar to ubiquitin-specific proteases. Though this gene is located on the X chromosome, it escapes X-inactivation. Mutations in this gene have been associated with Turner syndrome. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001039591.3

Inheritance

ClinVar variants

P:139U:1008B:241

Top phenotype

Intellectual developmental disorder, X-linked 99; Intellectual developmental disorder, X-linked 99, syndromic, female restricted

gnomAD constraint

pLI —, LoF o/e 0.01

Max pathogenic AF

—

Genomic locus

chrX:41,085,445-41,236,579

External References & Databases

Ensembl (ENSG00000124486)

Transcript & Mutation Effects

hg38 • Region Span ~151.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, X-linked 99, syndromic, female-restrictedDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010502

Submitter: G2P

intellectual developmental disorder, X-linked 99STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010487

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, X-linked 99, syndromic, female-restrictedSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010502

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, X-linked 99, syndromic, female-restrictedSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010502

Submitter: Genomics England PanelApp

X-linked syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0020119

Submitter: ClinGen

*USP9X* encodes a ubiquitin specific peptidase that removes ubiquitin marks from target proteins. The gene is located on chromosome X, but it escapes X-chromosome inactivation. Therefore, pathogenic variants in *USP9X* have been associated with X-linked syndromic intellectual disability in both females and males. *USP9X* was first reported in relation to X-linked recessive syndromic intellectual disability in 2009 when Tarpey et al. (PMID: 19377476) identified a family with 3 affected males with a frameshift variant in *USP9X*. In 2017, Reijnders et al. (PMID: 26833328) reported 17 females with a shared phenotype of developmental delay/intellectual disability, characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities. The majority of these females (n=13) had *de novo* truncating variants in *USP9X*, while the remaining had intragenic deletions in *USP9X* identified through microarray analyses. To date, more than 40 patients, males and females, have been reported in the literature with truncating or predicted deleterious missense variants in *USP9X* (PMIDs: 19377476, 24607389, 26833328, 28377321, 31443933, 33298948). The *USP9X* variants in females are predominantly null alleles leading to haploinsufficiency and causing a recognizable syndrome with intellectual disability and characteristic brain and congenital abnormalities (PMID: 26833328). In contrast, the majority of the reported variants in males are missense variants with partial loss of function, resulting in a distinctive neurodevelopmental and behavioral syndrome (PMID: 31443933). Complete loss of USP9X function in males is likely to be embryonic lethal. *USP9X* is a highly constrained gene with few truncating and missense variants reported in public databases. This gene-disease relationship is also supported by functional *in vivo* and *in vitro* studies showing that loss of *Usp9x* results in neuronal abnormalities. Brain-specific conditional deletion of *Usp9x* in mice results in early postnatal lethality with disrupted cellular organization of the neocortex and reduced corpus callosum and hippocampal size (PMID: 23861879). Additionally, loss of *Usp9x* in neurons results in reduced axonal length and arborization, as well as decreased neuronal migration (PMID: 23861879, 24607389). The mechanism of pathogenicity is loss of function, as indicated by functional studies in patient cells (PMIDs: 26833328, 31443933). In summary, there is definitive evidence supporting the relationship between *USP9X* and X-linked syndromic intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 17, 2021 (SOP Version 8).

intellectual developmental disorder, X-linked 99, syndromic, female-restrictedSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010502

Submitter: PanelApp Australia

intellectual developmental disorder, X-linked 99STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010487

Submitter: PanelApp Australia

X-linked female restricted facial dysmorphism-short stature-choanal atresia-intellectual disabilitySUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0018821

Submitter: Orphanet

non-syndromic X-linked intellectual disabilitySUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019181

Submitter: Orphanet

intellectual developmental disorder, X-linked 99STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010487

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked 99; Intellectual developmental disorder, X-linked 99, syndromic, female restrictedXL

Manifestation: Cardiovascular; Craniofacial; Dermatologic; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic

