intellectual disability, X-linked, with or without seizures, ARX-related

Summary

intellectual disability, X-linked, with or without seizures, ARX-related (MONDO:0010317) is a disease caused by ARX (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: ARX (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 702

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, X-linked, with or without seizures, ARX-related
Mondo ID	MONDO:0010317
MeSH	C563150, C564502
OMIM	300419
DOID	DOID:0112021
UMLS	C0796244
MedGen	208681
GARD	0005614
Is cancer (heuristic)	no

Also known as: ARX-related intellectual disability · intellectual developmental disorder, X-linked 29, X-linked recessive · intellectual disability, X-linked 52 · intellectual disability, X-linked, with or without seizures, ARX-related · mental retardation, X-linked 29 · mental retardation, X-linked 32 · mental retardation, X-linked 33 · mental retardation, X-linked 38 · mental retardation, X-linked 43 · mental retardation, X-linked 52 · mental retardation, X-linked 54 · mental retardation, X-linked 76 · mental retardation, X-linked 87 · mental retardation, X-linked, with or without seizures, ARX-RELATED · mental retardation, X-linked, with or without seizures, ARX-related · MRX52 · MRXARX

Data availability: 702 ClinVar variants · 2 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, with or without seizures, ARX-related

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 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 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

600 retrieved; paginated sample, class counts are floors:

297 likely benign, 186 uncertain significance, 51 conflicting classifications of pathogenicity, 32 pathogenic, 11 benign/likely benign, 9 benign, 7 likely pathogenic, 6 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070790	NM_139058.3(ARX):c.303_323dup (p.Ala109_Ala115dup)	ARX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074175	NM_139058.3(ARX):c.1443dup (p.Gly482fs)	ARX	Pathogenic	criteria provided, single submitter
11188	NM_139058.3(ARX):c.1058C>T (p.Pro353Leu)	ARX	Pathogenic	criteria provided, multiple submitters, no conflicts
11192	NM_139058.3(ARX):c.995G>A (p.Arg332His)	ARX	Pathogenic	criteria provided, multiple submitters, no conflicts
11194	NM_139058.3(ARX):c.1187dup (p.Gly397fs)	ARX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11198	NM_139058.3(ARX):c.98T>C (p.Leu33Pro)	ARX	Pathogenic	no assertion criteria provided
11202	NM_139058.3(ARX):c.309_341dup (p.Ala105_Ala115dup)	ARX	Pathogenic	criteria provided, multiple submitters, no conflicts
1374869	NM_139058.3(ARX):c.1125G>A (p.Trp375Ter)	ARX	Pathogenic	criteria provided, single submitter
1410535	NM_139058.3(ARX):c.642_645del (p.Pro215fs)	ARX	Pathogenic	criteria provided, single submitter
1434577	NM_139058.3(ARX):c.1120-2A>G	ARX	Pathogenic	criteria provided, single submitter
1494703	NM_139058.3(ARX):c.994C>G (p.Arg332Gly)	ARX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
157739	NM_139058.3(ARX):c.1111C>T (p.Arg371Ter)	ARX	Pathogenic	criteria provided, multiple submitters, no conflicts
1699422	NM_139058.3(ARX):c.502_503dup (p.Ser168fs)	ARX	Pathogenic	criteria provided, single submitter
1704274	NM_139058.3(ARX):c.1520_1526dup (p.Glu509fs)	ARX	Pathogenic	no assertion criteria provided
1993323	NM_139058.3(ARX):c.357_391del (p.Gly120fs)	ARX	Pathogenic	criteria provided, multiple submitters, no conflicts
2041609	NM_139058.3(ARX):c.590dup (p.Val198fs)	ARX	Pathogenic	criteria provided, single submitter
2059968	NM_139058.3(ARX):c.1111del (p.Arg371fs)	ARX	Pathogenic	criteria provided, single submitter
2098307	NM_139058.3(ARX):c.1497del (p.Leu500fs)	ARX	Pathogenic	criteria provided, single submitter
210327	NM_139058.3(ARX):c.306GGC[18] (p.Ala108_Ala115dup)	ARX	Pathogenic	criteria provided, multiple submitters, no conflicts
2103487	NM_139058.3(ARX):c.378_459del (p.Pro127fs)	ARX	Pathogenic	criteria provided, single submitter
2159557	NM_139058.3(ARX):c.1150C>T (p.Arg384Cys)	ARX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2427280	NC_000023.10:g.(?24483573)(25033854_?)del	ARX	Pathogenic	criteria provided, single submitter
2921880	NM_139058.3(ARX):c.409del (p.Glu137fs)	ARX	Pathogenic	criteria provided, single submitter
2940905	NM_139058.3(ARX):c.1180_1187del (p.His394fs)	ARX	Pathogenic	criteria provided, single submitter
2943777	NM_139058.3(ARX):c.1559del (p.Pro520fs)	ARX	Pathogenic	criteria provided, single submitter
2945226	NM_139058.3(ARX):c.193C>T (p.Gln65Ter)	ARX	Pathogenic	criteria provided, single submitter
2950977	NM_139058.3(ARX):c.486_489del (p.Ser162fs)	ARX	Pathogenic	criteria provided, single submitter
2953993	NM_139058.3(ARX):c.1273_1279del (p.Ala425fs)	ARX	Pathogenic	criteria provided, single submitter
29964	NM_139058.3(ARX):c.81C>G (p.Tyr27Ter)	ARX	Pathogenic/Likely pathogenic	no assertion criteria provided
3382594	NM_139058.3(ARX):c.880G>T (p.Glu294Ter)	ARX	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 8 · 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
ARX	Definitive	X-linked	X-linked complex neurodevelopmental disorder	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ARX	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
ARX	Orphanet:2508	Corpus callosum agenesis-abnormal genitalia syndrome
ARX	Orphanet:3175	X-linked spasticity-intellectual disability-epilepsy syndrome
ARX	Orphanet:364063	Infantile epileptic-dyskinetic encephalopathy
ARX	Orphanet:452	X-linked lissencephaly with abnormal genitalia
ARX	Orphanet:697160	Infantile epileptic spasms syndrome
ARX	Orphanet:777	X-linked non-syndromic intellectual disability
ARX	Orphanet:94083	Partington syndrome

