Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3

Summary

Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 (MONDO:0011428) is a disease caused by TP63 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: TP63 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 192

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3
Mondo ID	MONDO:0011428
MeSH	C565799
OMIM	604292
DOID	DOID:0060783
UMLS	C1858562
MedGen	347666
GARD	0024798
Is cancer (heuristic)	no

Also known as: ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome type 3 · ectrodactyly, ectodermal dysplasia, and cleft LIP/palate syndrome 3 · ectrodactyly, ectodermal dysplasia, and cleft Lip/palate syndrome type 3 · EEC syndrome 3 · EEC syndrome caused by mutation in TP63 · EEC3 · TP63 EEC syndrome

Data availability: 192 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › EEC syndrome › ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3

Related subtypes (1): ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 1

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

192 retrieved; paginated sample, class counts are floors:

91 uncertain significance, 31 conflicting classifications of pathogenicity, 25 benign/likely benign, 13 likely benign, 10 pathogenic, 9 benign, 7 likely pathogenic, 6 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
208163	NM_003722.5(TP63):c.740A>G (p.His247Arg)	TP63	Pathogenic	criteria provided, multiple submitters, no conflicts
208418	NM_003722.5(TP63):c.1037C>G (p.Ala346Gly)	TP63	Pathogenic	criteria provided, single submitter
279913	NM_003722.5(TP63):c.1027C>T (p.Arg343Trp)	TP63	Pathogenic	criteria provided, multiple submitters, no conflicts
478110	NM_003722.5(TP63):c.739C>T (p.His247Tyr)	TP63	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
635754	NM_003722.5(TP63):c.1350-75_1492del	TP63	Pathogenic	no assertion criteria provided
650760	NM_003722.5(TP63):c.952C>T (p.Arg318Cys)	TP63	Pathogenic	criteria provided, multiple submitters, no conflicts
6527	NM_003722.5(TP63):c.727C>T (p.Arg243Trp)	TP63	Pathogenic	criteria provided, multiple submitters, no conflicts
6528	NM_003722.5(TP63):c.728G>A (p.Arg243Gln)	TP63	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6529	NM_003722.5(TP63):c.1033T>C (p.Cys345Arg)	TP63	Pathogenic	no assertion criteria provided
6530	NM_003722.5(TP63):c.1691dup (p.Tyr564Ter)	TP63	Pathogenic	no assertion criteria provided
6532	NM_003722.5(TP63):c.955C>T (p.Arg319Cys)	TP63	Pathogenic	criteria provided, multiple submitters, no conflicts
6533	NM_003722.5(TP63):c.953G>A (p.Arg318His)	TP63	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6534	NM_003722.5(TP63):c.1028G>A (p.Arg343Gln)	TP63	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6541	NM_003722.5(TP63):c.1052A>G (p.Asp351Gly)	TP63	Pathogenic	criteria provided, single submitter
6550	NM_003722.5(TP63):c.797G>A (p.Arg266Gln)	TP63	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
689635	NM_003722.5(TP63):c.1685T>C (p.Leu562Pro)	TP63	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1325219	NM_003722.5(TP63):c.970_972del (p.Ile324del)	TP63	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344645	NM_003722.5(TP63):c.1012C>T (p.Arg338Cys)	TP63	Likely pathogenic	no assertion criteria provided
2203760	NM_003722.5(TP63):c.925A>G (p.Asn309Asp)	TP63	Likely pathogenic	criteria provided, single submitter
30348	NM_003722.5(TP63):c.797G>C (p.Arg266Pro)	TP63	Likely pathogenic	criteria provided, single submitter
3589070	NM_003722.5(TP63):c.345dup (p.Leu116fs)	TP63	Likely pathogenic	criteria provided, single submitter
3589074	NM_003722.5(TP63):c.1129+1G>A	TP63	Likely pathogenic	criteria provided, single submitter
4796625	NM_003722.5(TP63):c.733C>T (p.Pro245Ser)	TP63	Likely pathogenic	criteria provided, single submitter
1333323	NM_003722.5(TP63):c.802G>A (p.Glu268Lys)	TP63	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1370798	NM_003722.5(TP63):c.1537G>C (p.Ala513Pro)	TP63	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1412118	NM_003722.5(TP63):c.1814G>A (p.Arg605Gln)	TP63	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1433359	NM_003722.5(TP63):c.1807G>C (p.Asp603His)	TP63	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1476128	NM_003722.5(TP63):c.2003G>A (p.Arg668His)	TP63	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1503085	NM_003722.5(TP63):c.1352C>G (p.Thr451Ser)	TP63	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1561066	NM_003722.5(TP63):c.475C>T (p.Leu159Phe)	TP63	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · 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
TP63	Definitive	Autosomal dominant	ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TP63	Orphanet:1072	Ankyloblepharon filiforme adnatum-cleft palate syndrome
TP63	Orphanet:141291	Cleft lip and alveolus
TP63	Orphanet:1896	EEC syndrome
TP63	Orphanet:199302	Isolated cleft lip
TP63	Orphanet:199306	Cleft lip/palate
TP63	Orphanet:2440	Isolated split hand-split foot malformation
TP63	Orphanet:69085	Limb-mammary syndrome
TP63	Orphanet:93930	Classic bladder exstrophy
TP63	Orphanet:978	ADULT 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
TP63	HGNC:15979	ENSG00000073282	Q9H3D4	Tumor protein 63	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TP63	Tumor protein 63	Acts as a sequence specific DNA binding transcriptional activator or repressor.

