Developmental and epileptic encephalopathy, 21

Summary

Developmental and epileptic encephalopathy, 21 (MONDO:0014360) is a disease caused by NECAP1 (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: NECAP1 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 195

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 21
Mondo ID	MONDO:0014360
OMIM	615833
DOID	DOID:0080443
UMLS	C4014430
MedGen	862867
GARD	0016017
Is cancer (heuristic)	no

Also known as: DEE21 · developmental and epileptic encephalopathy 21 · early infantile epileptic encephalopathy caused by mutation in NECAP1 · EIEE21 · epileptic encephalopathy, early infantile, 21 · epileptic encephalopathy, early infantile, type 21 · NECAP1 early infantile epileptic encephalopathy

Data availability: 195 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 › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn disorder of amino acid transport › undetermined early-onset epileptic encephalopathy › developmental and epileptic encephalopathy, 21

Related subtypes (15): developmental and epileptic encephalopathy, 13, developmental and epileptic encephalopathy, 24, developmental and epileptic encephalopathy, 25, developmental and epileptic encephalopathy, 26, developmental and epileptic encephalopathy, 28, developmental and epileptic encephalopathy, 29, developmental and epileptic encephalopathy, 31A, developmental and epileptic encephalopathy, 32, developmental and epileptic encephalopathy, 33, developmental and epileptic encephalopathy, 41, developmental and epileptic encephalopathy, 42, developmental and epileptic encephalopathy, 44, developmental and epileptic encephalopathy, 45, developmental and epileptic encephalopathy, 46, developmental and epileptic encephalopathy, 47

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

195 retrieved; paginated sample, class counts are floors:

93 uncertain significance, 92 likely benign, 3 benign, 3 pathogenic, 1 pathogenic/likely pathogenic, 1 likely pathogenic, 1 conflicting classifications of pathogenicity, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3244256	NC_000012.11:g.(?7053285)(9027607_?)del	A2ML1	Pathogenic	criteria provided, single submitter
133341	NM_015509.4(NECAP1):c.142C>T (p.Arg48Ter)	NECAP1	Pathogenic/Likely pathogenic	no assertion criteria provided
1994553	NM_015509.4(NECAP1):c.258_273del (p.Asp87fs)	NECAP1	Pathogenic	criteria provided, single submitter
929499	NM_015509.4(NECAP1):c.301+1G>A	NECAP1	Pathogenic	no assertion criteria provided
2431545	NM_015509.4(NECAP1):c.38_39dup (p.Lys14Ter)	LOC126861440	Likely pathogenic	criteria provided, single submitter
475008	NM_015509.4(NECAP1):c.670G>A (p.Asp224Asn)	NECAP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1004385	NC_000012.11:g.(?6945914)(9027627_?)dup	ATN1	Uncertain significance	criteria provided, single submitter
2426174	NC_000012.11:g.(?8211333)(8248686_?)dup	C3AR1	Uncertain significance	criteria provided, single submitter
832123	NC_000012.12:g.(?7689858)(8096110_?)dup	C3AR1	Uncertain significance	criteria provided, single submitter
1024154	NM_015509.4(NECAP1):c.83A>T (p.Asn28Ile)	LOC126861440	Uncertain significance	criteria provided, single submitter
1389574	NM_015509.4(NECAP1):c.11A>G (p.Glu4Gly)	LOC126861440	Uncertain significance	criteria provided, single submitter
1951875	NM_015509.4(NECAP1):c.8C>G (p.Thr3Ser)	LOC126861440	Uncertain significance	criteria provided, single submitter
1955215	NM_015509.4(NECAP1):c.95+4C>T	LOC126861440	Uncertain significance	criteria provided, single submitter
2049234	NM_015509.4(NECAP1):c.26C>G (p.Ser9Cys)	LOC126861440	Uncertain significance	criteria provided, single submitter
2112496	NM_015509.4(NECAP1):c.88G>C (p.Gly30Arg)	LOC126861440	Uncertain significance	criteria provided, single submitter
2162382	NM_015509.4(NECAP1):c.95+3A>T	LOC126861440	Uncertain significance	criteria provided, single submitter
541850	NM_015509.4(NECAP1):c.10G>A (p.Glu4Lys)	LOC126861440	Uncertain significance	criteria provided, single submitter
575282	NM_015509.4(NECAP1):c.56T>C (p.Val19Ala)	LOC126861440	Uncertain significance	criteria provided, single submitter
975913	NM_015509.4(NECAP1):c.88G>A (p.Gly30Ser)	LOC126861440	Uncertain significance	criteria provided, single submitter
1005148	NM_015509.4(NECAP1):c.569C>T (p.Pro190Leu)	NECAP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1020404	NM_015509.4(NECAP1):c.305G>A (p.Arg102His)	NECAP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1023652	NM_015509.4(NECAP1):c.758G>A (p.Gly253Glu)	NECAP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1026219	NM_015509.4(NECAP1):c.136C>T (p.Arg46Cys)	NECAP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1026898	NM_015509.4(NECAP1):c.244G>A (p.Val82Met)	NECAP1	Uncertain significance	criteria provided, single submitter
1041851	NM_015509.4(NECAP1):c.812A>G (p.Asn271Ser)	NECAP1	Uncertain significance	criteria provided, single submitter
1047283	NM_015509.4(NECAP1):c.797C>T (p.Ala266Val)	NECAP1	Uncertain significance	criteria provided, single submitter
1052018	NM_015509.4(NECAP1):c.746A>G (p.Asn249Ser)	NECAP1	Uncertain significance	criteria provided, single submitter
1059438	NM_015509.4(NECAP1):c.734T>C (p.Val245Ala)	NECAP1	Uncertain significance	criteria provided, single submitter
1348120	NM_015509.4(NECAP1):c.430G>A (p.Asp144Asn)	NECAP1	Uncertain significance	criteria provided, single submitter
1351176	NM_015509.4(NECAP1):c.492+3G>A	NECAP1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
NECAP1	Strong	Autosomal recessive	developmental and epileptic encephalopathy, 21	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NECAP1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
ATN1	Orphanet:101	Dentatorubral pallidoluysian atrophy

