Developmental and epileptic encephalopathy, 19

Summary

Developmental and epileptic encephalopathy, 19 (MONDO:0014328) is a disease caused by GABRA1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: GABRA1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 62

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 19
Mondo ID	MONDO:0014328
OMIM	615744
DOID	DOID:0080431
NCIT	C142802
UMLS	C3810400
MedGen	816730
GARD	0016008
Is cancer (heuristic)	no

Also known as: DEE19 · developmental and epileptic encephalopathy 19 · Early Infantile epileptic encephalopathy 19 · early infantile epileptic encephalopathy caused by mutation in GABRA1 · EIEE19 · epileptic encephalopathy, early infantile, 19 · epileptic encephalopathy, early infantile, type 19 · GABRA1 early infantile epileptic encephalopathy

Data availability: 62 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

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, 19

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, 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, 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

62 retrieved; paginated sample, class counts are floors:

22 uncertain significance, 14 conflicting classifications of pathogenicity, 11 likely pathogenic, 9 pathogenic, 4 pathogenic/likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
127073	NM_001127644.2(GABRA1):c.751G>A (p.Gly251Ser)	GABRA1	Pathogenic	criteria provided, single submitter
127075	NM_001127644.2(GABRA1):c.917A>C (p.Lys306Thr)	GABRA1	Pathogenic	no assertion criteria provided
217878	NM_001127644.2(GABRA1):c.902G>A (p.Arg301Lys)	GABRA1	Pathogenic	no assertion criteria provided
242830	NM_001127644.2(GABRA1):c.1200del (p.Lys401fs)	GABRA1	Pathogenic	criteria provided, single submitter
265161	NM_001127644.2(GABRA1):c.640C>T (p.Arg214Cys)	GABRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265162	NM_001127644.2(GABRA1):c.641G>A (p.Arg214His)	GABRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4071944	NM_001127644.2(GABRA1):c.918G>T (p.Lys306Asn)	GABRA1	Pathogenic	criteria provided, single submitter
430503	NM_001127644.2(GABRA1):c.859G>T (p.Val287Leu)	GABRA1	Pathogenic	criteria provided, multiple submitters, no conflicts
568345	NM_001127644.2(GABRA1):c.869_888del (p.Val290fs)	GABRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
807607	NM_001127644.2(GABRA1):c.440G>A (p.Arg147Gln)	GABRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
813796	NM_001127644.2(GABRA1):c.787A>G (p.Met263Val)	GABRA1	Pathogenic	criteria provided, single submitter
992951	NM_001127644.2(GABRA1):c.995C>T (p.Ala332Val)	GABRA1	Pathogenic	criteria provided, single submitter
997693	NM_001127644.2(GABRA1):c.1015A>G (p.Lys339Glu)	GABRA1	Pathogenic	no assertion criteria provided
1801718	NM_001127644.2(GABRA1):c.269A>T (p.Asp90Val)	GABRA1	Likely pathogenic	criteria provided, single submitter
1803029	NM_001127644.2(GABRA1):c.839C>T (p.Pro280Leu)	GABRA1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1803975	NM_001127644.2(GABRA1):c.647A>T (p.Asn216Ile)	GABRA1	Likely pathogenic	criteria provided, single submitter
205525	NM_001127644.2(GABRA1):c.884C>T (p.Thr295Ile)	GABRA1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3376149	NM_001127644.2(GABRA1):c.328G>T (p.Val110Phe)	GABRA1	Likely pathogenic	criteria provided, single submitter
3770195	NM_001127644.2(GABRA1):c.953C>T (p.Ala318Val)	GABRA1	Likely pathogenic	criteria provided, single submitter
402327	NM_001127644.2(GABRA1):c.789G>A (p.Met263Ile)	GABRA1	Likely pathogenic	no assertion criteria provided
4530665	NM_001127644.2(GABRA1):c.226A>T (p.Ser76Cys)	GABRA1	Likely pathogenic	criteria provided, single submitter
870352	NM_001127644.2(GABRA1):c.643C>A (p.Leu215Ile)	GABRA1	Likely pathogenic	criteria provided, single submitter
981377	NM_001127644.2(GABRA1):c.922G>A (p.Ala308Thr)	GABRA1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
982025	NM_001127644.2(GABRA1):c.763A>T (p.Ile255Phe)	GABRA1	Likely pathogenic	criteria provided, single submitter
1123486	NM_001127644.2(GABRA1):c.197C>A (p.Thr66Asn)	GABRA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
127074	NM_001127644.2(GABRA1):c.335G>A (p.Arg112Gln)	GABRA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1801345	NM_001127644.2(GABRA1):c.785_786dup (p.Met263Ter)	GABRA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197167	NM_001127644.2(GABRA1):c.85C>T (p.Pro29Ser)	GABRA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
205521	NM_001127644.2(GABRA1):c.799C>A (p.Leu267Ile)	GABRA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
205528	NM_001127644.2(GABRA1):c.1130C>T (p.Pro377Leu)	GABRA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
GABRA1	Definitive	Autosomal dominant	developmental and epileptic encephalopathy, 19	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GABRA1	Orphanet:307	Juvenile myoclonic epilepsy
GABRA1	Orphanet:33069	Dravet syndrome
GABRA1	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
GABRA1	HGNC:4075	ENSG00000022355	P14867	Gamma-aminobutyric acid receptor subunit alpha-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GABRA1	Gamma-aminobutyric acid receptor subunit alpha-1	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: 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)
GABRA1	Other/Unknown	no		GABAAa_rcpt, GABBAa1_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
endothelial cell	1
lateral nuclear group of thalamus	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GABRA1	130	tissue_specific	marker	lateral nuclear group of thalamus, endothelial cell, middle temporal gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GABRA1	2,469

