Developmental and epileptic encephalopathy, 28

Summary

Developmental and epileptic encephalopathy, 28 (MONDO:0014533) is a disease caused by WWOX (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: WWOX (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 159

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 28
Mondo ID	MONDO:0014533
OMIM	616211
DOID	DOID:0080452
UMLS	C4015519
MedGen	863956
GARD	0016069
Is cancer (heuristic)	no

Also known as: DEE28 · developmental and epileptic encephalopathy 28 · early infantile epileptic encephalopathy caused by mutation in WWOX · EIEE28 · epileptic encephalopathy, early infantile, 28 · epileptic encephalopathy, early infantile, type 28 · WOREE syndrome · WWOX early infantile epileptic encephalopathy · WWOX-related epileptic encephalopathy

Data availability: 159 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 › 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, 28

Related subtypes (15): developmental and epileptic encephalopathy, 13, developmental and epileptic encephalopathy, 21, developmental and epileptic encephalopathy, 24, developmental and epileptic encephalopathy, 25, developmental and epileptic encephalopathy, 26, 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

159 retrieved; paginated sample, class counts are floors:

38 pathogenic, 37 uncertain significance, 20 benign, 18 benign/likely benign, 17 conflicting classifications of pathogenicity, 15 likely pathogenic, 13 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
4820083	Multiple alleles		Pathogenic	criteria provided, single submitter
2498155	NM_016373.4:c.517-94998_1056+78427del	LOC110120570	Pathogenic	criteria provided, single submitter
2500713	NM_016373.4(WWOX):c.606-1778_792-2744del	LOC112486209	Pathogenic	criteria provided, single submitter
180246	NM_016373.3(WWOX):c.-366-?_516+?del	LOC132090428	Pathogenic	no assertion criteria provided
978033	NC_000016.10:g.78152047_78188346del	LOC132090430	Pathogenic	criteria provided, single submitter
180248	NM_016373.4(WWOX):c.516+62335_517-3413del	LOC132090434	Pathogenic	no assertion criteria provided
100648	NM_016373.4(WWOX):c.1114G>C (p.Gly372Arg)	MAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1329854	NM_016373.4(WWOX):c.1171G>T (p.Glu391Ter)	MAF	Pathogenic	criteria provided, multiple submitters, no conflicts
450593	NM_016373.4(WWOX):c.1114G>T (p.Gly372Ter)	MAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1033412	NM_016373.4(WWOX):c.730C>T (p.Gln244Ter)	WWOX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068501	NM_016373.4(WWOX):c.127C>T (p.Gln43Ter)	WWOX	Pathogenic	criteria provided, multiple submitters, no conflicts
1072064	NM_016373.4(WWOX):c.321C>G (p.Tyr107Ter)	WWOX	Pathogenic	criteria provided, multiple submitters, no conflicts
1180630	NM_016373.4(WWOX):c.321C>A (p.Tyr107Ter)	WWOX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
120325	NM_016373.4(WWOX):c.160C>T (p.Arg54Ter)	WWOX	Pathogenic	criteria provided, multiple submitters, no conflicts
1338793	NM_016373.4:c.(516+1_517-1)_(605+1_606-1)del	WWOX	Pathogenic	criteria provided, single submitter
1339501	NM_016373.4(WWOX):c.409+1G>T	WWOX	Pathogenic	criteria provided, single submitter
1676782	NM_016373.4(WWOX):c.172+1G>C	WWOX	Pathogenic	criteria provided, single submitter
180247	NM_016373.4(WWOX):c.517-44258_606-268del	WWOX	Pathogenic	no assertion criteria provided
180249	NM_016373.4(WWOX):c.1005G>A (p.Trp335Ter)	WWOX	Pathogenic	no assertion criteria provided
180250	NM_016373.4(WWOX):c.46_49del (p.Asp16fs)	WWOX	Pathogenic	criteria provided, single submitter
180251	NM_016373.4(WWOX):c.140C>G (p.Pro47Arg)	WWOX	Pathogenic	no assertion criteria provided
1810421	NM_016373.4:c.517-11252_606-17640del	WWOX	Pathogenic	criteria provided, single submitter
183303	NM_016373.4(WWOX):c.606-1G>A	WWOX	Pathogenic	criteria provided, multiple submitters, no conflicts
2099038	NM_016373.4(WWOX):c.552dup (p.Ala185fs)	WWOX	Pathogenic	criteria provided, multiple submitters, no conflicts
241105	NM_016373.4(WWOX):c.790C>T (p.Arg264Ter)	WWOX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2500714	NM_016373.4(WWOX):c.982_998del (p.Tyr328fs)	WWOX	Pathogenic	criteria provided, single submitter
2579165	GRCh38/hg38 16q23.1(chr16:78099236-78100272)x0	WWOX	Pathogenic	criteria provided, single submitter
284393	NM_016373.4(WWOX):c.749C>G (p.Ser250Ter)	WWOX	Pathogenic	criteria provided, multiple submitters, no conflicts
3366918	NM_016373.4(WWOX):c.728dup (p.Gln244fs)	WWOX	Pathogenic	criteria provided, single submitter
3366919	NM_016373.4(WWOX):c.864G>A (p.Trp288Ter)	WWOX	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 9 · 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
WWOX	Strong	Autosomal recessive	developmental and epileptic encephalopathy, 28	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WWOX	Orphanet:251510	46,XY partial gonadal dysgenesis
WWOX	Orphanet:284282	Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to WWOX deficiency
WWOX	Orphanet:708171	Facial dysmorphism-corpus callosum hypoplasia-infantile epileptic encephalopathy
WWOX	Orphanet:99977	Squamous cell carcinoma of the esophagus
MAF	Orphanet:1272	Aymé-Gripp syndrome
MAF	Orphanet:1377	Cataract-microcornea syndrome
MAF	Orphanet:98984	Pulverulent cataract
MAF	Orphanet:98989	Cerulean cataract
NCF2	Orphanet:379	Chronic granulomatous disease

