Intellectual disability, autosomal recessive 6

Summary

Intellectual disability, autosomal recessive 6 (MONDO:0012614) is a disease caused by GRIK2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: GRIK2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 16

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal recessive 6
Mondo ID	MONDO:0012614
MeSH	C567017
OMIM	611092
DOID	DOID:0081182
UMLS	C1970198
MedGen	370848
GARD	0022542
Is cancer (heuristic)	no

Also known as: autosomal recessive non-syndromic intellectual disability caused by mutation in GRIK2 · GRIK2 autosomal recessive non-syndromic intellectual disability · intellectual developmental disorder, autosomal recessive 6 · intellectual disability, autosomal recessive 6 · intellectual disability, autosomal recessive type 6 · mental retardation, autosomal recessive 6 · mental retardation, autosomal recessive type 6 · MRT6

Data availability: 16 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 › non-syndromic intellectual disability › autosomal recessive non-syndromic intellectual disability › intellectual disability, autosomal recessive 6

Related subtypes (67): intellectual disability, autosomal recessive 1, intellectual disability, autosomal recessive 2, intellectual disability, autosomal recessive 3, intellectual disability, autosomal recessive 12, intellectual disability, autosomal recessive 5, intellectual disability, autosomal recessive 7, intellectual disability, autosomal recessive 9, intellectual disability, autosomal recessive 10, intellectual disability, autosomal recessive 11, intellectual disability, autosomal recessive 4, intellectual disability, autosomal recessive 13, intellectual disability, autosomal recessive 14, Rafiq syndrome, intellectual disability, autosomal recessive 16, intellectual disability, autosomal recessive 18, intellectual disability, autosomal recessive 31, intellectual disability, autosomal recessive 29, intellectual disability, autosomal recessive 27, intellectual disability, autosomal recessive 33, intellectual disability, autosomal recessive 30, intellectual disability, autosomal recessive 19, intellectual disability, autosomal recessive 23, intellectual disability, autosomal recessive 24, intellectual disability, autosomal recessive 25, intellectual disability, autosomal recessive 28, intellectual disability, autosomal recessive 34, intellectual disability, autosomal recessive 42, intellectual disability, autosomal recessive 43, intellectual disability, autosomal recessive 44, intellectual disability, autosomal recessive 45, intellectual disability, autosomal recessive 46, intellectual disability, autosomal recessive 47, Al-Raqad syndrome, intellectual disability, autosomal recessive 50, intellectual disability, autosomal recessive 51, intellectual disability, autosomal recessive 52, intellectual disability, autosomal recessive 54, intellectual disability, autosomal recessive 56, intellectual developmental disorder, autosomal recessive 74, intellectual disability, autosomal recessive 57, intellectual disability, autosomal recessive 58, intellectual disability, autosomal recessive 59, pontocerebellar hypoplasia type 1, intellectual disability, autosomal recessive 64, intellectual disability, autosomal recessive 65, intellectual developmental disorder, autosomal recessive 73, intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly, intellectual disability, autosomal recessive 61, intellectual developmental disorder, autosomal recessive 76, intellectual developmental disorder, autosomal recessive 77, intellectual disability, autosomal recessive 66, intellectual developmental disorder, autosomal recessive 67, intellectual developmental disorder, autosomal recessive 68, intellectual developmental disorder, autosomal recessive 69, intellectual developmental disorder, autosomal recessive 70, intellectual developmental disorder, autosomal recessive 71, intellectual developmental disorder, autosomal recessive 72, glycosylphosphatidylinositol biosynthesis defect 16, intellectual disability, autosomal recessive 60, intellectual disability, autosomal recessive 63, adenosine kinase deficiency, intellectual developmental disorder, autosomal recessive 78, intellectual developmental disorder, autosomal recessive 79, intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly, intellectual developmental disorder, autosomal recessive 81, intellectual developmental disorder, autosomal recessive 82, intellectual developmental disorder, autosomal recessive 83

