Developmental and epileptic encephalopathy, 45

Summary

Developmental and epileptic encephalopathy, 45 (MONDO:0014942) is a disease caused by GABRB1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: GABRB1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 22

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 45
Mondo ID	MONDO:0014942
OMIM	617153
DOID	DOID:0080428
UMLS	C4310691
MedGen	934658
GARD	0016203
Is cancer (heuristic)	no

Also known as: DEE45 · developmental and epileptic encephalopathy 45 · early infantile epileptic encephalopathy caused by mutation in GABRB1 · EIEE45 · epileptic encephalopathy, early infantile, 45 · epileptic encephalopathy, early infantile, 45; EIEE45 · epileptic encephalopathy, early infantile, type 45 · GABRB1 early infantile epileptic encephalopathy

Data availability: 22 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn disorder of amino acid transport › undetermined early-onset epileptic encephalopathy › developmental and epileptic encephalopathy, 45

Related subtypes (15): developmental and epileptic encephalopathy, 13, developmental and epileptic encephalopathy, 21, developmental and epileptic encephalopathy, 24, developmental and epileptic encephalopathy, 25, developmental and epileptic encephalopathy, 26, developmental and epileptic encephalopathy, 28, developmental and epileptic encephalopathy, 29, developmental and epileptic encephalopathy, 31A, developmental and epileptic encephalopathy, 32, developmental and epileptic encephalopathy, 33, developmental and epileptic encephalopathy, 41, developmental and epileptic encephalopathy, 42, developmental and epileptic encephalopathy, 44, developmental and epileptic encephalopathy, 46, developmental and epileptic encephalopathy, 47

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

22 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 4 likely pathogenic, 2 benign, 2 conflicting classifications of pathogenicity, 1 likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
265863	NM_000812.4(GABRB1):c.737T>C (p.Phe246Ser)	GABRB1	Pathogenic	no assertion criteria provided
265864	NM_000812.4(GABRB1):c.860C>T (p.Thr287Ile)	GABRB1	Likely pathogenic	criteria provided, single submitter
431076	NM_000812.4(GABRB1):c.157C>T (p.Arg53Trp)	GABRB1	Likely pathogenic	criteria provided, single submitter
982940	NM_000812.4(GABRB1):c.854C>A (p.Thr285Lys)	GABRB1	Likely pathogenic	criteria provided, single submitter
984675	NM_000812.4(GABRB1):c.740T>C (p.Ile247Thr)	GABRB1	Likely pathogenic	criteria provided, single submitter
1299345	NM_000812.4(GABRB1):c.757C>T (p.Pro253Ser)	GABRB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1704699	NM_000812.4(GABRB1):c.898A>T (p.Ile300Phe)	GABRB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1034301	NM_000812.4(GABRB1):c.629A>G (p.Gln210Arg)	GABRB1	Uncertain significance	criteria provided, single submitter
1377544	NM_000812.4(GABRB1):c.1142C>T (p.Ser381Leu)	GABRB1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1504558	NM_000812.4(GABRB1):c.1033G>C (p.Asp345His)	GABRB1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1805092	NM_000812.4(GABRB1):c.1243G>C (p.Gly415Arg)	GABRB1	Uncertain significance	criteria provided, single submitter
1962993	NM_000812.4(GABRB1):c.1108A>G (p.Ser370Gly)	GABRB1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2585086	NM_000812.4(GABRB1):c.74C>G (p.Ala25Gly)	GABRB1	Uncertain significance	criteria provided, single submitter
3236263	NM_000812.4(GABRB1):c.1399G>T (p.Val467Phe)	GABRB1	Uncertain significance	criteria provided, single submitter
3393108	NM_000812.4(GABRB1):c.158G>T (p.Arg53Leu)	GABRB1	Uncertain significance	criteria provided, single submitter
3778754	NM_000812.4(GABRB1):c.554C>T (p.Thr185Ile)	GABRB1	Uncertain significance	criteria provided, single submitter
4292361	NM_000812.4(GABRB1):c.725A>C (p.Asn242Thr)	GABRB1	Uncertain significance	criteria provided, single submitter
638346	NM_000812.4(GABRB1):c.307C>T (p.Pro103Ser)	GABRB1	Uncertain significance	criteria provided, multiple submitters, no conflicts
992731	NM_000812.4(GABRB1):c.1214G>A (p.Arg405His)	GABRB1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1280390	NM_000812.4(GABRB1):c.846A>G (p.Thr282=)	GABRB1	Benign	criteria provided, multiple submitters, no conflicts
1285290	NM_000812.4(GABRB1):c.80+24_80+25del	GABRB1	Benign	criteria provided, multiple submitters, no conflicts
2177482	NM_000812.4(GABRB1):c.618C>T (p.Ile206=)	GABRB1	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
GABRB1	Strong	Autosomal dominant	developmental and epileptic encephalopathy, 45	3