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: 19377476; 24607389; 26833328

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to USP9X variants in ClinVar

22 Conditions Cataloged

not providedTotal: 925

Inborn genetic diseasesTotal: 121

Intellectual disability, X-linked 99Total: 91

Intellectual disability, X-linked 99, syndromic, female-restrictedTotal: 89

USP9X-related disorderTotal: 65

not specifiedTotal: 64

Intellectual disabilityTotal: 10

See casesTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001039591.3. 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		1 clinvar	88 clinvar	164 clinvar	22 clinvar	275
missense	5 clinvar	32 clinvar	809 clinvar	47 clinvar	8 clinvar	901
nonsense	27 clinvar	8 clinvar	33 clinvar			68
start loss						0
frameshift	39 clinvar	16 clinvar	3 clinvar			58
splice donor/acceptor (+/-2bp)	4 clinvar	7 clinvar	75 clinvar			86
Total	75	64	1008	211	30	1388

Highest pathogenic variant AF is 0.0000027338888

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 32 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001039591.3	RefSeq	NP_001034680.2	44	MANE Select
ENST00000378308.7	Ensembl	ENSP00000367558.2	44	MANE Select
NM_001039590.3	RefSeq	NP_001034679.2	44	Standard
NM_001410748.1	RefSeq	NP_001397677.1	44	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Signal Transduction
Gene expression (Transcription)
Generic Transcription Pathway
Post-translational protein modification
Metabolism of proteins

Biological Process

negative regulation of transcription by RNA polymerase II
neuron migration
protein targeting to peroxisome
cell cycle
chromosome segregation

Molecular Function

cysteine-type endopeptidase activity
thiol-dependent ubiquitin-specific protease activity
protein binding
cysteine-type peptidase activity
thiol-dependent ubiquitinyl hydrolase activity

Cellular Component

cytoplasm
cytosol
membrane
growth cone

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000324545
Coding exons: 44
Length: 150945
Individuals with no LoFs: 125270
Homozygous LoFs: 4
Heterozygous LoFs: 10
Defined: 125284
p: 0.0000559

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	6.41	378	927	0.408	0.0000697	17036
Missense (PolyPhen)		118	434.43	0.27162		8322
Synonymous	0.407	311	320	0.971	0.0000237	4760
Loss of Function	8.86	1	93.5	0.0107	0.00000746	1619

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000084	0.000062	rare
Latino/Admixed American	0.00011	0.000087	rare
Ashkenazi Jewish	0.00014	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.000063	0.000046	rare
European (Non-Finnish)	0.000099	0.000071	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Deubiquitinase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins. May therefore play an important regulatory role at the level of protein turnover by preventing degradation of proteins through the removal of conjugated ubiquitin. Specifically hydrolyzes 'Lys-48'-, 'Lys- 29'- and 'Lys-33'-linked polyubiquitins chains. Essential component of TGF-beta/BMP signaling cascade. Specifically deubiquitinates monoubiquitinated SMAD4, opposing the activity of E3 ubiquitin-protein ligase TRIM33. Deubiquitinates alkylation repair enzyme ALKBH3. OTUD4 recruits USP7 and USP9X to stabilize ALKBH3, thereby promoting the repair of alkylated DNA lesions (PubMed:25944111). Regulates chromosome alignment and segregation in mitosis by regulating the localization of BIRC5/survivin to mitotic centromeres. Involved in axonal growth and neuronal cell migration (PubMed:16322459, PubMed:18254724, PubMed:19135894, PubMed:24607389). {ECO:0000269|PubMed:16322459, ECO:0000269|PubMed:18254724, ECO:0000269|PubMed:19135894, ECO:0000269|PubMed:24607389, ECO:0000269|PubMed:25944111}.;

Recessive Scores

pRec: 0.103

Intolerance Scores

RVIS EVS: -1.62
RVIS percentile EVS: 2.93

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.702

Gene Damage Prediction

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