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
ARX	HGNC:18060	ENSG00000004848	Q96QS3	Homeobox protein ARX	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ARX	Homeobox protein ARX	Transcription factor.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ARX	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf

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
left ovary	1
ovary	1
right ovary	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ARX	162	broad	marker	left ovary, ovary, right ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARX	758

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARX	Q96QS3	56.51

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
embryonic olfactory bulb interneuron precursor migration	1	8426.0×	0.001	ARX
cerebral cortex tangential migration	1	4213.0×	0.001	ARX
epithelial cell fate commitment	1	4213.0×	0.001	ARX
globus pallidus development	1	3370.4×	0.001	ARX
lipid digestion	1	3370.4×	0.001	ARX
cerebral cortex GABAergic interneuron migration	1	2808.7×	0.001	ARX
positive regulation of organ growth	1	1404.3×	0.002	ARX
cell proliferation in forebrain	1	1296.3×	0.002	ARX
regulation of epithelial cell proliferation	1	936.2×	0.002	ARX
neuron fate commitment	1	802.5×	0.002	ARX
organ growth	1	732.7×	0.002	ARX
neuron development	1	255.3×	0.006	ARX
axon guidance	1	90.6×	0.014	ARX
positive regulation of gene expression	1	38.7×	0.031	ARX
negative regulation of transcription by RNA polymerase II	1	17.7×	0.064	ARX
positive regulation of transcription by RNA polymerase II	1	14.9×	0.071	ARX
regulation of transcription by RNA polymerase II	1	11.7×	0.086	ARX

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ARX	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ARX

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)
ARX	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.