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
WWOX	HGNC:12799	ENSG00000186153	Q9NZC7	WW domain-containing oxidoreductase	gencc,clinvar
CLEC3A	HGNC:2052	ENSG00000166509	O75596	C-type lectin domain family 3 member A	clinvar
MAF	HGNC:6776	ENSG00000178573	O75444	Transcription factor Maf	clinvar
NCF2	HGNC:7661	ENSG00000116701	P19878	Neutrophil cytosol factor 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WWOX	WW domain-containing oxidoreductase	Putative oxidoreductase.
CLEC3A	C-type lectin domain family 3 member A	Promotes cell adhesion to laminin-332 and fibronectin.
MAF	Transcription factor Maf	Acts as a transcriptional activator or repressor.
NCF2	Neutrophil cytosol factor 2	Subunit of the phagocyte NADPH oxidase complex that mediates the transfer of electrons from cytosolic NADPH to O2 to produce the superoxide anion (O2(-)).

Protein-family classification

Druggable: 0 · Difficult: 3 · 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
Scaffold/PPI	2	8.6×	0.056
Transcription factor	1	2.1×	0.605
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WWOX	Scaffold/PPI	no		WW_dom, SDR_fam, WW_dom_sf
CLEC3A	Other/Unknown	no		C-type_lectin-like, C-type_lectin-like/link_sf, CTDL_fold
MAF	Transcription factor	no		bZIP_Maf, bZIP, TF_DNA-bd_sf
NCF2	Scaffold/PPI	no		PB1_dom, SH3_domain, TPR-like_helical_dom_sf

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
cervix squamous epithelium	1
cranial nerve II	1
parotid gland	1
male germ line stem cell (sensu Vertebrata) in testis	1
pancreatic ductal cell	1
tibia	1
germinal epithelium of ovary	1
gingiva	1
jejunal mucosa	1
leukocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WWOX	286	ubiquitous	marker	parotid gland, cervix squamous epithelium, cranial nerve II
CLEC3A	79	tissue_specific	marker	tibia, male germ line stem cell (sensu Vertebrata) in testis, pancreatic ductal cell
MAF	290	ubiquitous	marker	jejunal mucosa, germinal epithelium of ovary, gingiva
NCF2	205	broad	marker	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WWOX	5,892
MAF	4,111
NCF2	2,168
CLEC3A	716

