intellectual disability, X-linked 99

Summary

intellectual disability, X-linked 99 (MONDO:0010487) is a disease caused by USP9X (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: USP9X (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 87

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, X-linked 99
Mondo ID	MONDO:0010487
OMIM	300919
DOID	DOID:0112026
UMLS	C3806746
MedGen	813076
GARD	0022693
Is cancer (heuristic)	no

Also known as: intellectual developmental disorder, X-linked 99, X-linked recessive · intellectual disability, X-linked 99 · intellectual disability, X-linked type 99 · mental retardation, X-linked 99 · mental retardation, X-linked type 99 · MRX99 · non-syndromic X-linked intellectual disability caused by mutation in USP9X · USP9X non-syndromic X-linked intellectual disability

Data availability: 87 ClinVar variants · 3 GenCC gene-disease records.

Disease family

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

Related subtypes (51): intellectual disability, X-linked 23, intellectual disability, X-linked 20, intellectual disability, X-linked 14, intellectual disability, X-linked 50, intellectual disability, X-linked 21, intellectual disability, X-linked 58, intellectual disability, X-linked 72, intellectual disability, X-linked 53, intellectual disability, X-linked 73, intellectual disability, X-linked 42, intellectual disability, X-linked 63, intellectual disability, X-linked, with or without seizures, ARX-related, intellectual disability, X-linked 2, intellectual disability, X-linked 81, intellectual disability, X-linked 46, intellectual disability, X-linked 77, intellectual disability, X-linked 45, intellectual disability, X-linked 84, intellectual disability, X-linked 82, intellectual disability, X-linked 30, intellectual disability, X-linked 91, intellectual disability, X-linked 93, chromosome Xp11.22 duplication syndrome, intellectual disability, X-linked 95, intellectual disability, X-linked 96, intellectual disability, X-linked 97, intellectual disability, X-linked 19, intellectual disability, X-linked 89, intellectual disability, X-linked 41, intellectual disability, X-linked 90, intellectual disability, X-linked 92, intellectual disability, X-linked 88, intellectual disability, X-linked 100, intellectual disability, X-linked 101, intellectual disability, X-linked 102, intellectual disability, X-linked 61, intellectual disability, X-linked 103, intellectual disability, X-linked 104, intellectual disability, X-linked 105, intellectual disability, X-linked 1, methylmalonic acidemia with homocystinuria, type cblX, FRAXE intellectual disability, intellectual disability, X-linked 9, intellectual developmental disorder, X-linked 108, intellectual disability, X-linked 106, intellectual disability, X-linked 107, intellectual developmental disorder, X-linked 110, intellectual developmental disorder, X-linked 111, intellectual developmental disorder, X-linked 112, intellectual developmental disorder, X-linked 113, intellectual developmental disorder, X-linked 114

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

87 retrieved; paginated sample, class counts are floors:

