Aplasia cutis-enamel dysplasia syndrome

Summary

Aplasia cutis-enamel dysplasia syndrome (MONDO:0968978) is a disease caused by FOSL2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: FOSL2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	aplasia cutis-enamel dysplasia syndrome
Mondo ID	MONDO:0968978
OMIM	620789
Orphanet	697356
UMLS	C5935608
MedGen	1854704
Is cancer (heuristic)	no

Also known as: Congenital scalp aplasia cutis-enamel hypoplasia-developmental delay-intellectual disability syndrome · FOSL2-related neurodevelopmental disorder

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

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › syndromic intellectual disability › aplasia cutis-enamel dysplasia syndrome

Related subtypes (16): Smith-Magenis syndrome, intellectual disability, Buenos-Aires type, intellectual disability, Wolff type, CK syndrome, AHDC1-related intellectual disability - obstructive sleep apnea - mild dysmorphism syndrome, 7p22.1 microduplication syndrome, 9p13 microdeletion syndrome, 3q27.3 microdeletion syndrome, 9q31.1q31.3 microdeletion syndrome, Rubinstein-Taybi syndrome, X-linked syndromic intellectual disability, 9q33.3q34.11 microdeletion syndrome, autosomal recessive syndromic intellectual disability, autosomal dominant syndromic intellectual disability, 2p25.3 microduplication syndrome, dyneinopathy

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

5 retrieved; paginated sample, class counts are floors:

4 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3242357	NM_005253.4(FOSL2):c.595C>T (p.Arg199Ter)	FOSL2	Pathogenic	no assertion criteria provided
3242359	NM_005253.4(FOSL2):c.662_663del (p.Val221fs)	FOSL2	Pathogenic	no assertion criteria provided
3242360	NM_005253.4(FOSL2):c.605del (p.Pro202fs)	FOSL2	Pathogenic	no assertion criteria provided
3242361	NM_005253.4(FOSL2):c.579_589del (p.Ser194fs)	FOSL2	Pathogenic	no assertion criteria provided
3242358	NM_005253.4(FOSL2):c.619C>T (p.Gln207Ter)	FOSL2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · 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
FOSL2	Strong	Autosomal dominant	aplasia cutis-enamel dysplasia syndrome	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FOSL2	Orphanet:697356	Congenital scalp aplasia cutis-enamel hypoplasia-developmental delay-intellectual disability 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
FOSL2	HGNC:3798	ENSG00000075426	P15408	Fos-related antigen 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FOSL2	Fos-related antigen 2	Controls osteoclast survival and size.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FOSL2	Other/Unknown	no		AP-1, bZIP, bZIP_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
adrenal cortex	1
left adrenal gland	1
left adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FOSL2	283	ubiquitous	marker	left adrenal gland cortex, adrenal cortex, left adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FOSL2	3,137

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FOSL2	P15408	63.08

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
response to interleukin-7	1	16852.0×	8e-04	FOSL2
fat cell apoptotic process	1	16852.0×	8e-04	FOSL2
regulation of myofibroblast differentiation	1	16852.0×	8e-04	FOSL2
response to interleukin-13	1	8426.0×	8e-04	FOSL2
lung connective tissue development	1	8426.0×	8e-04	FOSL2
alveolar secondary septum development	1	8426.0×	8e-04	FOSL2
response to leukemia inhibitory factor	1	8426.0×	8e-04	FOSL2
NK T cell differentiation	1	4213.0×	0.001	FOSL2
myofibroblast differentiation	1	3370.4×	0.001	FOSL2
response to bleomycin	1	3370.4×	0.001	FOSL2
response to Gram-positive bacterium	1	2808.7×	0.001	FOSL2
insulin metabolic process	1	2407.4×	0.002	FOSL2
growth plate cartilage development	1	2106.5×	0.002	FOSL2
cell death	1	2106.5×	0.002	FOSL2
neutrophil differentiation	1	1872.4×	0.002	FOSL2
fat pad development	1	1685.2×	0.002	FOSL2
keratinocyte development	1	1532.0×	0.002	FOSL2
tissue remodeling	1	1296.3×	0.002	FOSL2
mucus secretion	1	1296.3×	0.002	FOSL2
collagen biosynthetic process	1	1053.2×	0.002	FOSL2
chondrocyte proliferation	1	1053.2×	0.002	FOSL2
smooth muscle tissue development	1	1053.2×	0.002	FOSL2
inflammatory response to antigenic stimulus	1	936.2×	0.002	FOSL2
regulation of multicellular organism growth	1	648.1×	0.003	FOSL2
B cell proliferation	1	481.5×	0.004	FOSL2
macrophage differentiation	1	468.1×	0.004	FOSL2
homeostasis of number of cells within a tissue	1	443.5×	0.004	FOSL2
osteoclast differentiation	1	343.9×	0.005	FOSL2
response to glucocorticoid	1	324.1×	0.005	FOSL2
chondrocyte differentiation	1	300.9×	0.005	FOSL2

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
FOSL2	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	FOSL2

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)
FOSL2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.