Developmental and epileptic encephalopathy, 59

Summary

Developmental and epileptic encephalopathy, 59 (MONDO:0033368) is a disease caused by GABBR2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: GABBR2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 37

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 59
Mondo ID	MONDO:0033368
OMIM	617904
DOID	DOID:0080291
UMLS	C4693550
MedGen	1633749
GARD	0025797
Is cancer (heuristic)	no

Also known as: DEE59 · developmental and epileptic encephalopathy 59 · EIEE59 · epileptic encephalopathy, early infantile, 59 · infantile epileptic encephalopathy 59

Data availability: 37 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 › hereditary neurological disease › Mendelian neurodevelopmental disorder › genetic developmental and epileptic encephalopathy › developmental and epileptic encephalopathy, 59

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, 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, 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

37 retrieved; paginated sample, class counts are floors:

17 uncertain significance, 6 conflicting classifications of pathogenicity, 4 benign, 4 likely pathogenic, 3 pathogenic, 2 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1691275	NM_005458.8(GABBR2):c.2084G>A (p.Ser695Asn)	GABBR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
496588	NM_005458.8(GABBR2):c.2077G>T (p.Gly693Trp)	GABBR2	Pathogenic	criteria provided, multiple submitters, no conflicts
496589	NM_005458.8(GABBR2):c.2084G>T (p.Ser695Ile)	GABBR2	Pathogenic	no assertion criteria provided
496590	NM_005458.8(GABBR2):c.2114T>A (p.Ile705Asn)	GABBR2	Pathogenic	no assertion criteria provided
496592	NM_005458.8(GABBR2):c.2119G>A (p.Ala707Thr)	GABBR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2430201	NM_005458.8(GABBR2):c.2072A>G (p.Tyr691Cys)	GABBR2	Likely pathogenic	criteria provided, single submitter
2444365	NM_005458.8(GABBR2):c.72_73insACCATGGTTCAGCCACATCTGTCACTTGCCAGTATTGGTACGCATTAAAGTAACTGGTCTGAAACGTTCTATCCAAGAACGCTTGAACTTCCAAGTTACTAATGAAGTAATTCAAC (p.Leu25delinsThrMetValGlnProHisLeuSerLeuAlaSerIleGlyThrHisTer)	GABBR2	Likely pathogenic	criteria provided, single submitter
3376344	NM_005458.8(GABBR2):c.2029G>A (p.Glu677Lys)	GABBR2	Likely pathogenic	criteria provided, single submitter
4072293	NM_005458.8(GABBR2):c.1723A>T (p.Thr575Ser)	GABBR2	Likely pathogenic	criteria provided, single submitter
2004414	NM_005458.8(GABBR2):c.1000-3C>T	GABBR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
446211	NM_005458.8(GABBR2):c.1699G>A (p.Ala567Thr)	GABBR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
571315	NM_005458.8(GABBR2):c.56C>T (p.Pro19Leu)	GABBR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
833649	NM_005458.8(GABBR2):c.2737A>G (p.Ser913Gly)	GABBR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
843039	NM_005458.8(GABBR2):c.68T>C (p.Leu23Pro)	GABBR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
964522	NM_005458.8(GABBR2):c.2412+3A>G	GABBR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1015213	NM_005458.8(GABBR2):c.131G>A (p.Arg44Gln)	GABBR2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1023217	NM_005458.8(GABBR2):c.1662+1G>A	GABBR2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1325607	NM_005458.8(GABBR2):c.166C>G (p.Leu56Val)	GABBR2	Uncertain significance	criteria provided, single submitter
1369304	NM_005458.8(GABBR2):c.2360G>A (p.Arg787His)	GABBR2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1496079	NM_005458.8(GABBR2):c.121G>T (p.Gly41Cys)	GABBR2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1679636	NM_005458.8(GABBR2):c.*1906T>C	GABBR2	Uncertain significance	criteria provided, single submitter
1708975	NM_005458.8(GABBR2):c.1065C>G (p.His355Gln)	GABBR2	Uncertain significance	criteria provided, single submitter
1709059	NM_005458.8(GABBR2):c.2195G>T (p.Ser732Ile)	GABBR2	Uncertain significance	criteria provided, single submitter
1709247	NM_005458.8(GABBR2):c.2206C>T (p.Leu736Phe)	GABBR2	Uncertain significance	criteria provided, single submitter
2476373	NM_005458.8(GABBR2):c.2777G>A (p.Arg926His)	GABBR2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2664175	NM_005458.8(GABBR2):c.2527T>G (p.Phe843Val)	GABBR2	Uncertain significance	criteria provided, single submitter
3892754	NM_005458.8(GABBR2):c.1213G>A (p.Glu405Lys)	GABBR2	Uncertain significance	criteria provided, single submitter
3892759	NM_005458.8(GABBR2):c.284G>T (p.Arg95Leu)	GABBR2	Uncertain significance	criteria provided, single submitter
3898039	NM_005458.8(GABBR2):c.1895C>A (p.Pro632Gln)	GABBR2	Uncertain significance	criteria provided, single submitter
4813517	NM_005458.8(GABBR2):c.2028G>A (p.Trp676Ter)	GABBR2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
GABBR2	Strong	Autosomal dominant	developmental and epileptic encephalopathy, 59	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GABBR2	Orphanet:3095	Atypical Rett syndrome
GABBR2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy

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
GABBR2	HGNC:4507	ENSG00000136928	O75899	Gamma-aminobutyric acid type B receptor subunit 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GABBR2	Gamma-aminobutyric acid type B receptor subunit 2	Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
GPCR	1	23.9×	0.042

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GABBR2	GPCR	yes		GPCR_3, ANF_lig-bd_rcpt, GPCR3_GABA-B

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
lateral nuclear group of thalamus	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GABBR2	193	broad	marker	Brodmann (1909) area 23, lateral nuclear group of thalamus, middle temporal gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GABBR2	1,980

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GABBR2	O75899	26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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 B receptor activation	1	543.8×	0.004	GABBR2
Activation of G protein gated Potassium channels	1	393.8×	0.004	GABBR2
Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits	1	393.8×	0.004	GABBR2
Class C/3 (Metabotropic glutamate/pheromone receptors)	1	292.8×	0.004	GABBR2
G alpha (i) signalling events	1	39.0×	0.026	GABBR2

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
neuron-glial cell signaling	1	3370.4×	0.002	GABBR2
negative regulation of adenylate cyclase activity	1	1404.3×	0.002	GABBR2
gamma-aminobutyric acid signaling pathway	1	543.6×	0.004	GABBR2
synaptic transmission, GABAergic	1	495.6×	0.004	GABBR2
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1	218.9×	0.006	GABBR2
chemical synaptic transmission	1	77.3×	0.015	GABBR2
G protein-coupled receptor signaling pathway	1	36.2×	0.028	GABBR2

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
GABBR2	BACLOFEN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GABBR2	4	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BACLOFEN	4	GABBR2
ARBACLOFEN	3	GABBR2
SGS-742	2	GABBR2
GAMMA-AMINOBUTYRIC ACID	1	GABBR2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GABBR2	57	Binding:35, Functional:21, ADMET:1

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

4 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)
BACLOFEN	4	GABBR2
ARBACLOFEN	3	GABBR2
SGS-742	2	GABBR2
GAMMA-AMINOBUTYRIC ACID	1	GABBR2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GABBR2
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.