intellectual disability, X-linked 99, syndromic, female-restricted

Summary

intellectual disability, X-linked 99, syndromic, female-restricted (MONDO:0010502) is a disease caused by USP9X (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: USP9X (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 82

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, X-linked 99, syndromic, female-restricted
Mondo ID	MONDO:0010502
OMIM	300968
DOID	DOID:0112025
UMLS	C4225416
MedGen	899839
GARD	0024732
Is cancer (heuristic)	no

Also known as: intellectual developmental disorder, X-linked 99, syndromic, female-restricted, X-linked dominant · intellectual disability, X-linked 99, syndromic, female-restricted · mental retardation, X-linked 99, syndromic, female-restricted · MRXS99F · USP9X X-linked syndromic intellectual disability · X-linked syndromic intellectual disability caused by mutation in USP9X

Data availability: 82 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › syndromic intellectual disability › X-linked syndromic intellectual disability › intellectual disability, X-linked 99, syndromic, female-restricted

Related subtypes (80): X-linked intellectual disability-psychosis-macroorchidism syndrome, X-linked intellectual disability-plagiocephaly syndrome, intellectual disability, X-linked 49, MEHMO syndrome, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability, Stocco dos Santos type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome, X-linked intellectual disability-cerebellar hypoplasia syndrome, Allan-Herndon-Dudley syndrome, syndromic X-linked intellectual disability Claes-Jensen type, X-linked intellectual disability-retinitis pigmentosa syndrome, syndromic X-linked intellectual disability 14, syndromic X-linked intellectual disability 94, intellectual disability, X-linked syndromic, Turner type, syndromic X-linked intellectual disability Shrimpton type, X-linked intellectual disability-craniofacioskeletal syndrome, syndromic X-linked intellectual disability Raymond type, syndromic X-linked intellectual disability 17, syndromic X-linked intellectual disability Nascimento type, syndromic X-linked intellectual disability Chudley-Schwartz type, X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome, X-linked intellectual disability, Cantagrel type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, intellectual disability, X-linked, syndromic, Bain type, Borjeson-Forssman-Lehmann syndrome, Coffin-Lowry syndrome, syndromic X-linked intellectual disability 5, X-linked intellectual disability-seizures-psoriasis syndrome, Renpenning syndrome, Partington syndrome, syndromic X-linked intellectual disability 12, severe X-linked intellectual disability, Gustavson type, syndromic X-linked intellectual disability Snyder type, Wilson-Turner syndrome, Prieto syndrome, skeletal dysplasia-intellectual disability syndrome, X-linked intellectual disability-spastic quadriparesis syndrome, early-onset parkinsonism-intellectual disability syndrome, X-linked intellectual disability, Schimke type, X-linked intellectual disability, Cilliers type, X-linked intellectual disability, van Esch type, X-linked intellectual disability-epilepsy syndrome, ATR-X-related syndrome, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, X-linked intellectual disability, Schutz type, X-linked intellectual disability-hypotonia-movement disorder syndrome, X-linked intellectual disability with isolated growth hormone deficiency, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-precocious puberty-obesity syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability-macrocephaly-macroorchidism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Seemanova type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, X-linked intellectual disability-acromegaly-hyperactivity syndrome, X-linked intellectual disability-corpus callosum agenesis-spastic quadriparesis syndrome, fried syndrome, X-linked intellectual disability-ataxia-apraxia syndrome, intellectual developmental disorder, X-linked, syndromic, Pilorge type, Paganini-Miozzo syndrome, intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type, intellectual disability, X-linked, syndromic, 35, intellectual disability, X-linked, syndromic, Houge type, MED12-related intellectual disability syndrome, NAA10-related syndrome, ATP6AP2-related disorder, X-linked intellectual disability with hypopituitarism, SOX3-related X-linked pituitary hormone deficiency with or without intellectual developmental disorder, intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies, intellectual developmental disorder, X-linked, syndromic 37, CASK-related intellectual disability

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

82 retrieved; paginated sample, class counts are floors:

33 uncertain significance, 25 pathogenic, 14 likely pathogenic, 6 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic, 1 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1299503	NM_001039591.3(USP9X):c.52C>T (p.Gln18Ter)	USP9X	Pathogenic	criteria provided, single submitter
1301402	NM_001039591.3(USP9X):c.1840_1843del (p.Thr614fs)	USP9X	Pathogenic	no assertion criteria provided
1338821	NM_001039591.3(USP9X):c.1812_1815del (p.Gln605fs)	USP9X	Pathogenic	criteria provided, multiple submitters, no conflicts
1695974	NM_001039591.3(USP9X):c.6679_6685delinsTCCTG (p.Lys2227_Tyr2229delinsSerTer)	USP9X	Pathogenic	no assertion criteria provided
1698973	NM_001039591.3(USP9X):c.6991dup (p.Tyr2331fs)	USP9X	Pathogenic	criteria provided, single submitter
1710266	NM_001039591.3(USP9X):c.2281dup (p.Tyr761fs)	USP9X	Pathogenic	no assertion criteria provided
223094	NM_001039591.3(USP9X):c.2554C>T (p.Arg852Ter)	USP9X	Pathogenic	no assertion criteria provided
223095	NM_001039591.3(USP9X):c.3028-2A>G	USP9X	Pathogenic	no assertion criteria provided
223096	NM_001039591.3(USP9X):c.2644_2645insA (p.Arg882fs)	USP9X	Pathogenic	criteria provided, single submitter
223097	NM_001039591.3(USP9X):c.3763C>T (p.Gln1255Ter)	USP9X	Pathogenic	no assertion criteria provided
223098	NM_001039591.3(USP9X):c.1111C>T (p.Arg371Ter)	USP9X	Pathogenic	no assertion criteria provided
2500869	NM_001039591.3(USP9X):c.323-1G>A	USP9X	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2500934	NM_001039591.3(USP9X):c.6547del (p.Phe2182_Val2183insTer)	USP9X	Pathogenic	criteria provided, single submitter
2628099	NM_001039591.3(USP9X):c.4135_4136del (p.Leu1379fs)	USP9X	Pathogenic	no assertion criteria provided
2691016	NM_001039591.3(USP9X):c.7096C>T (p.Arg2366Ter)	USP9X	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280380	NM_001039591.3(USP9X):c.1140G>A (p.Trp380Ter)	USP9X	Pathogenic	criteria provided, single submitter
3376688	NM_001039591.3(USP9X):c.7206C>A (p.Tyr2402Ter)	USP9X	Pathogenic	criteria provided, single submitter
3377434	NM_001039591.3(USP9X):c.3022G>T (p.Gly1008Ter)	USP9X	Pathogenic	criteria provided, single submitter
3764643	NM_001039591.3(USP9X):c.2746C>T (p.Arg916Ter)	USP9X	Pathogenic	criteria provided, multiple submitters, no conflicts
4056422	NM_001039591.3(USP9X):c.5551_5557del (p.Glu1851fs)	USP9X	Pathogenic	criteria provided, single submitter
4532804	NM_001039591.3(USP9X):c.6045dup (p.Leu2016fs)	USP9X	Pathogenic	criteria provided, single submitter
4685517	NM_001039591.3(USP9X):c.6773del (p.Pro2258fs)	USP9X	Pathogenic	criteria provided, single submitter
4795915	NM_001039591.3(USP9X):c.7306C>T (p.Gln2436Ter)	USP9X	Pathogenic	criteria provided, single submitter
488635	NM_001039591.3(USP9X):c.4756del (p.Ala1587fs)	USP9X	Pathogenic	criteria provided, single submitter
547925	NM_001039591.3(USP9X):c.44del (p.Asn15fs)	USP9X	Pathogenic	criteria provided, single submitter
984625	NM_001039591.3(USP9X):c.6458dup (p.Ser2153fs)	USP9X	Pathogenic	no assertion criteria provided
984638	NM_001039591.3(USP9X):c.6004C>T (p.Arg2002Ter)	USP9X	Pathogenic	no assertion criteria provided
4820082	NC_000023.11:g.40956124_41175757delinsGTA	LOC113875024	Likely pathogenic	criteria provided, single submitter
1333376	NM_001039591.3(USP9X):c.2602del (p.Tyr868fs)	USP9X	Likely pathogenic	criteria provided, single submitter
1338822	NM_001039591.3(USP9X):c.5186A>G (p.His1729Arg)	USP9X	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
USP9X	Definitive	X-linked	intellectual disability, X-linked 99, syndromic, female-restricted	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
USP9X	Orphanet:480880	X-linked female restricted facial dysmorphism-short stature-choanal atresia-intellectual disability
USP9X	Orphanet:777	X-linked non-syndromic intellectual disability

