epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic features

Summary

epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic features (MONDO:0859564) is a disease caused by GABRA3 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: GABRA3 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 13

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic features
Mondo ID	MONDO:0859564
OMIM	301091
UMLS	C5774178
MedGen	1823952
GARD	0026742
Is cancer (heuristic)	no

Data availability: 13 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › epilepsy › monogenic epilepsy › epilepsy, X-linked, with or without impaired intellectual development and dysmorphic features › epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic features

Related subtypes (1): epilepsy, X-linked 1, with variable learning disabilities and behavior disorders

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

13 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 4 pathogenic, 1 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1799557	NM_000808.4(GABRA3):c.497C>T (p.Thr166Met)	GABRA3	Pathogenic	no assertion criteria provided
1799560	NM_000808.4(GABRA3):c.725A>T (p.Gln242Leu)	GABRA3	Pathogenic	no assertion criteria provided
985441	NM_000808.4(GABRA3):c.1421A>G (p.Tyr474Cys)	GABRA3	Pathogenic	criteria provided, single submitter
1799559	NC_000023.11:g.152277607_152451201dup	MIR105-2	Pathogenic	no assertion criteria provided
2576557	NM_000808.4(GABRA3):c.830A>G (p.Tyr277Cys)	GABRA3	Likely pathogenic	criteria provided, single submitter
2578421	NM_000808.4(GABRA3):c.931+5G>A	GABRA3	Uncertain significance	criteria provided, single submitter
3377352	NM_000808.4(GABRA3):c.1371A>C (p.Lys457Asn)	GABRA3	Uncertain significance	criteria provided, single submitter
3901156	NM_000808.4(GABRA3):c.590A>T (p.Asp197Val)	GABRA3	Uncertain significance	criteria provided, single submitter
4078729	NM_000808.4(GABRA3):c.263-30381T>C	GABRA3	Uncertain significance	criteria provided, single submitter
4078730	NM_000808.4(GABRA3):c.262+9958T>C	GABRA3	Uncertain significance	criteria provided, single submitter
4280663	NM_000808.4(GABRA3):c.1385T>C (p.Ile462Thr)	GABRA3	Uncertain significance	criteria provided, single submitter
4293541	NM_000808.4(GABRA3):c.1060A>C (p.Ile354Leu)	GABRA3	Uncertain significance	criteria provided, single submitter
2673264	NM_000808.4(GABRA3):c.1258G>A (p.Ala420Thr)	GABRA3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
GABRA3	Definitive	X-linked	epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic features	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GABRA3	Orphanet:79102	Thyrotoxic periodic paralysis

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GABRA3	HGNC:4077	ENSG00000011677	P34903	Gamma-aminobutyric acid receptor subunit alpha-3	gencc,clinvar
MIR105-2	HGNC:31493	ENSG00000207818		microRNA 105-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GABRA3	Gamma-aminobutyric acid receptor subunit alpha-3	Alpha subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GABRA3	Other/Unknown	no		GABAAa_rcpt, GABBAa3_rcpt, GABAA/Glycine_rcpt
MIR105-2	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	1
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cingulate cortex	1
cortical plate	1
prefrontal cortex	1
blood	1
gastrocnemius	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GABRA3	106	broad	yes	cortical plate, prefrontal cortex, cingulate cortex
MIR105-2	10		yes	blood, right lobe of liver, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GABRA3	1,295
MIR105-2	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GABRA3	P34903	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
GABA receptor activation	1	317.2×	0.003	GABRA3

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
inhibitory synapse assembly	1	624.1×	0.003	GABRA3
gamma-aminobutyric acid signaling pathway	1	543.6×	0.003	GABRA3
synaptic transmission, GABAergic	1	495.6×	0.003	GABRA3
chloride transmembrane transport	1	237.3×	0.004	GABRA3

Therapeutics

Drug target analysis

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

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
GABRA3	ENZALUTAMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GABRA3	29	4
MIR105-2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ENZALUTAMIDE	4	GABRA3
DIAZEPAM	4	GABRA3
LIOTHYRONINE	4	GABRA3
GANAXOLONE	4	GABRA3
BREXANOLONE	4	GABRA3
APALUTAMIDE	4	GABRA3
FLUMAZENIL	4	GABRA3
CLONAZEPAM	4	GABRA3
FLUNITRAZEPAM	4	GABRA3
CHLORDIAZEPOXIDE	4	GABRA3
TRIAZOLAM	4	GABRA3
ZOLPIDEM	4	GABRA3
PROPOFOL	4	GABRA3
ESZOPICLONE	4	GABRA3
ALPRAZOLAM	4	GABRA3
DELORAZEPAM	2	GABRA3
FLAVONE	2	GABRA3
PROGABIDE	2	GABRA3
ABECARNIL	2	GABRA3
BAICALEIN	2	GABRA3
MK-0777	2	GABRA3
DARIGABAT	2	GABRA3
BRETAZENIL	2	GABRA3
PANADIPLON	2	GABRA3
AZD7325	2	GABRA3
BASMISANIL	2	GABRA3
MUSCIMOL	1	GABRA3
GAMMA-AMINOBUTYRIC ACID	1	GABRA3
AZD6280	1	GABRA3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GABRA3	400	Binding:324, Functional:70, ADMET:3, Toxicity:3

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GABRA3	400

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

29 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)
ENZALUTAMIDE	4	GABRA3
DIAZEPAM	4	GABRA3
LIOTHYRONINE	4	GABRA3
GANAXOLONE	4	GABRA3
BREXANOLONE	4	GABRA3
APALUTAMIDE	4	GABRA3
FLUMAZENIL	4	GABRA3
CLONAZEPAM	4	GABRA3
FLUNITRAZEPAM	4	GABRA3
CHLORDIAZEPOXIDE	4	GABRA3
TRIAZOLAM	4	GABRA3
ZOLPIDEM	4	GABRA3
PROPOFOL	4	GABRA3
ESZOPICLONE	4	GABRA3
ALPRAZOLAM	4	GABRA3
DELORAZEPAM	2	GABRA3
FLAVONE	2	GABRA3
PROGABIDE	2	GABRA3
ABECARNIL	2	GABRA3
BAICALEIN	2	GABRA3
MK-0777	2	GABRA3
DARIGABAT	2	GABRA3
BRETAZENIL	2	GABRA3
PANADIPLON	2	GABRA3
AZD7325	2	GABRA3
BASMISANIL	2	GABRA3
MUSCIMOL	1	GABRA3
GAMMA-AMINOBUTYRIC ACID	1	GABRA3
AZD6280	1	GABRA3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GABRA3
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	MIR105-2

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)
MIR105-2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.