Cleft lip/palate-ectodermal dysplasia syndrome

Summary

Cleft lip/palate-ectodermal dysplasia syndrome (MONDO:0009151) is a disease caused by NECTIN1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: NECTIN1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 152

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cleft lip/palate-ectodermal dysplasia syndrome
Mondo ID	MONDO:0009151
OMIM	225060
Orphanet	320317, 3253
DOID	DOID:0060773
NCIT	C122656
SNOMED CT	716248001
UMLS	C2931488
MedGen	444067
GARD	0000375
Is cancer (heuristic)	no

Also known as: autosomal recessive ectodermal dysplasia · Bustos Simosa pinto Cisternas syndrome · cleft lip/palate-ectodermal dysplasia syndrome · cleft lip/palate-syndactyly-pili torti · cleft lip/palate-syndactyly-pili torti syndrome · CLEPD · CLPED1 · ectodermal dysplasia margarita island type · ectodermal dysplasia type 4 · ectodermal dysplasia, cleft lip and palate, intellectual disability, and syndactyly · ectodermal dysplasia, cleft lip and palate, mental retardation, and syndactyly · ED4 · syndactyly-ectodermal dysplasia-cleft/lip palate · Zlotogora syndrome · Zlotogora-Ogur syndrome

Data availability: 152 ClinVar variants · 5 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › orofacial cleft › cleft lip/palate-ectodermal dysplasia syndrome

Related subtypes (15): cleft lip, orofacial cleft 1, orofacial cleft 2, orofacial cleft 4, orofacial cleft 9, orofacial cleft 12, orofacial cleft 13, familial median cleft of the upper and lower lips, cleft lip and alveolus, cleft lip/palate, cleft palate, orofacial cleft 8, GRHL3-related orofacial clefting, orofacial cleft 7, ARHGAP29-related non-syndromic orofacial cleft

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

152 retrieved; paginated sample, class counts are floors:

109 uncertain significance, 21 conflicting classifications of pathogenicity, 9 likely benign, 6 benign, 4 pathogenic, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1697231	NM_002855.5(NECTIN1):c.400C>T (p.Arg134Ter)	NECTIN1	Pathogenic	no assertion criteria provided
8969	NM_002855.5(NECTIN1):c.554G>A (p.Trp185Ter)	NECTIN1	Pathogenic	no assertion criteria provided
8970	NM_002855.5(NECTIN1):c.556del (p.Glu186fs)	NECTIN1	Pathogenic	criteria provided, single submitter
8971	NM_002855.5(NECTIN1):c.969dup (p.Thr324fs)	NECTIN1	Pathogenic	no assertion criteria provided
3061953	NM_002855.5(NECTIN1):c.226C>T (p.Gln76Ter)	NECTIN1	Likely pathogenic	criteria provided, single submitter
4278246	NM_002855.5(NECTIN1):c.1544G>A (p.Trp515Ter)	NECTIN1	Likely pathogenic	criteria provided, single submitter
984386	NM_002855.5(NECTIN1):c.472C>T (p.Arg158Ter)	NECTIN1	Likely pathogenic	no assertion criteria provided
709934	NM_002855.5(NECTIN1):c.596G>A (p.Arg199Gln)	NECTIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
716974	NM_002855.5(NECTIN1):c.1347C>T (p.Gly449=)	NECTIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
716975	NM_002855.5(NECTIN1):c.264C>T (p.Ser88=)	NECTIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
719352	NM_002855.5(NECTIN1):c.375G>A (p.Glu125=)	NECTIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
721451	NM_002855.5(NECTIN1):c.1548C>T (p.Tyr516=)	NECTIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
731361	NM_002855.5(NECTIN1):c.79+4A>G	NECTIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
740218	NM_002855.5(NECTIN1):c.618G>A (p.Thr206=)	NECTIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
745097	NM_002855.5(NECTIN1):c.561T>A (p.Thr187=)	NECTIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
746878	NM_002855.5(NECTIN1):c.431-4G>A	NECTIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
748554	NM_002855.5(NECTIN1):c.423G>A (p.Thr141=)	NECTIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
750950	NM_002855.5(NECTIN1):c.565T>C (p.Leu189=)	NECTIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
786830	NM_002855.5(NECTIN1):c.130G>A (p.Gly44Ser)	NECTIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
793005	NM_002855.5(NECTIN1):c.431-5C>T	NECTIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
877300	NM_002855.5(NECTIN1):c.*2751G>A	NECTIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
877468	NM_002855.5(NECTIN1):c.480G>A (p.Lys160=)	NECTIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
878431	NM_002855.5(NECTIN1):c.1520G>A (p.Gly507Glu)	NECTIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
878490	NM_002855.5(NECTIN1):c.177C>T (p.Ser59=)	NECTIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
879023	NM_002855.5(NECTIN1):c.1194C>T (p.Asn398=)	NECTIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
879024	NM_002855.5(NECTIN1):c.1182C>T (p.His394=)	NECTIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
880238	NM_002855.5(NECTIN1):c.635G>A (p.Arg212His)	NECTIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
880239	NM_002855.5(NECTIN1):c.629G>A (p.Arg210His)	NECTIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029485	NM_002855.5(NECTIN1):c.328C>T (p.Arg110Cys)	NECTIN1	Uncertain significance	criteria provided, multiple submitters, no conflicts
877236	NM_002855.5(NECTIN1):c.*3714A>T	NECTIN1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 4 · 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
NECTIN1	Strong	Autosomal recessive	cleft lip/palate-ectodermal dysplasia syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NECTIN1	Orphanet:141291	Cleft lip and alveolus
NECTIN1	Orphanet:199302	Isolated cleft lip
NECTIN1	Orphanet:199306	Cleft lip/palate
NECTIN1	Orphanet:3253	Cleft lip/palate-ectodermal dysplasia 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
NECTIN1	HGNC:9706	ENSG00000110400	Q15223	Nectin-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NECTIN1	Nectin-1	Cell adhesion molecule that promotes cell-cell contacts and plays important roles in the development of the nervous system.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Antibody/Immunoglobulin	1	29.2×	0.034

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NECTIN1	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom

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
esophagus mucosa	1
lower esophagus mucosa	1
skin of abdomen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NECTIN1	261	ubiquitous	marker	lower esophagus mucosa, skin of abdomen, esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NECTIN1	1,597

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NECTIN1	Q15223	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Nectin/Necl trans heterodimerization	1	1427.5×	0.004	NECTIN1
Adherens junctions interactions	1	248.3×	0.007	NECTIN1
Cell-cell junction organization	1	248.3×	0.007	NECTIN1
Cell junction organization	1	187.2×	0.007	NECTIN1
Cell-Cell communication	1	137.6×	0.007	NECTIN1

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
desmosome organization	1	2106.5×	0.003	NECTIN1
protein localization to cell junction	1	1872.4×	0.003	NECTIN1
lens morphogenesis in camera-type eye	1	1296.3×	0.003	NECTIN1
enamel mineralization	1	1203.7×	0.003	NECTIN1
iron ion transport	1	887.0×	0.003	NECTIN1
regulation of synapse assembly	1	702.2×	0.004	NECTIN1
cochlea morphogenesis	1	581.1×	0.004	NECTIN1
symbiont entry into host cell	1	401.2×	0.005	NECTIN1
heterophilic cell-cell adhesion	1	337.0×	0.005	NECTIN1
retina development in camera-type eye	1	255.3×	0.006	NECTIN1
homophilic cell-cell adhesion	1	140.4×	0.010	NECTIN1
cell-cell adhesion	1	101.5×	0.012	NECTIN1
axon guidance	1	90.6×	0.013	NECTIN1
immune response	1	47.1×	0.023	NECTIN1
cell adhesion	1	37.5×	0.027	NECTIN1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NECTIN1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NECTIN1	1	Binding:1

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	1	NECTIN1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
NECTIN1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.