intellectual disability, X-linked 101

Summary

intellectual disability, X-linked 101 (MONDO:0010489) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 17

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, X-linked 101
Mondo ID	MONDO:0010489
OMIM	300928
DOID	DOID:0112048
UMLS	C3890168
MedGen	855517
GARD	0022694
Is cancer (heuristic)	no

Also known as: intellectual developmental disorder, X-linked 101, X-linked recessive · intellectual disability, X-linked 101 · intellectual disability, X-linked type 101 · mental retardation, X-linked 101 · mental retardation, X-linked type 101 · MID2 non-syndromic X-linked intellectual disability · MRX101 · non-syndromic X-linked intellectual disability caused by mutation in MID2

Data availability: 17 ClinVar variants · 1 GenCC gene-disease record.

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 101

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 99, intellectual disability, X-linked 100, 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

17 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 2 likely pathogenic, 2 conflicting classifications of pathogenicity, 1 benign, 1 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
143857	NM_012216.4(MID2):c.1040G>A (p.Arg347Gln)	LOC101928335	Pathogenic/Likely pathogenic	no assertion criteria provided
818208	NM_012216.4(MID2):c.1447del (p.Ser483fs)	LOC101928335	Pathogenic	criteria provided, single submitter
1047926	NM_012216.4(MID2):c.2070del (p.Phe691fs)	LOC101928335	Likely pathogenic	no assertion criteria provided
1343245	NM_012216.4(MID2):c.1432C>T (p.Arg478Ter)	LOC101928335	Likely pathogenic	criteria provided, single submitter
4054864	NM_012216.4(MID2):c.1427C>T (p.Ala476Val)	LOC101928335	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
800883	NM_012216.4(MID2):c.1558G>A (p.Gly520Ser)	LOC101928335	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1709693	NM_012216.4(MID2):c.1131_1133delinsAGA (p.Asp377_Ala378delinsGluAsp)	LOC101928335	Uncertain significance	criteria provided, single submitter
2431776	NM_012216.4(MID2):c.1090G>T (p.Ala364Ser)	LOC101928335	Uncertain significance	criteria provided, single submitter
2433749	NM_012216.4(MID2):c.1414A>G (p.Arg472Gly)	LOC101928335	Uncertain significance	criteria provided, single submitter
2671901	NM_012216.4(MID2):c.1106T>C (p.Leu369Pro)	LOC101928335	Uncertain significance	criteria provided, single submitter
2691674	NM_012216.4(MID2):c.1435+1G>A	LOC101928335	Uncertain significance	criteria provided, multiple submitters, no conflicts
1301698	NM_012216.4(MID2):c.373A>G (p.Thr125Ala)	MID2	Uncertain significance	criteria provided, single submitter
224103	NM_012216.4(MID2):c.448G>T (p.Ala150Ser)	MID2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2442092	NM_012216.4(MID2):c.308T>G (p.Ile103Ser)	MID2	Uncertain significance	criteria provided, single submitter
548625	NM_012216.4(MID2):c.491G>A (p.Arg164His)	MID2	Uncertain significance	criteria provided, single submitter
988733	NM_001039591.3(USP9X):c.3410C>T (p.Pro1137Leu)	USP9X	Uncertain significance	criteria provided, multiple submitters, no conflicts
1321169	NM_012216.4(MID2):c.180A>C (p.Ser60=)	MID2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · 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
MID2	Supportive	X-linked	non-syndromic X-linked intellectual disability	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MID2	Orphanet:777	X-linked non-syndromic intellectual disability
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

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MID2	HGNC:7096	ENSG00000080561	Q9UJV3	Probable E3 ubiquitin-protein ligase MID2	gencc,clinvar
USP9X	HGNC:12632	ENSG00000124486	Q93008	Ubiquitin carboxyl-terminal hydrolase 9X	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MID2	Probable E3 ubiquitin-protein ligase MID2	E3 ubiquitin ligase that plays a role in microtubule stabilization.
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: 1 · Unknown: 0 · Druggable fraction: 0.5

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	18.3×	0.108
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MID2	Transcription factor	no		Znf_B-box, Znf_RING, B30.2/SPRY
USP9X	Protease	yes		Peptidase_C19_UCH, ARM-type_fold, USP_CS

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cartilage tissue	1
islet of Langerhans	1
tibialis anterior	1
endometrium epithelium	1
middle frontal gyrus	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MID2	258	ubiquitous	marker	tibialis anterior, islet of Langerhans, cartilage tissue
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
MID2	1,172

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MID2	Q9UJV3	4
USP9X	Q93008	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 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 2 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	1685.2×	0.007	USP9X
protein import into peroxisome matrix, receptor recycling	1	1203.7×	0.007	USP9X
positive regulation of TORC2 signaling	1	1053.2×	0.007	USP9X
positive regulation of protein binding	1	936.2×	0.007	USP9X
monoubiquitinated protein deubiquitination	1	936.2×	0.007	USP9X
DNA alkylation repair	1	766.0×	0.007	USP9X
protein localization to microtubule	1	648.1×	0.007	MID2
protein deubiquitination involved in ubiquitin-dependent protein catabolic process	1	648.1×	0.007	USP9X
negative regulation of viral transcription	1	526.6×	0.007	MID2
suppression of viral release by host	1	495.6×	0.007	MID2
female gamete generation	1	401.2×	0.008	USP9X
host-mediated suppression of symbiont invasion	1	351.1×	0.008	MID2
protein K63-linked deubiquitination	1	312.1×	0.008	USP9X
amyloid fibril formation	1	300.9×	0.008	USP9X
axon extension	1	247.8×	0.009	USP9X
negative regulation of proteasomal ubiquitin-dependent protein catabolic process	1	200.6×	0.011	USP9X
regulation of circadian rhythm	1	129.6×	0.015	USP9X
rhythmic process	1	125.8×	0.015	USP9X
positive regulation of autophagy	1	104.0×	0.017	MID2
BMP signaling pathway	1	100.3×	0.017	USP9X
protein deubiquitination	1	88.7×	0.018	USP9X
chromosome segregation	1	86.9×	0.018	USP9X
protein K48-linked ubiquitination	1	84.3×	0.018	MID2
transforming growth factor beta receptor signaling pathway	1	79.5×	0.018	USP9X
neuron migration	1	66.9×	0.021	USP9X
regulation of protein stability	1	62.9×	0.021	USP9X
intracellular protein localization	1	52.3×	0.025	USP9X
cilium assembly	1	36.8×	0.033	USP9X
positive regulation of canonical NF-kappaB signal transduction	1	36.3×	0.033	MID2
protein stabilization	1	33.4×	0.035	USP9X

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
MID2	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): 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: 2; 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	1	MID2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MID2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.