Developmental and epileptic encephalopathy, 74

Summary

Developmental and epileptic encephalopathy, 74 (MONDO:0032725) is a disease caused by GABRG2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: GABRG2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 30

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 74
Mondo ID	MONDO:0032725
OMIM	618396
DOID	DOID:0112210
UMLS	C5193074
MedGen	1680535
GARD	0016349
Is cancer (heuristic)	no

Also known as: DEE74 · developmental and epileptic encephalopathy 74 · EIEE74 · EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 74 · epileptic encephalopathy, early infantile, 74

Data availability: 30 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neurological disease › Mendelian neurodevelopmental disorder › genetic developmental and epileptic encephalopathy › developmental and epileptic encephalopathy, 74

Related subtypes (104): developmental and epileptic encephalopathy, 9, developmental and epileptic encephalopathy, 8, developmental and epileptic encephalopathy, 2, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, developmental and epileptic encephalopathy, 1, developmental and epileptic encephalopathy, 3, developmental and epileptic encephalopathy, 4, microcephaly, seizures, and developmental delay, developmental and epileptic encephalopathy, 5, developmental and epileptic encephalopathy, 7, developmental and epileptic encephalopathy, 11, neonatal-onset encephalopathy with rigidity and seizures, developmental and epileptic encephalopathy, 14, developmental and epileptic encephalopathy, 15, developmental and epileptic encephalopathy, 17, developmental and epileptic encephalopathy, 18, developmental and epileptic encephalopathy, 19, developmental and epileptic encephalopathy, 23, developmental and epileptic encephalopathy, 27, developmental and epileptic encephalopathy, 30, developmental and epileptic encephalopathy, 50, developmental and epileptic encephalopathy, 35, developmental and epileptic encephalopathy, 37, developmental and epileptic encephalopathy, 38, developmental and epileptic encephalopathy, 40, developmental and epileptic encephalopathy, 48, developmental and epileptic encephalopathy, 49, developmental and epileptic encephalopathy, 51, Lennox-Gastaut syndrome, developmental and epileptic encephalopathy 91, developmental and epileptic encephalopathy 92, developmental and epileptic encephalopathy 93, developmental and epileptic encephalopathy 96, developmental and epileptic encephalopathy, 90, developmental and epileptic encephalopathy, 85, with or without midline brain defects, developmental and epileptic encephalopathy, 67, developmental and epileptic encephalopathy, 86, developmental and epileptic encephalopathy, 87, developmental and epileptic encephalopathy, 88, developmental and epileptic encephalopathy 6B, developmental and epileptic encephalopathy 97, developmental and epileptic encephalopathy 98, developmental and epileptic encephalopathy 99, developmental and epileptic encephalopathy 100, developmental and epileptic encephalopathy 101, developmental and epileptic encephalopathy 89, developmental and epileptic encephalopathy 102, developmental and epileptic encephalopathy 103, developmental and epileptic encephalopathy 104, developmental and epileptic encephalopathy 105 with hypopituitarism, developmental and epileptic encephalopathy 106, developmental and epileptic encephalopathy 107, developmental and epileptic encephalopathy, 68, developmental and epileptic encephalopathy, 69, developmental and epileptic encephalopathy, 70, developmental and epileptic encephalopathy, 71, developmental and epileptic encephalopathy, 72, developmental and epileptic encephalopathy, 75, developmental and epileptic encephalopathy, 76, developmental and epileptic encephalopathy, 77, developmental and epileptic encephalopathy, 78, developmental and epileptic encephalopathy, 79, developmental and epileptic encephalopathy, 80, developmental and epileptic encephalopathy, 81, developmental and epileptic encephalopathy, 82, developmental and epileptic encephalopathy, 83, developmental and epileptic encephalopathy, 84, developmental and epileptic encephalopathy, 52, developmental and epileptic encephalopathy, 53, developmental and epileptic encephalopathy, 54, developmental and epileptic encephalopathy, 55, developmental and epileptic encephalopathy, 56, developmental and epileptic encephalopathy, 57, developmental and epileptic encephalopathy, 58, developmental and epileptic encephalopathy, 59, developmental and epileptic encephalopathy, 60, developmental and epileptic encephalopathy, 61, developmental and epileptic encephalopathy, 62, developmental and epileptic encephalopathy, 63, developmental and epileptic encephalopathy, 64, developmental and epileptic encephalopathy, 65, developmental and epileptic encephalopathy, 73, developmental and epileptic encephalopathy, 66, developmental and epileptic encephalopathy, 6A, non-neonatal early infantile epileptic encephalopathy, Dravet syndrome, neonatal-onset developmental and epileptic encephalopathy, hemiplegic migraine-developmental and epileptic encephalopathy spectrum, DNM1-encephalopathy and neurodevelopmental disorder, TMEM63B-related developmental and epileptic encephalopathy with anemia, developmental and epileptic encephalopathy 108, developmental and epileptic encephalopathy 109, developmental and epileptic encephalopathy 110, developmental and epileptic encephalopathy 111, developmental and epileptic encephalopathy 112, developmental and epileptic encephalopathy 113, developmental and epileptic encephalopathy 114, developmental and epileptic encephalopathy 115, developmental and epileptic encephalopathy 116, developmental and epileptic encephalopathy 118, developmental and epileptic encephalopathy 120, developmental and epileptic encephalopathy 121, developmental and epileptic encephalopathy 119