56 uncertain significance, 13 likely pathogenic, 6 conflicting classifications of pathogenicity, 4 likely benign, 4 pathogenic, 2 pathogenic/likely pathogenic, 1 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1034402	NM_001039591.3(USP9X):c.2026C>T (p.Gln676Ter)	USP9X	Pathogenic	criteria provided, single submitter
127090	NM_001039591.3(USP9X):c.6278T>A (p.Leu2093His)	USP9X	Pathogenic	no assertion criteria provided
127091	NM_001039591.3(USP9X):c.7526del (p.Gln2509fs)	USP9X	Pathogenic	no assertion criteria provided
1331725	NM_001039591.3(USP9X):c.6254G>A (p.Arg2085His)	USP9X	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2500869	NM_001039591.3(USP9X):c.323-1G>A	USP9X	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
816935	NM_001039591.3(USP9X):c.260del (p.Pro87fs)	USP9X	Pathogenic	criteria provided, single submitter
1301879	NM_001039591.3(USP9X):c.3559-1G>C	USP9X	Likely pathogenic	criteria provided, single submitter
1685472	NM_001039591.3(USP9X):c.3905C>T (p.Ala1302Val)	USP9X	Likely pathogenic	criteria provided, single submitter
1703761	NM_001039591.3(USP9X):c.1511C>T (p.Ala504Val)	USP9X	Likely pathogenic	criteria provided, single submitter
1804703	NM_001039591.3(USP9X):c.5636ATT[2] (p.Tyr1881del)	USP9X	Likely pathogenic	criteria provided, single submitter
2584357	NM_001039591.3(USP9X):c.5198G>A (p.Cys1733Tyr)	USP9X	Likely pathogenic	criteria provided, single submitter
3235897	NM_001039591.3(USP9X):c.1738_1741del (p.Phe580fs)	USP9X	Likely pathogenic	criteria provided, single submitter
3256592	NM_001039591.3(USP9X):c.539C>T (p.Pro180Leu)	USP9X	Likely pathogenic	criteria provided, single submitter
3376809	NM_001039591.3(USP9X):c.5357T>C (p.Ile1786Thr)	USP9X	Likely pathogenic	criteria provided, single submitter
3382218	NM_001039591.3(USP9X):c.1028T>C (p.Leu343Ser)	USP9X	Likely pathogenic	criteria provided, single submitter
3897834	NM_001039591.3(USP9X):c.1333A>G (p.Ile445Val)	USP9X	Likely pathogenic	criteria provided, single submitter
4072033	NM_001039591.3(USP9X):c.5369C>T (p.Pro1790Leu)	USP9X	Likely pathogenic	criteria provided, single submitter
4795909	NM_001039591.3(USP9X):c.1618dup (p.Cys540fs)	USP9X	Likely pathogenic	criteria provided, single submitter
620023	NM_001039591.3(USP9X):c.671T>C (p.Leu224Pro)	USP9X	Likely pathogenic	criteria provided, single submitter
1028480	NM_001039591.3(USP9X):c.131C>T (p.Pro44Leu)	USP9X	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2073589	NM_001039591.3(USP9X):c.4882C>A (p.Pro1628Thr)	USP9X	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2499604	NM_001039591.3(USP9X):c.4973G>A (p.Arg1658Gln)	USP9X	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
384654	NM_001039591.3(USP9X):c.1315-4A>G	USP9X	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
520886	NM_001039591.3(USP9X):c.4163A>G (p.Asn1388Ser)	USP9X	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
872821	NM_001039591.3(USP9X):c.6360A>G (p.Ile2120Met)	USP9X	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2580912	NM_031407.7(HUWE1):c.484C>G (p.Arg162Gly)	HUWE1	Uncertain significance	criteria provided, single submitter
1028481	NM_001039591.3(USP9X):c.1700T>C (p.Ile567Thr)	USP9X	Uncertain significance	criteria provided, single submitter
1028975	NM_001039591.3(USP9X):c.2888C>A (p.Ala963Asp)	USP9X	Uncertain significance	criteria provided, single submitter
1028976	NM_001039591.3(USP9X):c.4829A>G (p.Asn1610Ser)	USP9X	Uncertain significance	criteria provided, single submitter
1028977	NM_001039591.3(USP9X):c.6359T>C (p.Ile2120Thr)	USP9X	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 3 · 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
HUWE1	Orphanet:528084	Non-specific syndromic intellectual disability

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
USP9X	HGNC:12632	ENSG00000124486	Q93008	Ubiquitin carboxyl-terminal hydrolase 9X	gencc,clinvar
HUWE1	HGNC:30892	ENSG00000086758	Q7Z6Z7	E3 ubiquitin-protein ligase HUWE1	clinvar
NTF4	HGNC:8024	ENSG00000225950	P34130	Neurotrophin-4	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.
HUWE1	E3 ubiquitin-protein ligase HUWE1	E3 ubiquitin-protein ligase which mediates ubiquitination and subsequent proteasomal degradation of target proteins.
NTF4	Neurotrophin-4	Target-derived survival factor for peripheral sensory sympathetic neurons.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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	12.2×	0.239
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
USP9X	Protease	yes		Peptidase_C19_UCH, ARM-type_fold, USP_CS
HUWE1	Enzyme (other)	yes	2.3.2.26	HECT_dom, WWE_dom, UBA-like_sf
NTF4	Other/Unknown	no		Nerve_growth_factor-rel, Nerve_growth_factor_CS, Nerve_growth_factor-like

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
skin of abdomen	2
endometrium epithelium	1
middle frontal gyrus	1
secondary oocyte	1
right lobe of thyroid gland	1
skin of leg	1
male germ line stem cell (sensu Vertebrata) in testis	1
skeletal muscle tissue	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
HUWE1	300	ubiquitous	marker	skin of leg, skin of abdomen, right lobe of thyroid gland
NTF4	93	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, skeletal muscle tissue, skin of abdomen

