Developmental and epileptic encephalopathy 93

Summary

Developmental and epileptic encephalopathy 93 (MONDO:0020632) is a disease caused by variants in ATP6V1A and ATP6V1B2, with 3 cohort genes. The dominant Reactome pathway is Ion channel transport (3 cohort genes).

At a glance

• Causal genes: ATP6V1A (GenCC Definitive), ATP6V1B2 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 44

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy 93
Mondo ID	MONDO:0020632
OMIM	618012
DOID	DOID:0112275
UMLS	C4693934
MedGen	1642888
GARD	0016285
Is cancer (heuristic)	no

Also known as: DEE93 · developmental and epileptic encephalopathy 93 · epileptic encephalopathy, infantile or early childhood, 3

Data availability: 44 ClinVar variants · 5 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 93

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 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

44 retrieved; paginated sample, class counts are floors:

24 uncertain significance, 8 pathogenic, 7 likely pathogenic, 2 pathogenic/likely pathogenic, 1 benign/likely benign, 1 conflicting classifications of pathogenicity, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1512702	NM_001690.4(ATP6V1A):c.955C>T (p.Pro319Ser)	ATP6V1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1722511	NM_001690.4(ATP6V1A):c.1088G>T (p.Gly363Val)	ATP6V1A	Pathogenic	no assertion criteria provided
1722512	NM_001690.4(ATP6V1A):c.1068G>T (p.Glu356Asp)	ATP6V1A	Pathogenic	no assertion criteria provided
2570676	NM_001690.4(ATP6V1A):c.1294T>A (p.Phe432Ile)	ATP6V1A	Pathogenic	criteria provided, single submitter
545524	NM_001690.4(ATP6V1A):c.298G>T (p.Asp100Tyr)	ATP6V1A	Pathogenic	criteria provided, single submitter
545525	NM_001690.4(ATP6V1A):c.1045G>A (p.Asp349Asn)	ATP6V1A	Pathogenic	no assertion criteria provided
545526	NM_001690.4(ATP6V1A):c.80C>G (p.Pro27Arg)	ATP6V1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
545527	NM_001690.4(ATP6V1A):c.1112A>G (p.Asp371Gly)	ATP6V1A	Pathogenic	no assertion criteria provided
973261	NM_001690.4(ATP6V1A):c.967A>G (p.Arg323Gly)	ATP6V1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3850	NM_000053.4(ATP7B):c.1708-1G>C	ATP7B	Pathogenic	criteria provided, multiple submitters, no conflicts
1029520	NM_001690.4(ATP6V1A):c.1649T>C (p.Met550Thr)	ATP6V1A	Likely pathogenic	criteria provided, single submitter
1172608	NM_001690.4(ATP6V1A):c.790T>C (p.Ser264Pro)	ATP6V1A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2627987	NM_001690.4(ATP6V1A):c.299A>T (p.Asp100Val)	ATP6V1A	Likely pathogenic	criteria provided, single submitter
3363195	NM_001690.4(ATP6V1A):c.1068G>C (p.Glu356Asp)	ATP6V1A	Likely pathogenic	criteria provided, single submitter
3377061	NM_001690.4(ATP6V1A):c.958G>A (p.Val320Ile)	ATP6V1A	Likely pathogenic	criteria provided, single submitter
4536633	NM_001690.4(ATP6V1A):c.1069G>C (p.Ala357Pro)	ATP6V1A	Likely pathogenic	criteria provided, single submitter
584428	NM_001690.4(ATP6V1A):c.1123C>A (p.Pro375Thr)	ATP6V1A	Likely pathogenic	criteria provided, single submitter
1986311	NM_001690.4(ATP6V1A):c.1798G>A (p.Asp600Asn)	ATP6V1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1213799	NM_001690.4(ATP6V1A):c.596T>C (p.Val199Ala)	ATP6V1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1285435	NM_001690.4(ATP6V1A):c.1031T>C (p.Val344Ala)	ATP6V1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1675929	NM_001690.4(ATP6V1A):c.1337C>T (p.Pro446Leu)	ATP6V1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1679669	NM_001690.4(ATP6V1A):c.248G>A (p.Gly83Asp)	ATP6V1A	Uncertain significance	criteria provided, single submitter
2052568	NM_001690.4(ATP6V1A):c.65A>G (p.His22Arg)	ATP6V1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2429372	NM_001690.4(ATP6V1A):c.31G>T (p.Asp11Tyr)	ATP6V1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2439387	NM_001690.4(ATP6V1A):c.280A>G (p.Ile94Val)	ATP6V1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2576576	NM_001690.4(ATP6V1A):c.548G>C (p.Gly183Ala)	ATP6V1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2585058	NM_001690.4(ATP6V1A):c.1660G>A (p.Ala554Thr)	ATP6V1A	Uncertain significance	criteria provided, single submitter
3148969	NM_001690.4(ATP6V1A):c.1720A>G (p.Met574Val)	ATP6V1A	Uncertain significance	criteria provided, single submitter
3362355	NM_001690.4(ATP6V1A):c.1282A>T (p.Ile428Phe)	ATP6V1A	Uncertain significance	criteria provided, single submitter
3362670	NM_001690.4(ATP6V1A):c.1227_1228del	ATP6V1A	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 6 · 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
ATP6V1A	Definitive	Autosomal dominant	developmental and epileptic encephalopathy 93	11
ATP6V1B2	Strong	Autosomal dominant	developmental and epileptic encephalopathy 93	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP6V1A	Orphanet:357074	Autosomal recessive cutis laxa type 2, classic type
ATP6V1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
ATP6V1B2	Orphanet:3473	Zimmermann-Laband syndrome
ATP6V1B2	Orphanet:79499	Autosomal dominant deafness-onychodystrophy syndrome
ATP6V1B2	Orphanet:79500	DOORS syndrome
ATP7B	Orphanet:905	Wilson disease

