Developmental and epileptic encephalopathy, 78

Summary

Developmental and epileptic encephalopathy, 78 (MONDO:0032812) is a disease caused by GABRA2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: GABRA2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 30

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 78
Mondo ID	MONDO:0032812
OMIM	618557
DOID	DOID:0112214
UMLS	C5231409
MedGen	1684724
GARD	0016365
Is cancer (heuristic)	no

Also known as: DEE78 · developmental and epileptic encephalopathy 78 · EIEE78 · EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 78 · epileptic encephalopathy, early infantile, 78

Data availability: 30 ClinVar variants · 4 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, 78

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, 74, developmental and epileptic encephalopathy, 75, developmental and epileptic encephalopathy, 76, developmental and epileptic encephalopathy, 77, 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:

12 uncertain significance, 6 pathogenic, 6 likely pathogenic, 4 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1675200	NM_000807.4(GABRA2):c.855del (p.Phe285fs)	GABRA2	Pathogenic	no assertion criteria provided
1685836	NM_000807.4(GABRA2):c.995C>T (p.Ala332Val)	GABRA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2571202	NM_000807.4(GABRA2):c.881C>T (p.Thr294Ile)	GABRA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3338107	NM_000807.4(GABRA2):c.988_989insTTATG (p.Glu330fs)	GABRA2	Pathogenic	criteria provided, single submitter
4526429	NM_000807.4(GABRA2):c.895A>C (p.Ser299Arg)	GABRA2	Pathogenic	criteria provided, single submitter
689388	NM_000807.4(GABRA2):c.871C>G (p.Leu291Val)	GABRA2	Pathogenic	no assertion criteria provided
689389	NM_000807.4(GABRA2):c.788T>C (p.Met263Thr)	GABRA2	Pathogenic	no assertion criteria provided
689390	NM_000807.4(GABRA2):c.975C>A (p.Phe325Leu)	GABRA2	Pathogenic	no assertion criteria provided
3338106	NM_000807.4(GABRA2):c.644T>C (p.Leu215Ser)	GABRA2	Likely pathogenic	criteria provided, single submitter
3338108	NM_000807.4(GABRA2):c.460C>G (p.Leu154Val)	GABRA2	Likely pathogenic	criteria provided, single submitter
3377080	NM_000807.4(GABRA2):c.850G>T (p.Val284Leu)	GABRA2	Likely pathogenic	criteria provided, single submitter
689387	NM_000807.4(GABRA2):c.875C>A (p.Thr292Lys)	GABRA2	Likely pathogenic	criteria provided, single submitter
976773	NM_000807.4(GABRA2):c.875C>T (p.Thr292Ile)	GABRA2	Likely pathogenic	criteria provided, single submitter
3765735	NM_003403.5(YY1):c.1133C>G (p.Thr378Ser)	YY1	Likely pathogenic	criteria provided, single submitter
1334582	NM_000807.4(GABRA2):c.923C>T (p.Ala308Val)	GABRA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1342366	NM_000807.4(GABRA2):c.764T>C (p.Ile255Thr)	GABRA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1709312	NM_000807.4(GABRA2):c.862A>G (p.Thr288Ala)	GABRA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3254673	NM_000807.4(GABRA2):c.787A>G (p.Met263Val)	GABRA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1325559	NM_000807.4(GABRA2):c.76G>T (p.Val26Leu)	GABRA2	Uncertain significance	criteria provided, single submitter
1417022	NM_000807.4(GABRA2):c.29T>C (p.Met10Thr)	GABRA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2102687	NM_000807.4(GABRA2):c.166C>T (p.Arg56Trp)	GABRA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2431997	NM_000807.4(GABRA2):c.1118A>G (p.Asn373Ser)	GABRA2	Uncertain significance	criteria provided, single submitter
2432000	NM_000807.4(GABRA2):c.1174A>G (p.Thr392Ala)	GABRA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3236469	NM_000807.4(GABRA2):c.334C>T (p.Arg112Ter)	GABRA2	Uncertain significance	criteria provided, single submitter
3242039	NM_000807.4(GABRA2):c.527A>G (p.Asp176Gly)	GABRA2	Uncertain significance	criteria provided, single submitter
3254988	NM_000807.4(GABRA2):c.55del (p.Val19fs)	GABRA2	Uncertain significance	criteria provided, single submitter
3376148	NM_000807.4(GABRA2):c.763A>T (p.Ile255Phe)	GABRA2	Uncertain significance	criteria provided, single submitter
4292829	NM_000807.4(GABRA2):c.865A>G (p.Thr289Ala)	GABRA2	Uncertain significance	criteria provided, single submitter
617630	NM_000807.4(GABRA2):c.1003A>C (p.Asn335His)	GABRA2	Uncertain significance	criteria provided, single submitter
976220	NM_000807.4(GABRA2):c.438del (p.Arg147fs)	GABRA2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 3 · 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
GABRA2	Strong	Autosomal dominant	developmental and epileptic encephalopathy, 78	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GABRA2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
YY1	Orphanet:506358	Gabriele-de Vries syndrome
YY1	Orphanet:97279	Insulinoma