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HUWE1	5,793
USP9X	3,484
NTF4	985

Intra-cohort edges

A	B	Sources
HUWE1	USP9X	intact, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HUWE1	Q7Z6Z7	19
USP9X	Q93008	4
NTF4	P34130	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
NTF4 activates NTRK2 (TRKB) signaling	1	1903.3×	0.009	NTF4
Activated NTRK2 signals through PLCG1	1	951.7×	0.009	NTF4
Activated NTRK2 signals through PI3K	1	543.8×	0.010	NTF4
Activated NTRK2 signals through RAS	1	380.7×	0.011	NTF4
Activated NTRK2 signals through FRS2 and FRS3	1	317.2×	0.011	NTF4
Downregulation of SMAD2/3:SMAD4 transcriptional activity	1	122.8×	0.020	USP9X
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	1	122.8×	0.020	USP9X
RHOV GTPase cycle	1	95.2×	0.020	USP9X
RHOU GTPase cycle	1	92.8×	0.020	USP9X
Peroxisomal protein import	1	57.7×	0.029	USP9X
Constitutive Signaling by Aberrant PI3K in Cancer	1	42.3×	0.036	NTF4
Amyloid fiber formation	1	34.3×	0.040	USP9X
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	32.3×	0.040	NTF4
PIP3 activates AKT signaling	1	22.3×	0.054	NTF4
Ub-specific processing proteases	1	17.7×	0.063	USP9X
Antigen processing: Ubiquitination & Proteasome degradation	1	12.4×	0.083	HUWE1
Neutrophil degranulation	1	7.7×	0.124	HUWE1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sensory organ boundary specification	1	5617.3×	0.005	NTF4
taste bud development	1	5617.3×	0.005	NTF4
ganglion mother cell fate determination	1	2808.7×	0.007	NTF4
mechanoreceptor differentiation	1	1123.5×	0.008	NTF4
cytosolic ciliogenesis	1	1123.5×	0.008	USP9X
negative regulation of peroxisome proliferator activated receptor signaling pathway	1	936.2×	0.008	HUWE1
protein import into peroxisome matrix, receptor recycling	1	802.5×	0.008	USP9X
negative regulation of mitochondrial fusion	1	702.2×	0.008	HUWE1
ameloblast differentiation	1	702.2×	0.008	NTF4
positive regulation of TORC2 signaling	1	702.2×	0.008	USP9X
positive regulation of protein binding	1	624.1×	0.008	USP9X
monoubiquitinated protein deubiquitination	1	624.1×	0.008	USP9X
DNA alkylation repair	1	510.7×	0.008	USP9X
positive regulation of type 2 mitophagy	1	510.7×	0.008	HUWE1
nerve growth factor signaling pathway	1	432.1×	0.009	NTF4
protein deubiquitination involved in ubiquitin-dependent protein catabolic process	1	432.1×	0.009	USP9X
nerve development	1	312.1×	0.011	NTF4
innervation	1	295.6×	0.011	NTF4
protein branched polyubiquitination	1	280.9×	0.011	HUWE1
female gamete generation	1	267.5×	0.011	USP9X
membrane fusion	1	208.1×	0.013	HUWE1
protein K63-linked deubiquitination	1	208.1×	0.013	USP9X
amyloid fibril formation	1	200.6×	0.013	USP9X
axon extension	1	165.2×	0.014	USP9X
obsolete positive regulation of protein targeting to mitochondrion	1	165.2×	0.014	HUWE1
base-excision repair	1	156.0×	0.015	HUWE1
long-term memory	1	140.4×	0.016	NTF4
negative regulation of proteasomal ubiquitin-dependent protein catabolic process	1	133.8×	0.016	USP9X
protein monoubiquitination	1	114.6×	0.018	HUWE1
adult locomotory behavior	1	100.3×	0.020	NTF4

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
HUWE1	0	0
NTF4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ETAVOPIVAT	2	USP9X

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
USP9X	41	Binding:41
HUWE1	4	Binding:3, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HUWE1	2.3.2.26	HECT-type E3 ubiquitin transferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	1	HUWE1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NTF4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HUWE1	4	—
NTF4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.