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NECAP1	HGNC:24539	ENSG00000089818	Q8NC96	Adaptin ear-binding coat-associated protein 1	gencc,clinvar
C3AR1	HGNC:1319	ENSG00000171860	Q16581	C3a anaphylatoxin chemotactic receptor	clinvar
A2ML1	HGNC:23336	ENSG00000166535	A8K2U0	Alpha-2-macroglobulin-like protein 1	clinvar
ATN1	HGNC:3033	ENSG00000111676	P54259	Atrophin-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NECAP1	Adaptin ear-binding coat-associated protein 1	Involved in endocytosis.
C3AR1	C3a anaphylatoxin chemotactic receptor	Receptor for the chemotactic and inflammatory peptide anaphylatoxin C3a, stimulating chemotaxis, granule enzyme release and superoxide anion production.
A2ML1	Alpha-2-macroglobulin-like protein 1	Is able to inhibit all four classes of proteinases by a unique ’trapping’ mechanism.
ATN1	Atrophin-1	Transcriptional corepressor.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

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
Complement	1	67.0×	0.045
GPCR	1	6.0×	0.235
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NECAP1	Other/Unknown	no		PH-like_dom_sf, NECAP_PHear
C3AR1	GPCR	yes		GPCR_Rhodpsn, Formyl_rcpt-rel, Anaphtx_C3AR1
A2ML1	Complement	yes		Macroglobln_a2, MG2, Terpenoid_cyclase/PrenylTrfase
ATN1	Other/Unknown	no		Atrophin-like, Atrophin-1

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cortical plate	1
prefrontal cortex	1
leukocyte	1
monocyte	1
mononuclear cell	1
gingiva	1
gingival epithelium	1
lower esophagus mucosa	1
adenohypophysis	1
right hemisphere of cerebellum	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NECAP1	279	ubiquitous	marker	cortical plate, prefrontal cortex, cerebellar cortex
C3AR1	262	broad	marker	monocyte, mononuclear cell, leukocyte
A2ML1	176	tissue_specific	marker	lower esophagus mucosa, gingiva, gingival epithelium
ATN1	223	ubiquitous	marker	right hemisphere of cerebellum, adenohypophysis, right uterine tube

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
C3AR1	2,278
ATN1	1,732
A2ML1	1,128
NECAP1	862