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GABRA2	HGNC:4076	ENSG00000151834	P47869	Gamma-aminobutyric acid receptor subunit alpha-2	gencc,clinvar
YY1	HGNC:12856	ENSG00000100811	P25490	Transcriptional repressor protein YY1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GABRA2	Gamma-aminobutyric acid receptor subunit alpha-2	Alpha subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain.
YY1	Transcriptional repressor protein YY1	Multifunctional transcription factor that exhibits positive and negative control on a large number of cellular and viral genes by binding to sites overlapping the transcription start site.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GABRA2	Other/Unknown	no		GABAAa_rcpt, GABBAa2_rcpt, GABAA/Glycine_rcpt
YY1	Transcription factor	no		Znf_C2H2_type, YY1-like, Znf_C2H2_sf

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
entorhinal cortex	1
frontal pole	1
postcentral gyrus	1
cortical plate	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GABRA2	195	broad	marker	frontal pole, entorhinal cortex, postcentral gyrus
YY1	279	ubiquitous	marker	ventricular zone, ganglionic eminence, cortical plate

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
YY1	4,986
GABRA2	1,505

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GABRA2	P47869	8
YY1	P25490	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TFAP2 (AP-2) family regulates transcription of growth factors and their receptors	1	380.7×	0.016	YY1
GABA receptor activation	1	158.6×	0.016	GABRA2
DNA Damage Recognition in GG-NER	1	142.8×	0.016	YY1
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	1	73.2×	0.022	YY1
UCH proteinases	1	62.1×	0.022	YY1
Activation of anterior HOX genes in hindbrain development during early embryogenesis	1	45.7×	0.025	YY1
Estrogen-dependent gene expression	1	37.8×	0.026	YY1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
RNA localization	1	4213.0×	0.004	YY1
immunoglobulin heavy chain V-D-J recombination	1	4213.0×	0.004	YY1
response to prostaglandin F	1	2808.7×	0.004	YY1
response to UV-C	1	842.6×	0.008	YY1
negative regulation of cell growth involved in cardiac muscle cell development	1	702.2×	0.008	YY1
positive regulation of telomere maintenance in response to DNA damage	1	561.7×	0.008	YY1
negative regulation of interferon-beta production	1	526.6×	0.008	YY1
regulation of DNA strand elongation	1	526.6×	0.008	YY1
regulation of chromosome organization	1	468.1×	0.008	YY1
camera-type eye morphogenesis	1	383.0×	0.009	YY1
negative regulation of miRNA transcription	1	312.1×	0.009	YY1
inhibitory synapse assembly	1	312.1×	0.009	GABRA2
gamma-aminobutyric acid signaling pathway	1	271.8×	0.010	GABRA2
synaptic transmission, GABAergic	1	247.8×	0.010	GABRA2
regulation of DNA replication	1	183.2×	0.012	YY1
positive regulation of DNA repair	1	179.3×	0.012	YY1
regulation of embryonic development	1	165.2×	0.012	YY1
cellular response to UV	1	147.8×	0.012	YY1
cellular response to interleukin-1	1	140.4×	0.012	YY1
regulation of DNA repair	1	138.1×	0.012	YY1
telomere maintenance	1	133.8×	0.012	YY1
chloride transmembrane transport	1	118.7×	0.013	GABRA2
B cell differentiation	1	109.4×	0.014	YY1
anterior/posterior pattern specification	1	90.6×	0.016	YY1
double-strand break repair via homologous recombination	1	78.0×	0.018	YY1
regulation of cell cycle	1	37.3×	0.035	YY1
chromatin remodeling	1	36.5×	0.035	YY1
negative regulation of gene expression	1	34.5×	0.036	YY1
DNA damage response	1	26.8×	0.045	YY1
positive regulation of gene expression	1	19.4×	0.059	YY1

