syndromic X-linked intellectual disability 94

Summary

syndromic X-linked intellectual disability 94 (MONDO:0010402) is a disease caused by GRIA3 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GRIA3 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 84
• Phenotypes (HPO): 57

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		14	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

57 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0001533	Slender build	Frequent (30-79%)
HP:0002342	Intellectual disability, moderate	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000054	Micropenis	Occasional (5-29%)
HP:0000126	Hydronephrosis	Occasional (5-29%)
HP:0000188	Short upper lip	Occasional (5-29%)
HP:0000189	Narrow palate	Occasional (5-29%)
HP:0000194	Open mouth	Occasional (5-29%)
HP:0000248	Brachycephaly	Occasional (5-29%)
HP:0000256	Macrocephaly	Occasional (5-29%)
HP:0000272	Malar flattening	Occasional (5-29%)
HP:0000297	Facial hypotonia	Occasional (5-29%)
HP:0000303	Mandibular prognathia	Occasional (5-29%)
HP:0000322	Short philtrum	Occasional (5-29%)
HP:0000336	Prominent supraorbital ridges	Occasional (5-29%)
HP:0000400	Macrotia	Occasional (5-29%)
HP:0000490	Deeply set eye	Occasional (5-29%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0000675	Macrodontia of permanent maxillary central incisor	Occasional (5-29%)
HP:0000718	Aggressive behavior	Occasional (5-29%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0000742	Self-mutilation	Occasional (5-29%)
HP:0000817	Reduced eye contact	Occasional (5-29%)
HP:0001256	Intellectual disability, mild	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001265	Hyporeflexia	Occasional (5-29%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0001320	Cerebellar vermis hypoplasia	Occasional (5-29%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0001382	Joint hypermobility	Occasional (5-29%)
HP:0001763	Pes planus	Occasional (5-29%)
HP:0002069	Bilateral tonic-clonic seizure	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002133	Status epilepticus	Occasional (5-29%)
HP:0002360	Sleep abnormality	Occasional (5-29%)
HP:0002460	Distal muscle weakness	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002719	Recurrent infections	Occasional (5-29%)
HP:0002808	Kyphosis	Occasional (5-29%)
HP:0002816	Genu recurvatum	Occasional (5-29%)
HP:0003487	Babinski sign	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0006863	Severe expressive language delay	Occasional (5-29%)
HP:0006951	Retrocerebellar cyst	Occasional (5-29%)
HP:0006979	Sleep-wake cycle disturbance	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	syndromic X-linked intellectual disability 94
Mondo ID	MONDO:0010402
MeSH	C567479
OMIM	300699
Orphanet	364028
DOID	DOID:0060823
UMLS	C2678051
MedGen	437111
GARD	0027794
Is cancer (heuristic)	no

Also known as: intellectual developmental disorder, X-linked, syndromic, Wu type, X-linked recessive · intellectual disability, X-linked 94 · intellectual disability, X-linked, syndromic, Wu type · mental retardation, X-linked 94 · mental retardation, X-linked, syndromic 29 · mental retardation, X-linked, syndromic, Wu type · MRX94 · MRXS29 · MRXSW · syndromic X-linked intellectual disability 29 · syndromic X-linked intellectual disability 94 · syndromic X-linked intellectual disability type 94 · syndromic X-linked intellectual disability Wu type

Data availability: 84 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 › syndromic X-linked intellectual disability 94

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, 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 99, syndromic, female-restricted, 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

84 retrieved; paginated sample, class counts are floors:

39 uncertain significance, 12 conflicting classifications of pathogenicity, 11 pathogenic, 9 benign, 6 likely pathogenic, 4 pathogenic/likely pathogenic, 2 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
10356	NM_007325.5(GRIA3):c.2497G>A (p.Gly833Arg)	GRIA3	Pathogenic	criteria provided, single submitter
10357	NM_007325.5(GRIA3):c.1891C>A (p.Arg631Ser)	GRIA3	Pathogenic	no assertion criteria provided
10358	NM_007325.5(GRIA3):c.2117T>C (p.Met706Thr)	GRIA3	Pathogenic	no assertion criteria provided
10359	NC_000023.11:g.(?123184278)(123490915_?)del	GRIA3	Pathogenic	no assertion criteria provided
127195	NM_007325.5(GRIA3):c.1888G>C (p.Gly630Arg)	GRIA3	Pathogenic	no assertion criteria provided
1334442	NM_007325.5(GRIA3):c.2038_2040delinsTGT (p.Gly680Cys)	GRIA3	Pathogenic	criteria provided, single submitter
1344571	NM_007325.5(GRIA3):c.1844C>T (p.Ala615Val)	GRIA3	Pathogenic	no assertion criteria provided
1527932	NM_007325.5(GRIA3):c.1180C>T (p.Arg394Ter)	GRIA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685862	NM_007325.5(GRIA3):c.1450_1453dup (p.Pro485fs)	GRIA3	Pathogenic	criteria provided, single submitter
197168	NM_007325.5(GRIA3):c.646C>T (p.Arg216Ter)	GRIA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2500994	NM_007325.5(GRIA3):c.1957G>T (p.Ala653Ser)	GRIA3	Pathogenic	criteria provided, single submitter
2584384	NM_007325.5(GRIA3):c.1949C>T (p.Ala650Val)	GRIA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3024301	NM_000828.5(GRIA3):c.2359G>A (p.Glu787Lys)	GRIA3	Pathogenic	criteria provided, single submitter
431114	NM_007325.5(GRIA3):c.1964T>C (p.Phe655Ser)	GRIA3	Pathogenic	criteria provided, single submitter
981267	NM_007325.5(GRIA3):c.1888G>A (p.Gly630Arg)	GRIA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2500995	NM_007325.5(GRIA3):c.1973T>C (p.Val658Ala)	GRIA3	Likely pathogenic	criteria provided, single submitter
2506483	NM_007325.5(GRIA3):c.307G>T (p.Gly103Ter)	GRIA3	Likely pathogenic	criteria provided, single submitter
3075673	NM_007325.5(GRIA3):c.1170_1173del (p.Ser391fs)	GRIA3	Likely pathogenic	criteria provided, single submitter
3236820	NM_007325.5(GRIA3):c.1373T>C (p.Leu458Pro)	GRIA3	Likely pathogenic	criteria provided, single submitter
4536620	NM_007325.5(GRIA3):c.2397G>T (p.Trp799Cys)	GRIA3	Likely pathogenic	criteria provided, single submitter
4819863	NM_007325.5(GRIA3):c.2340del (p.Ala781fs)	GRIA3	Likely pathogenic	criteria provided, single submitter
1028874	NM_007325.5(GRIA3):c.69G>A (p.Leu23=)	GRIA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1704977	NM_007325.5(GRIA3):c.1994T>C (p.Ile665Thr)	GRIA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1804942	NM_007325.5(GRIA3):c.1544G>A (p.Arg515His)	GRIA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2049629	NM_007325.5(GRIA3):c.771G>A (p.Leu257=)	GRIA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
224091	NM_007325.5(GRIA3):c.466T>C (p.Tyr156His)	GRIA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
224120	NM_007325.5(GRIA3):c.580G>A (p.Gly194Arg)	GRIA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2959440	NM_007325.5(GRIA3):c.123G>A (p.Met41Ile)	GRIA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
383739	NM_007325.5(GRIA3):c.1957G>A (p.Ala653Thr)	GRIA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
426660	NM_007325.5(GRIA3):c.527C>T (p.Ala176Val)	GRIA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
GRIA3	Definitive	X-linked	X-linked complex neurodevelopmental disorder	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GRIA3	Orphanet:364028	X-linked intellectual disability due to GRIA3 mutations

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
GRIA3	HGNC:4573	ENSG00000125675	P42263	Glutamate receptor 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GRIA3	Glutamate receptor 3	Ionotropic glutamate receptor that functions as a ligand-gated cation channel, gated by L-glutamate and glutamatergic agonists such as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), quisqualic acid, and kainic acid.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GRIA3	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt

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
Brodmann (1909) area 23	1
middle temporal gyrus	1
primary visual cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GRIA3	205	broad	marker	Brodmann (1909) area 23, middle temporal gyrus, primary visual cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GRIA3	2,380

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GRIA3	P42263	83.98

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Activation of AMPA receptors	1	2855.0×	0.002	GRIA3
Trafficking of GluR2-containing AMPA receptors	1	671.8×	0.002	GRIA3
Trafficking of AMPA receptors	1	543.8×	0.002	GRIA3
Unblocking of NMDA receptors, glutamate binding and activation	1	543.8×	0.002	GRIA3
Synaptic adhesion-like molecules	1	543.8×	0.002	GRIA3

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
protein heterotetramerization	1	1053.2×	0.003	GRIA3
glutamate receptor signaling pathway	1	936.2×	0.003	GRIA3
synaptic transmission, glutamatergic	1	358.6×	0.005	GRIA3
long-term synaptic potentiation	1	280.9×	0.005	GRIA3
protein homotetramerization	1	237.3×	0.005	GRIA3
modulation of chemical synaptic transmission	1	183.2×	0.005	GRIA3

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · 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).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
GRIA3	PERAMPANEL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GRIA3	7	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PERAMPANEL	4	GRIA3
CYCLOTHIAZIDE	4	GRIA3
GLUTAMIC ACID	3	GRIA3
TEZAMPANEL ANHYDROUS	2	GRIA3
SELFOTEL	2	GRIA3
KAINIC ACID	2	GRIA3
FARAMPATOR	2	GRIA3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GRIA3	126	Binding:113, Functional:13

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
GRIA3	126

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

7 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)
PERAMPANEL	4	GRIA3
CYCLOTHIAZIDE	4	GRIA3
GLUTAMIC ACID	3	GRIA3
TEZAMPANEL ANHYDROUS	2	GRIA3
SELFOTEL	2	GRIA3
KAINIC ACID	2	GRIA3
FARAMPATOR	2	GRIA3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GRIA3
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	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.