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)
TP63	Transcription factor	no		SAM, p53_tumour_suppressor, p53-like_TF_DNA-bd_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
skin of hip	1
upper arm skin	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TP63	207	broad	marker	upper leg skin, skin of hip, upper arm skin

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TP63	2,893

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TP63	Q9H3D4	26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. 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
Activation of PUMA and translocation to mitochondria	1	1142.0×	0.003	TP63
TP53 Regulates Transcription of Caspase Activators and Caspases	1	951.7×	0.003	TP63
TP53 Regulates Transcription of Death Receptors and Ligands	1	951.7×	0.003	TP63
Regulation of TP53 Activity through Association with Co-factors	1	815.7×	0.003	TP63
TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain	1	761.3×	0.003	TP63
Developmental Lineage of Mammary Stem Cells	1	761.3×	0.003	TP63
TP53 Regulates Transcription of Genes Involved in Cytochrome C Release	1	543.8×	0.003	TP63
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	543.8×	0.003	TP63
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	456.8×	0.003	TP63
Pyroptosis	1	423.0×	0.003	TP63
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	1	278.5×	0.004	TP63
TP53 Regulates Metabolic Genes	1	129.8×	0.008	TP63

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
ectoderm and mesoderm interaction	1	16852.0×	0.001	TP63
epidermal cell division	1	16852.0×	0.001	TP63
cloacal septation	1	8426.0×	0.001	TP63
squamous basal epithelial stem cell differentiation involved in prostate gland acinus development	1	8426.0×	0.001	TP63
positive regulation of somatic stem cell population maintenance	1	8426.0×	0.001	TP63
regulation of epidermal cell division	1	5617.3×	0.001	TP63
female genitalia morphogenesis	1	5617.3×	0.001	TP63
negative regulation of mesoderm development	1	5617.3×	0.001	TP63
prostatic bud formation	1	4213.0×	0.001	TP63
polarized epithelial cell differentiation	1	2808.7×	0.002	TP63
negative regulation of keratinocyte differentiation	1	1685.2×	0.003	TP63
positive regulation of fibroblast apoptotic process	1	1685.2×	0.003	TP63
epithelial cell development	1	1532.0×	0.003	TP63
skin morphogenesis	1	1404.3×	0.003	TP63
negative regulation of intracellular estrogen receptor signaling pathway	1	1123.5×	0.003	TP63
positive regulation of cell cycle G1/S phase transition	1	1123.5×	0.003	TP63
establishment of planar polarity	1	1053.2×	0.003	TP63
positive regulation of keratinocyte proliferation	1	991.3×	0.003	TP63
sympathetic nervous system development	1	936.2×	0.003	TP63
cranial skeletal system development	1	936.2×	0.003	TP63
post-anal tail morphogenesis	1	732.7×	0.003	TP63
proximal/distal pattern formation	1	648.1×	0.003	TP63
negative regulation of cellular senescence	1	648.1×	0.003	TP63
protein tetramerization	1	624.1×	0.003	TP63
embryonic hindlimb morphogenesis	1	581.1×	0.003	TP63
keratinocyte proliferation	1	581.1×	0.003	TP63
positive regulation of apoptotic signaling pathway	1	581.1×	0.003	TP63
positive regulation of stem cell proliferation	1	526.6×	0.003	TP63
hair follicle morphogenesis	1	495.6×	0.003	TP63
embryonic forelimb morphogenesis	1	495.6×	0.003	TP63

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
TP63	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	TP63

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)
TP63	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.