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
GABRA2	ENZALUTAMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GABRA2	46	4
YY1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ENZALUTAMIDE	4	GABRA2
DIAZEPAM	4	GABRA2
LIOTHYRONINE	4	GABRA2
GANAXOLONE	4	GABRA2
BREXANOLONE	4	GABRA2
APALUTAMIDE	4	GABRA2
FLUMAZENIL	4	GABRA2
CLONAZEPAM	4	GABRA2
FLUNITRAZEPAM	4	GABRA2
ZALEPLON	4	GABRA2
CHLORDIAZEPOXIDE	4	GABRA2
TRIAZOLAM	4	GABRA2
ZOLPIDEM	4	GABRA2
PROPOFOL	4	GABRA2
ESZOPICLONE	4	GABRA2
PENTOBARBITAL	4	GABRA2
ALPRAZOLAM	4	GABRA2
ETOMIDATE	4	GABRA2
CANDESARTAN CILEXETIL	4	GABRA2
SIMVASTATIN	4	GABRA2
EPINASTINE	4	GABRA2
GLAFENINE	4	GABRA2
TIPRANAVIR	4	GABRA2
BENPERIDOL	4	GABRA2
ASENAPINE	4	GABRA2
TROGLITAZONE	4	GABRA2
CLOZAPINE	4	GABRA2
CHLORAMBUCIL	4	GABRA2
CRIZOTINIB	4	GABRA2
AZELASTINE	4	GABRA2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GABRA2	385	Binding:327, Functional:52, 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
GABRA2	385

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

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	GABRA2
DIAZEPAM	4	GABRA2
LIOTHYRONINE	4	GABRA2
GANAXOLONE	4	GABRA2
BREXANOLONE	4	GABRA2
APALUTAMIDE	4	GABRA2
FLUMAZENIL	4	GABRA2
CLONAZEPAM	4	GABRA2
FLUNITRAZEPAM	4	GABRA2
ZALEPLON	4	GABRA2
CHLORDIAZEPOXIDE	4	GABRA2
TRIAZOLAM	4	GABRA2
ZOLPIDEM	4	GABRA2
PROPOFOL	4	GABRA2
ESZOPICLONE	4	GABRA2
PENTOBARBITAL	4	GABRA2
ALPRAZOLAM	4	GABRA2
ETOMIDATE	4	GABRA2
CANDESARTAN CILEXETIL	4	GABRA2
SIMVASTATIN	4	GABRA2
EPINASTINE	4	GABRA2
GLAFENINE	4	GABRA2
TIPRANAVIR	4	GABRA2
BENPERIDOL	4	GABRA2
ASENAPINE	4	GABRA2
TROGLITAZONE	4	GABRA2
CLOZAPINE	4	GABRA2
CHLORAMBUCIL	4	GABRA2
CRIZOTINIB	4	GABRA2
AZELASTINE	4	GABRA2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GABRA2
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	YY1

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)
YY1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.