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
USP9X	HGNC:12632	ENSG00000124486	Q93008	Ubiquitin carboxyl-terminal hydrolase 9X	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
USP9X	Ubiquitin carboxyl-terminal hydrolase 9X	Deubiquitinase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
USP9X	Protease	yes		Peptidase_C19_UCH, ARM-type_fold, USP_CS

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endometrium epithelium	1
middle frontal gyrus	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
USP9X	295	ubiquitous	marker	middle frontal gyrus, endometrium epithelium, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
USP9X	3,484

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
USP9X	Q93008	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Downregulation of SMAD2/3:SMAD4 transcriptional activity	1	368.4×	0.006	USP9X
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	1	368.4×	0.006	USP9X
RHOV GTPase cycle	1	285.5×	0.006	USP9X
RHOU GTPase cycle	1	278.5×	0.006	USP9X
Peroxisomal protein import	1	173.0×	0.008	USP9X
Amyloid fiber formation	1	102.9×	0.011	USP9X
Ub-specific processing proteases	1	53.1×	0.019	USP9X

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cytosolic ciliogenesis	1	3370.4×	0.003	USP9X
protein import into peroxisome matrix, receptor recycling	1	2407.4×	0.003	USP9X
positive regulation of TORC2 signaling	1	2106.5×	0.003	USP9X
positive regulation of protein binding	1	1872.4×	0.003	USP9X
monoubiquitinated protein deubiquitination	1	1872.4×	0.003	USP9X
DNA alkylation repair	1	1532.0×	0.003	USP9X
protein deubiquitination involved in ubiquitin-dependent protein catabolic process	1	1296.3×	0.003	USP9X
female gamete generation	1	802.5×	0.004	USP9X
protein K63-linked deubiquitination	1	624.1×	0.004	USP9X
amyloid fibril formation	1	601.9×	0.004	USP9X
axon extension	1	495.6×	0.005	USP9X
negative regulation of proteasomal ubiquitin-dependent protein catabolic process	1	401.2×	0.006	USP9X
regulation of circadian rhythm	1	259.3×	0.008	USP9X
rhythmic process	1	251.5×	0.008	USP9X
BMP signaling pathway	1	200.6×	0.009	USP9X
protein deubiquitination	1	177.4×	0.009	USP9X
chromosome segregation	1	173.7×	0.009	USP9X
transforming growth factor beta receptor signaling pathway	1	159.0×	0.009	USP9X
neuron migration	1	133.8×	0.011	USP9X
regulation of protein stability	1	125.8×	0.011	USP9X
intracellular protein localization	1	104.7×	0.012	USP9X
cilium assembly	1	73.6×	0.017	USP9X
protein stabilization	1	66.9×	0.018	USP9X
cell migration	1	61.5×	0.018	USP9X
cell division	1	46.2×	0.023	USP9X
protein ubiquitination	1	41.4×	0.025	USP9X
negative regulation of transcription by RNA polymerase II	1	17.7×	0.056	USP9X

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
USP9X	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ETAVOPIVAT	2	USP9X

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
USP9X	41	Binding:41

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
ETAVOPIVAT	2	USP9X

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	USP9X
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.