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

30 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 7 likely pathogenic, 5 pathogenic, 4 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic, 1 not provided, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1793515	NM_198904.4(GABRG2):c.259+1G>A	GABRG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
205541	NM_198904.4(GABRG2):c.316G>A (p.Ala106Thr)	GABRG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
205549	NM_198904.4(GABRG2):c.967C>T (p.Arg323Trp)	GABRG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3280411	NM_198904.4(GABRG2):c.892A>T (p.Lys298Ter)	GABRG2	Pathogenic	criteria provided, multiple submitters, no conflicts
379114	NM_198904.4(GABRG2):c.269C>T (p.Thr90Met)	GABRG2	Pathogenic	criteria provided, multiple submitters, no conflicts
60708	NM_198904.4(GABRG2):c.968G>A (p.Arg323Gln)	GABRG2	Pathogenic	criteria provided, multiple submitters, no conflicts
625863	NM_198904.4(GABRG2):c.844C>T (p.Pro282Ser)	GABRG2	Pathogenic	criteria provided, multiple submitters, no conflicts
934755	NM_198904.4(GABRG2):c.529C>T (p.Arg177Ter)	GABRG2	Pathogenic	criteria provided, multiple submitters, no conflicts
1320172	NM_198904.4(GABRG2):c.666G>A (p.Trp222Ter)	GABRG2	Likely pathogenic	criteria provided, single submitter
1709541	NM_198904.4(GABRG2):c.737_740del (p.Arg246fs)	GABRG2	Likely pathogenic	criteria provided, single submitter
1803032	NM_198904.4(GABRG2):c.631+4A>G	GABRG2	Likely pathogenic	criteria provided, single submitter
2627049	NM_198904.4(GABRG2):c.875T>C (p.Val292Ala)	GABRG2	Likely pathogenic	no assertion criteria provided
408211	NM_198904.4(GABRG2):c.1061G>T (p.Gly354Val)	GABRG2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4294391	NM_198904.4(GABRG2):c.928A>C (p.Thr310Pro)	GABRG2	Likely pathogenic	criteria provided, single submitter
975991	NM_198903.2:c.-61_889+60del	GABRG2	Likely pathogenic	criteria provided, single submitter
1309068	NM_198904.4(GABRG2):c.1403A>G (p.Tyr468Cys)	GABRG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1431649	NM_198904.4(GABRG2):c.419A>G (p.Asn140Ser)	GABRG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
521954	NM_198904.4(GABRG2):c.853C>G (p.Leu285Val)	GABRG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
794672	NM_198904.4(GABRG2):c.1153-8C>G	GABRG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028381	NM_198904.4(GABRG2):c.632-5G>A	GABRG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1028382	NM_198904.4(GABRG2):c.770-12G>A	GABRG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1057064	NM_198904.4(GABRG2):c.389G>A (p.Ser130Asn)	GABRG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1325835	NM_198904.4(GABRG2):c.1358C>T (p.Ala453Val)	GABRG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1341757	NM_198904.4(GABRG2):c.108-3373G>A	GABRG2	Uncertain significance	criteria provided, single submitter
1679139	NM_198904.4(GABRG2):c.416G>A (p.Ser139Asn)	GABRG2	Uncertain significance	criteria provided, single submitter
581040	NM_198904.4(GABRG2):c.353C>T (p.Ala118Val)	GABRG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
626111	NM_198904.4(GABRG2):c.690C>A (p.Gly230=)	GABRG2	Uncertain significance	criteria provided, single submitter
931825	NM_198904.4(GABRG2):c.787T>C (p.Ser263Pro)	GABRG2	Uncertain significance	criteria provided, single submitter
585903	NM_198904.4(GABRG2):c.631+1248A>G	GABRG2	Benign	criteria provided, multiple submitters, no conflicts
2663882	NM_198904.4(GABRG2):c.947C>A (p.Thr316Asn)	GABRG2	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 5 · 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
GABRG2	Strong	Autosomal dominant	developmental and epileptic encephalopathy, 74	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GABRG2	Orphanet:1945	Self-limited epilepsy with centrotemporal spikes
GABRG2	Orphanet:33069	Dravet syndrome
GABRG2	Orphanet:36387	Genetic epilepsy with febrile seizure plus
GABRG2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
GABRG2	Orphanet:64280	Childhood absence epilepsy