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ATP6V1A	HGNC:851	ENSG00000114573	P38606	V-type proton ATPase catalytic subunit A	gencc,clinvar
ATP6V1B2	HGNC:854	ENSG00000147416	P21281	V-type proton ATPase subunit B, brain isoform	gencc
ATP7B	HGNC:870	ENSG00000123191	P35670	Copper-transporting ATPase 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP6V1A	V-type proton ATPase catalytic subunit A	Catalytic subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.
ATP6V1B2	V-type proton ATPase subunit B, brain isoform	Non-catalytic subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.
ATP7B	Copper-transporting ATPase 2	Copper ion transmembrane transporter involved in the export of copper out of the cells.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATP6V1A	Other/Unknown	no		ATPase_F1/V1/A1_a/bsu_nucl-bd, ATPase_F1/V1/A1_a/bsu_N, ATPase_V1-cplx_asu
ATP6V1B2	Other/Unknown	no		ATPase_F1/V1/A1_a/bsu_nucl-bd, ATPase_F1/V1/A1_a/bsu_N, ATPase_V1-cplx_bsu
ATP7B	Transcription factor	no	7.2.2.8	P_typ_ATPase, HMA_dom, HMA_Cu_ion-bd

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1
lateral nuclear group of thalamus	1
monocyte	1
pons	1
nasal cavity epithelium	1
nasal cavity mucosa	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP6V1A	300	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, endothelial cell
ATP6V1B2	300	ubiquitous	marker	pons, monocyte, lateral nuclear group of thalamus
ATP7B	205	ubiquitous	marker	nasal cavity epithelium, right testis, nasal cavity mucosa

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP6V1A	3,301
ATP6V1B2	2,898
ATP7B	2,536

Intra-cohort edges

A	B	Sources
ATP6V1A	ATP6V1B2	biogrid_interaction, intact, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP7B	P35670	13
ATP6V1A	P38606	8
ATP6V1B2	P21281	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Ion channel transport	3	96.0×	9e-06	ATP6V1A, ATP6V1B2, ATP7B
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	2	447.8×	3e-05	ATP6V1A, ATP6V1B2
Insulin receptor recycling	2	253.8×	4e-05	ATP6V1A, ATP6V1B2
Transferrin endocytosis and recycling	2	245.6×	4e-05	ATP6V1A, ATP6V1B2
ROS and RNS production in phagocytes	2	223.9×	4e-05	ATP6V1A, ATP6V1B2
Amino acids regulate mTORC1	2	133.6×	1e-04	ATP6V1A, ATP6V1B2
Ion transport by P-type ATPases	1	69.2×	0.016	ATP7B
Transport of small molecules	1	8.4×	0.115	ATP7B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
synaptic vesicle lumen acidification	2	624.1×	6e-05	ATP6V1A, ATP6V1B2
vacuolar acidification	2	488.5×	6e-05	ATP6V1A, ATP6V1B2
ATP metabolic process	2	312.1×	1e-04	ATP6V1A, ATP6V1B2
proton transmembrane transport	2	208.1×	2e-04	ATP6V1A, ATP6V1B2
regulation of macroautophagy	2	197.1×	2e-04	ATP6V1A, ATP6V1B2
copper ion export	1	1872.4×	0.002	ATP7B
obsolete sequestering of calcium ion	1	1123.5×	0.003	ATP7B
viral translational frameshifting	1	936.2×	0.003	ATP7B
copper ion import	1	802.5×	0.003	ATP7B
cellular response to increased oxygen levels	1	702.2×	0.003	ATP6V1A
copper ion transport	1	561.7×	0.004	ATP7B
Golgi lumen acidification	1	561.7×	0.004	ATP6V1A
response to copper ion	1	510.7×	0.004	ATP7B
endosomal lumen acidification	1	401.2×	0.004	ATP6V1A
intracellular pH reduction	1	401.2×	0.004	ATP6V1A
xenobiotic detoxification by transmembrane export across the plasma membrane	1	374.5×	0.004	ATP7B
intracellular copper ion homeostasis	1	312.1×	0.005	ATP7B
lysosomal lumen acidification	1	224.7×	0.006	ATP6V1A
intracellular zinc ion homeostasis	1	160.5×	0.008	ATP7B
lactation	1	140.4×	0.009	ATP7B
intracellular iron ion homeostasis	1	81.4×	0.014	ATP6V1A
monoatomic ion transmembrane transport	1	69.3×	0.016	ATP7B
protein maturation	1	54.5×	0.019	ATP7B
establishment of localization in cell	1	53.5×	0.019	ATP7B

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
ATP6V1B2	ENOXACIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATP6V1B2	1	4
ATP6V1A	0	0
ATP7B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ENOXACIN	4	ATP6V1B2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ATP6V1B2	3	Binding:3
ATP6V1A	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATP7B	7.2.2.8, 7.2.2.9	P-type Cu+ transporter, P-type Cu2+ transporter

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 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)
ENOXACIN	4	ATP6V1B2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ATP6V1B2
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	2	ATP6V1A, ATP7B

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ATP6V1A	2	ATP6V1B2
ATP7B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.