Neurodevelopmental disorder with language impairment and behavioral abnormalities

Summary

Neurodevelopmental disorder with language impairment and behavioral abnormalities (MONDO:0030060) is a disease caused by GRIA2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: GRIA2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 67

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodevelopmental disorder with language impairment and behavioral abnormalities
Mondo ID	MONDO:0030060
OMIM	618917
UMLS	C5394502
MedGen	1708389
GARD	0027923
Is cancer (heuristic)	no

Also known as: GRIA2-related complex neurodevelopmental disorder · NEDLIB · NEURODEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND BEHAVIORAL ABNORMALITIES · neurodevelopmental disorder with language impairment and behavioral abnormalities

Data availability: 67 ClinVar variants · 7 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › complex neurodevelopmental disorder › neurodevelopmental disorder with language impairment and behavioral abnormalities

Related subtypes (14): pervasive developmental disorder, Prader-Willi syndrome, intellectual disability, autosomal dominant 29, neurodevelopmental disorder with severe motor impairment and absent language, X-linked complex neurodevelopmental disorder, neonatal encephalopathy with non-epileptic myoclonus, complex neurodevelopmental disorder with or without congenital anomalies, complex neurodevelopmental disorder with motor features, AFG2B-related complex neurodevelopmental disorder with motor features and hearing loss, developmental and epileptic encephalopathy, syndromic complex neurodevelopmental disorder, DEAF1-associated neurodevelopmental disorder, NACC1-related neurodevelopmental disorder with epilepsy, cataracts and episodic irritability, GRIN-related complex neurodevelopmental disorder

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

67 retrieved; paginated sample, class counts are floors:

28 uncertain significance, 24 likely pathogenic, 11 pathogenic, 2 conflicting classifications of pathogenicity, 1 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
4795122	NC_000004.12:g.(157332798_157336882)del		Pathogenic	criteria provided, single submitter
1174085	NM_001083619.3(GRIA2):c.258del (p.Val85_Tyr86insTer)	GRIA2	Pathogenic	no assertion criteria provided
1685861	NM_001083619.3(GRIA2):c.1927G>A (p.Ala643Thr)	GRIA2	Pathogenic	criteria provided, single submitter
1698825	NM_001083619.3(GRIA2):c.506del (p.Ala169fs)	GRIA2	Pathogenic	criteria provided, single submitter
1701007	NM_001083619.3(GRIA2):c.2375G>A (p.Gly792Glu)	GRIA2	Pathogenic	criteria provided, multiple submitters, no conflicts
1708230	NM_001083619.3(GRIA2):c.699C>A (p.Tyr233Ter)	GRIA2	Pathogenic	criteria provided, single submitter
1803979	NM_001083619.3(GRIA2):c.1589_1619dup (p.Asp540delinsGluValGlnThrArgSerValPheLeuSerTer)	GRIA2	Pathogenic	criteria provided, single submitter
2501002	NM_001083619.3(GRIA2):c.1940T>C (p.Val647Ala)	GRIA2	Pathogenic	criteria provided, single submitter
2920713	NM_001083619.3(GRIA2):c.2263dup (p.Ile755fs)	GRIA2	Pathogenic	criteria provided, single submitter
4813763	NM_001083619.3(GRIA2):c.2076G>A (p.Trp692Ter)	GRIA2	Pathogenic	criteria provided, single submitter
929842	NM_001083619.3(GRIA2):c.1939G>C (p.Val647Leu)	GRIA2	Pathogenic	criteria provided, single submitter
1012507	NM_001083619.3(GRIA2):c.967C>T (p.Arg323Ter)	GRIA2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1064411	NM_001083619.3(GRIA2):c.2363G>T (p.Trp788Leu)	GRIA2	Likely pathogenic	criteria provided, single submitter
1064412	NM_001083619.3(GRIA2):c.2375G>T (p.Gly792Val)	GRIA2	Likely pathogenic	criteria provided, single submitter
1064413	NM_001083619.3(GRIA2):c.1819C>G (p.Gln607Glu)	GRIA2	Likely pathogenic	criteria provided, single submitter
1064414	NM_001083619.3(GRIA2):c.1937C>A (p.Thr646Asn)	GRIA2	Likely pathogenic	criteria provided, single submitter
1064415	NM_001083619.3(GRIA2):c.1932C>A (p.Phe644Leu)	GRIA2	Likely pathogenic	criteria provided, single submitter
1064417	NM_001083619.3(GRIA2):c.2435A>G (p.Asn812Ser)	GRIA2	Likely pathogenic	criteria provided, single submitter
1064418	NM_001083619.3(GRIA2):c.2420C>T (p.Ala807Val)	GRIA2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1320197	NM_001083619.3(GRIA2):c.1958_1960delinsTCTACAGCAC (p.Pro653fs)	GRIA2	Likely pathogenic	criteria provided, single submitter
1679184	NM_001083619.3(GRIA2):c.1589A>T (p.Lys530Met)	GRIA2	Likely pathogenic	criteria provided, single submitter
2501001	NM_001083619.3(GRIA2):c.1859G>A (p.Arg620His)	GRIA2	Likely pathogenic	criteria provided, single submitter
2576545	NM_001083619.3(GRIA2):c.830G>A (p.Trp277Ter)	GRIA2	Likely pathogenic	criteria provided, single submitter
2584383	NM_001083619.3(GRIA2):c.2188A>T (p.Asn730Tyr)	GRIA2	Likely pathogenic	criteria provided, single submitter
2584460	NM_001083619.3(GRIA2):c.1916C>G (p.Ala639Gly)	GRIA2	Likely pathogenic	criteria provided, single submitter
2683746	NM_001083619.3(GRIA2):c.1883T>C (p.Phe628Ser)	GRIA2	Likely pathogenic	no assertion criteria provided
2692488	NM_001083619.3(GRIA2):c.1667G>A (p.Gly556Glu)	GRIA2	Likely pathogenic	criteria provided, single submitter
3896725	NM_001083619.3(GRIA2):c.1565C>G (p.Ser522Cys)	GRIA2	Likely pathogenic	criteria provided, single submitter
4293804	NM_001083619.3(GRIA2):c.1045A>T (p.Lys349Ter)	GRIA2	Likely pathogenic	criteria provided, single submitter
4294034	NM_001083619.3(GRIA2):c.1934T>C (p.Leu645Pro)	GRIA2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 0 · 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
GRIA2	Definitive	Autosomal dominant	neurodevelopmental disorder with language impairment and behavioral abnormalities	7