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
GABRG2	HGNC:4087	ENSG00000113327	P18507	Gamma-aminobutyric acid receptor subunit gamma-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GABRG2	Gamma-aminobutyric acid receptor subunit gamma-2	Gamma 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)
GABRG2	Other/Unknown	no		GABRG-1/4, GABBAg2_rcpt, GABAA/Glycine_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
superior frontal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GABRG2	174	tissue_specific	marker	middle temporal gyrus, Brodmann (1909) area 23, superior frontal gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GABRG2	2,392

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GABRG2	P18507	75

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	GABRG2
Signaling by ERBB4	1	271.9×	0.004	GABRG2

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	GABRG2
inhibitory synapse assembly	1	624.1×	0.003	GABRG2
gamma-aminobutyric acid signaling pathway	1	543.6×	0.003	GABRG2
synaptic transmission, GABAergic	1	495.6×	0.003	GABRG2
adult behavior	1	468.1×	0.003	GABRG2
chloride transmembrane transport	1	237.3×	0.005	GABRG2
post-embryonic development	1	205.5×	0.005	GABRG2

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
GABRG2	ENZALUTAMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GABRG2	55	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ENZALUTAMIDE	4	GABRG2
DIAZEPAM	4	GABRG2
LIOTHYRONINE	4	GABRG2
GANAXOLONE	4	GABRG2
BREXANOLONE	4	GABRG2
APALUTAMIDE	4	GABRG2
FLUMAZENIL	4	GABRG2
CLONAZEPAM	4	GABRG2
FLUNITRAZEPAM	4	GABRG2
CHLORDIAZEPOXIDE	4	GABRG2
TRIAZOLAM	4	GABRG2
ZOLPIDEM	4	GABRG2
LINDANE	4	GABRG2
PROPOFOL	4	GABRG2
ZALEPLON	4	GABRG2
STIRIPENTOL	4	GABRG2
ZURANOLONE	4	GABRG2
ALPRAZOLAM	4	GABRG2
ETOMIDATE	4	GABRG2
ESZOPICLONE	4	GABRG2
PENTOBARBITAL	4	GABRG2
CANDESARTAN CILEXETIL	4	GABRG2
SIMVASTATIN	4	GABRG2
EPINASTINE	4	GABRG2
GLAFENINE	4	GABRG2
TIPRANAVIR	4	GABRG2
BENPERIDOL	4	GABRG2
ASENAPINE	4	GABRG2
TROGLITAZONE	4	GABRG2
CLOZAPINE	4	GABRG2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GABRG2	1,155	Binding:940, Functional:201, ADMET:10, Toxicity:4

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GABRG2	1,155

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

30 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	GABRG2
DIAZEPAM	4	GABRG2
LIOTHYRONINE	4	GABRG2
GANAXOLONE	4	GABRG2
BREXANOLONE	4	GABRG2
APALUTAMIDE	4	GABRG2
FLUMAZENIL	4	GABRG2
CLONAZEPAM	4	GABRG2
FLUNITRAZEPAM	4	GABRG2
CHLORDIAZEPOXIDE	4	GABRG2
TRIAZOLAM	4	GABRG2
ZOLPIDEM	4	GABRG2
LINDANE	4	GABRG2
PROPOFOL	4	GABRG2
ZALEPLON	4	GABRG2
STIRIPENTOL	4	GABRG2
ZURANOLONE	4	GABRG2
ALPRAZOLAM	4	GABRG2
ETOMIDATE	4	GABRG2
ESZOPICLONE	4	GABRG2
PENTOBARBITAL	4	GABRG2
CANDESARTAN CILEXETIL	4	GABRG2
SIMVASTATIN	4	GABRG2
EPINASTINE	4	GABRG2
GLAFENINE	4	GABRG2
TIPRANAVIR	4	GABRG2
BENPERIDOL	4	GABRG2
ASENAPINE	4	GABRG2
TROGLITAZONE	4	GABRG2
CLOZAPINE	4	GABRG2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GABRG2
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.