Developmental and epileptic encephalopathy, 67

Summary

Developmental and epileptic encephalopathy, 67 (MONDO:0029138) is a disease caused by CUX2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: CUX2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 70

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 67
Mondo ID	MONDO:0029138
OMIM	618141
DOID	DOID:0112203
UMLS	C4748341
MedGen	1648285
GARD	0016295
Is cancer (heuristic)	no

Also known as: DEE67 · developmental and epileptic encephalopathy 67 · EIEE67 · epileptic encephalopathy, early infantile, 67

Data availability: 70 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, 67

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, 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

70 retrieved; paginated sample, class counts are floors:

57 uncertain significance, 4 benign/likely benign, 3 benign, 3 conflicting classifications of pathogenicity, 1 pathogenic, 1 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1296981	NM_015267.4(CUX2):c.2834C>T (p.Thr945Met)	CUX2	Pathogenic	no assertion criteria provided
585015	NM_015267.4(CUX2):c.1768G>A (p.Glu590Lys)	CUX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2500118	NM_015267.4(CUX2):c.560del (p.Lys187fs)	CUX2	Likely pathogenic	criteria provided, single submitter
1175839	NM_015267.4(CUX2):c.79G>T (p.Val27Phe)	CUX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1701211	NM_015267.4(CUX2):c.3702T>G (p.Asp1234Glu)	CUX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
734838	NM_015267.4(CUX2):c.4108G>A (p.Gly1370Arg)	CUX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1098638	NM_015267.4(CUX2):c.3133C>T (p.Pro1045Ser)	CUX2	Uncertain significance	criteria provided, single submitter
1299609	NM_015267.4(CUX2):c.2502dup (p.Glu835fs)	CUX2	Uncertain significance	criteria provided, single submitter
1339195	NM_015267.4(CUX2):c.2482G>C (p.Asp828His)	CUX2	Uncertain significance	criteria provided, single submitter
1342335	NM_015267.4(CUX2):c.1267C>G (p.Pro423Ala)	CUX2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1342530	NM_015267.4(CUX2):c.137T>C (p.Ile46Thr)	CUX2	Uncertain significance	criteria provided, single submitter
1675513	NM_015267.4(CUX2):c.4297C>T (p.Pro1433Ser)	CUX2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1696486	NM_015267.4(CUX2):c.1603C>T (p.Pro535Ser)	CUX2	Uncertain significance	criteria provided, single submitter
1696662	NM_015267.4(CUX2):c.1481C>T (p.Pro494Leu)	CUX2	Uncertain significance	criteria provided, single submitter
1708073	NM_015267.4(CUX2):c.1816_1822del (p.Lys606fs)	CUX2	Uncertain significance	criteria provided, single submitter
1709625	NM_015267.4(CUX2):c.1913C>T (p.Pro638Leu)	CUX2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1709690	NM_015267.4(CUX2):c.2101C>A (p.Arg701Ser)	CUX2	Uncertain significance	criteria provided, single submitter
1805119	NM_015267.4(CUX2):c.1571C>T (p.Ala524Val)	CUX2	Uncertain significance	criteria provided, single submitter
1805934	NM_015267.4(CUX2):c.1945G>A (p.Asp649Asn)	CUX2	Uncertain significance	criteria provided, single submitter
1806080	NM_015267.4(CUX2):c.223-1G>A	CUX2	Uncertain significance	criteria provided, single submitter
1895408	NM_015267.4(CUX2):c.2408T>A (p.Val803Glu)	CUX2	Uncertain significance	criteria provided, single submitter
2358152	NM_015267.4(CUX2):c.1631C>T (p.Ala544Val)	CUX2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2407709	NM_015267.4(CUX2):c.3008G>A (p.Ser1003Asn)	CUX2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2431827	NM_015267.4(CUX2):c.4141A>C (p.Lys1381Gln)	CUX2	Uncertain significance	criteria provided, single submitter
2431917	NM_015267.4(CUX2):c.646G>T (p.Ala216Ser)	CUX2	Uncertain significance	criteria provided, single submitter
2440643	NM_015267.4(CUX2):c.1006G>A (p.Ala336Thr)	CUX2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2440644	NM_015267.4(CUX2):c.3556G>T (p.Ala1186Ser)	CUX2	Uncertain significance	criteria provided, single submitter
2440646	NM_015267.4(CUX2):c.2501C>G (p.Pro834Arg)	CUX2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2440647	NM_015267.4(CUX2):c.2531A>G (p.Asp844Gly)	CUX2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2440648	NM_015267.4(CUX2):c.561-4G>A	CUX2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
CUX2	Strong	Autosomal dominant	developmental and epileptic encephalopathy, 67	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CUX2	Orphanet:2382	Lennox-Gastaut syndrome

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
CUX2	HGNC:19347	ENSG00000111249	O14529	Homeobox protein cut-like 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CUX2	Homeobox protein cut-like 2	Transcription factor involved in the control of neuronal proliferation and differentiation in the brain.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CUX2	Transcription factor	no		HD, CUT_dom, Homeodomain-like_sf

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
buccal mucosa cell	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CUX2	144	broad	marker	middle temporal gyrus, buccal mucosa cell, Brodmann (1909) area 23

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CUX2	2,026

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CUX2	O14529	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
short-term memory	1	1296.3×	0.003	CUX2
positive regulation of dendrite morphogenesis	1	887.0×	0.003	CUX2
positive regulation of dendritic spine morphogenesis	1	887.0×	0.003	CUX2
positive regulation of excitatory postsynaptic potential	1	526.6×	0.004	CUX2
cognition	1	285.6×	0.006	CUX2
positive regulation of synapse assembly	1	244.2×	0.006	CUX2
positive regulation of gene expression	1	38.7×	0.033	CUX2
negative regulation of transcription by RNA polymerase II	1	17.7×	0.063	CUX2
regulation of transcription by RNA polymerase II	1	11.7×	0.086	CUX2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
CUX2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	1	CUX2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CUX2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.