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
GABRB1	HGNC:4081	ENSG00000163288	P18505	Gamma-aminobutyric acid receptor subunit beta-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GABRB1	Gamma-aminobutyric acid receptor subunit beta-1	Beta 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: 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)
GABRB1	Other/Unknown	no		GABAAb_rcpt, GABAA/Glycine_rcpt, Neurotrans-gated_channel_TM

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
entorhinal cortex	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GABRB1	172	tissue_specific	marker	Brodmann (1909) area 23, middle temporal gyrus, entorhinal cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GABRB1	1,537

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GABRB1	P18505	3

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
GABA receptor activation	1	317.2×	0.004	GABRB1
Signaling by ERBB4	1	271.9×	0.004	GABRB1

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
cellular response to histamine	1	2808.7×	0.002	GABRB1
ovulation cycle	1	2407.4×	0.002	GABRB1
central nervous system neuron development	1	802.5×	0.003	GABRB1
gamma-aminobutyric acid signaling pathway	1	543.6×	0.003	GABRB1
response to progesterone	1	495.6×	0.003	GABRB1
synaptic transmission, GABAergic	1	495.6×	0.003	GABRB1
chloride transmembrane transport	1	237.3×	0.006	GABRB1
response to toxic substance	1	210.7×	0.006	GABRB1
monoatomic ion transport	1	156.0×	0.007	GABRB1
signal transduction	1	16.1×	0.062	GABRB1

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
GABRB1	ENZALUTAMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GABRB1	18	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ENZALUTAMIDE	4	GABRB1
DIAZEPAM	4	GABRB1
LIOTHYRONINE	4	GABRB1
GANAXOLONE	4	GABRB1
BREXANOLONE	4	GABRB1
APALUTAMIDE	4	GABRB1
FLUMAZENIL	4	GABRB1
CLONAZEPAM	4	GABRB1
PROPOFOL	4	GABRB1
LINDANE	4	GABRB1
ZOLPIDEM	4	GABRB1
DELORAZEPAM	2	GABRB1
FLAVONE	2	GABRB1
PROGABIDE	2	GABRB1
ABECARNIL	2	GABRB1
BAICALEIN	2	GABRB1
MUSCIMOL	1	GABRB1
GAMMA-AMINOBUTYRIC ACID	1	GABRB1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GABRB1	266	Binding:219, Functional:39, ADMET:5, Toxicity:3

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GABRB1	266

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

18 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	GABRB1
DIAZEPAM	4	GABRB1
LIOTHYRONINE	4	GABRB1
GANAXOLONE	4	GABRB1
BREXANOLONE	4	GABRB1
APALUTAMIDE	4	GABRB1
FLUMAZENIL	4	GABRB1
CLONAZEPAM	4	GABRB1
PROPOFOL	4	GABRB1
LINDANE	4	GABRB1
ZOLPIDEM	4	GABRB1
DELORAZEPAM	2	GABRB1
FLAVONE	2	GABRB1
PROGABIDE	2	GABRB1
ABECARNIL	2	GABRB1
BAICALEIN	2	GABRB1
MUSCIMOL	1	GABRB1
GAMMA-AMINOBUTYRIC ACID	1	GABRB1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GABRB1
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.