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GABRA1	P14867	86

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	GABRA1
Signaling by ERBB4	1	271.9×	0.004	GABRA1

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	GABRA1
gamma-aminobutyric acid signaling pathway	1	543.6×	0.003	GABRA1
synaptic transmission, GABAergic	1	495.6×	0.003	GABRA1
chloride transmembrane transport	1	237.3×	0.004	GABRA1

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
GABRA1	DIAZEPAM

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GABRA1	60	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DIAZEPAM	4	GABRA1
FLUNITRAZEPAM	4	GABRA1
ESZOPICLONE	4	GABRA1
FLUMAZENIL	4	GABRA1
TRIAZOLAM	4	GABRA1
ALPRAZOLAM	4	GABRA1
ETOMIDATE	4	GABRA1
ZOLPIDEM	4	GABRA1
ENZALUTAMIDE	4	GABRA1
LIOTHYRONINE	4	GABRA1
GANAXOLONE	4	GABRA1
BREXANOLONE	4	GABRA1
APALUTAMIDE	4	GABRA1
CLONAZEPAM	4	GABRA1
LINDANE	4	GABRA1
CHLORDIAZEPOXIDE	4	GABRA1
PROPOFOL	4	GABRA1
ZALEPLON	4	GABRA1
STIRIPENTOL	4	GABRA1
ZURANOLONE	4	GABRA1
CANDESARTAN CILEXETIL	4	GABRA1
SIMVASTATIN	4	GABRA1
EPINASTINE	4	GABRA1
GLAFENINE	4	GABRA1
TIPRANAVIR	4	GABRA1
BENPERIDOL	4	GABRA1
ASENAPINE	4	GABRA1
TROGLITAZONE	4	GABRA1
CLOZAPINE	4	GABRA1
CHLORAMBUCIL	4	GABRA1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GABRA1	842	Binding:701, Functional:124, ADMET:13, Toxicity:4

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GABRA1	842

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)
DIAZEPAM	4	GABRA1
FLUNITRAZEPAM	4	GABRA1
ESZOPICLONE	4	GABRA1
FLUMAZENIL	4	GABRA1
TRIAZOLAM	4	GABRA1
ALPRAZOLAM	4	GABRA1
ETOMIDATE	4	GABRA1
ZOLPIDEM	4	GABRA1
ENZALUTAMIDE	4	GABRA1
LIOTHYRONINE	4	GABRA1
GANAXOLONE	4	GABRA1
BREXANOLONE	4	GABRA1
APALUTAMIDE	4	GABRA1
CLONAZEPAM	4	GABRA1
LINDANE	4	GABRA1
CHLORDIAZEPOXIDE	4	GABRA1
PROPOFOL	4	GABRA1
ZALEPLON	4	GABRA1
STIRIPENTOL	4	GABRA1
ZURANOLONE	4	GABRA1
CANDESARTAN CILEXETIL	4	GABRA1
SIMVASTATIN	4	GABRA1
EPINASTINE	4	GABRA1
GLAFENINE	4	GABRA1
TIPRANAVIR	4	GABRA1
BENPERIDOL	4	GABRA1
ASENAPINE	4	GABRA1
TROGLITAZONE	4	GABRA1
CLOZAPINE	4	GABRA1
CHLORAMBUCIL	4	GABRA1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GABRA1
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.