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
GRIA2	HGNC:4572	ENSG00000120251	P42262	Glutamate receptor 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GRIA2	Glutamate receptor 2	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)
GRIA2	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
frontal pole	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GRIA2	212	broad	marker	frontal pole, Brodmann (1909) area 23, middle temporal gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GRIA2	3,547

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GRIA2	P42262	16

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	GRIA2
Trafficking of GluR2-containing AMPA receptors	1	671.8×	0.002	GRIA2
MECP2 regulates neuronal receptors and channels	1	601.0×	0.002	GRIA2
Unblocking of NMDA receptors, glutamate binding and activation	1	543.8×	0.002	GRIA2
Long-term potentiation	1	475.8×	0.002	GRIA2

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
ionotropic glutamate receptor signaling pathway	1	1296.3×	0.002	GRIA2
synaptic transmission, glutamatergic	1	358.6×	0.004	GRIA2
modulation of chemical synaptic transmission	1	183.2×	0.005	GRIA2

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
GRIA2	CYCLOTHIAZIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GRIA2	6	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CYCLOTHIAZIDE	4	GRIA2
GLUTAMIC ACID	3	GRIA2
TEZAMPANEL ANHYDROUS	2	GRIA2
SELFOTEL	2	GRIA2
KAINIC ACID	2	GRIA2
GSK-729327	1	GRIA2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GRIA2	192	Binding:163, Functional:25, ADMET:4

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GRIA2	192

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

6 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)
CYCLOTHIAZIDE	4	GRIA2
GLUTAMIC ACID	3	GRIA2
TEZAMPANEL ANHYDROUS	2	GRIA2
SELFOTEL	2	GRIA2
KAINIC ACID	2	GRIA2
GSK-729327	1	GRIA2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GRIA2
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.