Intra-cohort edges

A	B	Sources
CLEC3A	WWOX	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NCF2	P19878	7
WWOX	Q9NZC7	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CLEC3A	O75596	92.50
MAF	O75444	62.21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 33. 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
Cross-presentation of particulate exogenous antigens (phagosomes)	1	475.8×	0.030	NCF2
Negative regulation of activity of TFAP2 (AP-2) family transcription factors	1	380.7×	0.030	WWOX
Activation of the TFAP2 (AP-2) family of transcription factors	1	317.2×	0.030	WWOX
RUNX2 regulates bone development	1	271.9×	0.030	MAF
RHO GTPases Activate NADPH Oxidases	1	152.3×	0.033	NCF2
RUNX2 regulates osteoblast differentiation	1	152.3×	0.033	MAF
Nuclear signaling by ERBB4	1	115.3×	0.033	WWOX
ROS and RNS production in phagocytes	1	112.0×	0.033	NCF2
Antigen processing-Cross presentation	1	105.7×	0.033	NCF2
Detoxification of Reactive Oxygen Species	1	100.2×	0.033	NCF2
Transcriptional regulation by RUNX2	1	84.6×	0.035	MAF
Signaling by VEGF	1	73.2×	0.037	NCF2
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	1	48.8×	0.047	MAF
Cellular response to chemical stress	1	47.6×	0.047	NCF2
VEGFA-VEGFR2 Pathway	1	46.4×	0.047	NCF2
RAC2 GTPase cycle	1	42.3×	0.048	NCF2
RAC3 GTPase cycle	1	39.6×	0.049	NCF2
Class I MHC mediated antigen processing & presentation	1	23.4×	0.076	NCF2
RHO GTPase Effectors	1	22.7×	0.076	NCF2
RAC1 GTPase cycle	1	20.4×	0.077	NCF2
RHO GTPase cycle	1	20.0×	0.077	NCF2
Signaling by Receptor Tyrosine Kinases	1	17.2×	0.085	NCF2
Cellular responses to stress	1	12.3×	0.114	NCF2
Signaling by Rho GTPases	1	11.4×	0.115	NCF2
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	11.2×	0.115	NCF2
Cellular responses to stimuli	1	10.5×	0.117	NCF2
Adaptive Immune System	1	9.9×	0.119	NCF2
Innate Immune System	1	8.5×	0.133	NCF2
RNA Polymerase II Transcription	1	7.5×	0.145	MAF
Gene expression (Transcription)	1	6.0×	0.175	MAF

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
positive regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	383.0×	0.019	WWOX
regulation of chondrocyte differentiation	1	351.1×	0.019	MAF
respiratory burst	1	324.1×	0.019	NCF2
megakaryocyte differentiation	1	300.9×	0.019	MAF
lens fiber cell differentiation	1	263.3×	0.019	MAF
superoxide metabolic process	1	247.8×	0.019	NCF2
integrated stress response signaling	1	175.5×	0.021	MAF
superoxide anion generation	1	168.5×	0.021	NCF2
intrinsic apoptotic signaling pathway by p53 class mediator	1	145.3×	0.022	WWOX
skeletal system morphogenesis	1	123.9×	0.023	WWOX
positive regulation of extrinsic apoptotic signaling pathway	1	113.9×	0.023	WWOX
inner ear development	1	93.6×	0.024	MAF
negative regulation of Wnt signaling pathway	1	86.0×	0.024	WWOX
cellular defense response	1	79.5×	0.024	NCF2
extrinsic apoptotic signaling pathway	1	76.6×	0.024	WWOX
response to nutrient	1	73.9×	0.024	MAF
cellular response to transforming growth factor beta stimulus	1	69.1×	0.025	WWOX
phagocytosis	1	60.2×	0.027	NCF2
ossification	1	56.9×	0.027	CLEC3A
skeletal system development	1	31.4×	0.045	CLEC3A
osteoblast differentiation	1	30.3×	0.045	WWOX
Wnt signaling pathway	1	24.9×	0.052	WWOX
in utero embryonic development	1	18.0×	0.067	MAF
transcription by RNA polymerase II	1	17.6×	0.067	MAF
positive regulation of gene expression	1	9.7×	0.115	MAF
innate immune response	1	8.4×	0.127	NCF2
negative regulation of transcription by RNA polymerase II	1	4.4×	0.223	MAF
positive regulation of transcription by RNA polymerase II	1	3.7×	0.252	WWOX
regulation of transcription by RNA polymerase II	1	2.9×	0.302	MAF

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 4

Druggability breadth: 0 of 4 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
WWOX	0	0
CLEC3A	0	0
MAF	0	0
NCF2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	4	WWOX, CLEC3A, MAF, NCF2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
WWOX	0	—
CLEC3A	0	—
MAF	0	—
NCF2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.