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
C3AR1	Q16581	18
A2ML1	A8K2U0	5
NECAP1	Q8NC96	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATN1	P54259	49.25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 28. Enrichment computed across 4 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
Cell recruitment (pro-inflammatory response)	1	380.7×	0.051	C3AR1
Complement cascade	1	211.5×	0.051	C3AR1
Purinergic signaling in leishmaniasis infection	1	141.0×	0.051	C3AR1
trans-Golgi Network Vesicle Budding	1	84.6×	0.051	NECAP1
Regulation of Complement cascade	1	77.7×	0.051	C3AR1
PTEN Regulation	1	76.1×	0.051	ATN1
Golgi Associated Vesicle Biogenesis	1	66.8×	0.051	NECAP1
Regulation of PTEN gene transcription	1	59.5×	0.051	ATN1
Leishmania infection	1	54.4×	0.051	C3AR1
Parasitic Infection Pathways	1	54.4×	0.051	C3AR1
Cargo recognition for clathrin-mediated endocytosis	1	34.9×	0.066	NECAP1
Signal Transduction	2	6.8×	0.066	C3AR1, ATN1
Intracellular signaling by second messengers	1	30.4×	0.070	ATN1
Clathrin-mediated endocytosis	1	28.4×	0.070	NECAP1
Class A/1 (Rhodopsin-like receptors)	1	24.7×	0.070	C3AR1
Peptide ligand-binding receptors	1	24.7×	0.070	C3AR1
PIP3 activates AKT signaling	1	22.3×	0.072	ATN1
GPCR ligand binding	1	21.4×	0.072	C3AR1
GPCR downstream signalling	1	14.5×	0.099	C3AR1
Signaling by GPCR	1	13.4×	0.100	C3AR1
G alpha (i) signalling events	1	13.0×	0.100	C3AR1
Membrane Trafficking	1	12.4×	0.100	NECAP1
Vesicle-mediated transport	1	11.6×	0.102	NECAP1
Innate Immune System	1	8.5×	0.130	C3AR1
Infectious disease	1	8.3×	0.130	C3AR1
Neutrophil degranulation	1	7.7×	0.134	C3AR1
Disease	1	4.4×	0.214	C3AR1
Immune System	1	4.3×	0.214	C3AR1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of endopeptidase activity	1	4213.0×	0.007	A2ML1
cell killing	1	2106.5×	0.007	ATN1
presynaptic endocytosis	1	842.6×	0.011	NECAP1
maintenance of cell polarity	1	601.9×	0.012	ATN1
complement receptor mediated signaling pathway	1	280.9×	0.021	C3AR1
positive regulation of macrophage chemotaxis	1	200.6×	0.023	C3AR1
positive regulation of neutrophil chemotaxis	1	162.0×	0.023	C3AR1
blood circulation	1	127.7×	0.023	C3AR1
positive regulation of vascular endothelial growth factor production	1	123.9×	0.023	C3AR1
response to food	1	123.9×	0.023	ATN1
determination of adult lifespan	1	108.0×	0.024	ATN1
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1	54.7×	0.042	C3AR1
post-embryonic development	1	51.4×	0.042	ATN1
neuron apoptotic process	1	46.3×	0.042	ATN1
calcium-mediated signaling	1	45.8×	0.042	C3AR1
male gonad development	1	39.0×	0.045	ATN1
multicellular organism growth	1	34.2×	0.045	ATN1
chemotaxis	1	34.0×	0.045	C3AR1
phospholipase C-activating G protein-coupled receptor signaling pathway	1	32.9×	0.045	C3AR1
positive regulation of cytosolic calcium ion concentration	1	29.3×	0.045	C3AR1
central nervous system development	1	28.9×	0.045	ATN1
positive regulation of angiogenesis	1	28.9×	0.045	C3AR1
vesicle-mediated transport	1	24.1×	0.052	NECAP1
cell migration	1	15.4×	0.077	ATN1
protein transport	1	11.0×	0.102	NECAP1
inflammatory response	1	9.4×	0.113	C3AR1
G protein-coupled receptor signaling pathway	1	9.1×	0.113	C3AR1
spermatogenesis	1	8.8×	0.113	ATN1
negative regulation of transcription by RNA polymerase II	1	4.4×	0.207	ATN1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 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
C3AR1	LOPERAMIDE HYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
C3AR1	1	4
NECAP1	0	0
A2ML1	0	0
ATN1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LOPERAMIDE HYDROCHLORIDE	4	C3AR1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
C3AR1	75	Functional:45, Binding:28, ADMET:2
ATN1	5	Binding:5

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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)
LOPERAMIDE HYDROCHLORIDE	4	C3AR1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	C3AR1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	A2ML1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	NECAP1, ATN1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NECAP1	0	—
A2ML1	0	—
ATN1	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.