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

16 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
16087	GRIK2, DEL/INV, EX7-11	GRIK2	Pathogenic	no assertion criteria provided
189252	NM_021956.5(GRIK2):c.592C>T (p.Arg198Ter)	GRIK2	Pathogenic	no assertion criteria provided
1028234	NM_021956.5(GRIK2):c.922G>A (p.Asp308Asn)	GRIK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028232	NM_021956.5(GRIK2):c.2310G>T (p.Met770Ile)	GRIK2	Uncertain significance	criteria provided, single submitter
1028233	NM_021956.5(GRIK2):c.662G>A (p.Gly221Asp)	GRIK2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033987	NM_021956.5(GRIK2):c.1073G>T (p.Arg358Leu)	GRIK2	Uncertain significance	criteria provided, single submitter
1033988	NM_021956.5(GRIK2):c.1138A>T (p.Thr380Ser)	GRIK2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033989	NM_021956.5(GRIK2):c.2625A>T (p.Leu875Phe)	GRIK2	Uncertain significance	criteria provided, single submitter
1033990	NM_021956.5(GRIK2):c.969G>A (p.Met323Ile)	GRIK2	Uncertain significance	criteria provided, single submitter
1325562	NM_021956.5(GRIK2):c.1628G>A (p.Arg543His)	GRIK2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2441774	NM_021956.5(GRIK2):c.1095+2T>A	GRIK2	Uncertain significance	criteria provided, single submitter
3592843	NM_021956.5(GRIK2):c.368A>G (p.Asn123Ser)	GRIK2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3592844	NM_021956.5(GRIK2):c.1939A>T (p.Ile647Phe)	GRIK2	Uncertain significance	criteria provided, single submitter
435363	NM_021956.5(GRIK2):c.613C>T (p.Pro205Ser)	GRIK2	Uncertain significance	criteria provided, multiple submitters, no conflicts
977375	NM_021956.5(GRIK2):c.1525A>C (p.Lys509Gln)	GRIK2	Uncertain significance	criteria provided, single submitter
445349	NM_021956.5(GRIK2):c.2296G>A (p.Val766Ile)	GRIK2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 2 · 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
GRIK2	Definitive	Autosomal recessive	intellectual disability, autosomal recessive 6	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GRIK2	Orphanet:528084	Non-specific syndromic intellectual disability
GRIK2	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability

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
GRIK2	HGNC:4580	ENSG00000164418	Q13002	Glutamate receptor ionotropic, kainate 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GRIK2	Glutamate receptor ionotropic, kainate 2	Ionotropic glutamate receptor that functions as a cation-permeable ligand-gated ion channel, gated by L-glutamate and the glutamatergic agonist 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)
GRIK2	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
cerebellar cortex	1
cerebellar hemisphere	1
cerebellar vermis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GRIK2	213	broad	marker	cerebellar vermis, cerebellar cortex, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GRIK2	2,154

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GRIK2	Q13002	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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 Na-permeable kainate receptors	1	5710.0×	4e-04	GRIK2
Activation of Ca-permeable Kainate Receptor	1	1142.0×	9e-04	GRIK2

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
detection of cold stimulus involved in thermoception	1	16852.0×	0.001	GRIK2
modulation of excitatory postsynaptic potential	1	2106.5×	0.003	GRIK2
negative regulation of synaptic transmission, glutamatergic	1	1685.2×	0.003	GRIK2
inhibitory postsynaptic potential	1	1685.2×	0.003	GRIK2
regulation of short-term neuronal synaptic plasticity	1	1123.5×	0.003	GRIK2
positive regulation of synaptic transmission	1	1123.5×	0.003	GRIK2
regulation of long-term neuronal synaptic plasticity	1	991.3×	0.003	GRIK2
glutamate receptor signaling pathway	1	936.2×	0.003	GRIK2
regulation of JNK cascade	1	887.0×	0.003	GRIK2
receptor clustering	1	624.1×	0.003	GRIK2
neuronal action potential	1	481.5×	0.004	GRIK2
presynaptic modulation of chemical synaptic transmission	1	455.5×	0.004	GRIK2
behavioral fear response	1	432.1×	0.004	GRIK2
synaptic transmission, glutamatergic	1	358.6×	0.004	GRIK2
positive regulation of neuron apoptotic process	1	271.8×	0.005	GRIK2
neuron apoptotic process	1	185.2×	0.006	GRIK2
modulation of chemical synaptic transmission	1	183.2×	0.006	GRIK2
intracellular calcium ion homeostasis	1	145.3×	0.008	GRIK2
negative regulation of neuron apoptotic process	1	110.9×	0.009	GRIK2
chemical synaptic transmission	1	77.3×	0.013	GRIK2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · 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).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GRIK2	2	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
GLUTAMIC ACID	3	GRIK2
KAINIC ACID	2	GRIK2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GRIK2	92	Binding:66, Functional:26

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

2 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)
GLUTAMIC ACID	3	GRIK2
KAINIC ACID	2	GRIK2

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	GRIK2
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.