Mandibulofacial dysostosis with alopecia

Summary

Mandibulofacial dysostosis with alopecia (MONDO:0014608) is a disease caused by EDNRA (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: EDNRA (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 13

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	mandibulofacial dysostosis with alopecia
Mondo ID	MONDO:0014608
OMIM	616367
Orphanet	443995
DOID	DOID:0060365
UMLS	C4225349
MedGen	898794
GARD	0017758
Is cancer (heuristic)	no

Also known as: mandibulofacial dysostosis with alopecia · MFDA

Data availability: 13 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › mandibulofacial dysostosis with alopecia

Related subtypes (35): Neu-Laxova syndrome, cutaneous mycosis, integumentary system benign neoplasm, integumentary system cancer, nipple neoplasm, nail disorder, disorder of pilosebaceous unit, Bartholin duct cyst, benign mammary dysplasia, skin disorder, breast fibrosis, breast mucosa-associated lymphoid tissue lymphoma, panniculitis, alopecia-epilepsy-pyorrhea-intellectual disability syndrome, autosomal dominant deafness - onychodystrophy syndrome, keratoderma hereditarium mutilans, Rombo syndrome, Sjogren-Larsson syndrome, mucosulfatidosis, ichthyosis prematurity syndrome, ANE syndrome, frontonasal dysplasia with alopecia and genital anomaly, peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome, cutis laxa, X-linked ichthyosis syndrome, demodicidosis, Proteus-like syndrome, familial atypical multiple mole melanoma syndrome, familial tumoral calcinosis, subcutaneous tissue disorder, Bartholin gland neoplasm, pseudoxanthoma elasticum (inherited or acquired), skin appendage disorder, keratinization disease, paraneoplastic cutaneous syndrome

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

13 retrieved; paginated sample, class counts are floors:

4 benign/likely benign, 3 benign, 2 pathogenic, 2 uncertain significance, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
190323	NM_001957.4(EDNRA):c.386A>T (p.Tyr129Phe)	EDNRA	Pathogenic	no assertion criteria provided
190324	NM_001957.4(EDNRA):c.907G>A (p.Glu303Lys)	EDNRA	Pathogenic	no assertion criteria provided
3236382	NM_001957.4(EDNRA):c.955T>A (p.Trp319Arg)	EDNRA	Uncertain significance	criteria provided, single submitter
3893037	NM_001957.4(EDNRA):c.742A>C (p.Met248Leu)	EDNRA	Uncertain significance	criteria provided, single submitter
1166335	NM_001957.4(EDNRA):c.24A>G (p.Ala8=)	EDNRA	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1244028	NM_001957.4(EDNRA):c.969T>C (p.His323=)	EDNRA	Benign	criteria provided, multiple submitters, no conflicts
1255371	NM_001957.4(EDNRA):c.1005G>A (p.Glu335=)	EDNRA	Benign	criteria provided, multiple submitters, no conflicts
1256683	NM_001957.4(EDNRA):c.748-19_748-18insCT	EDNRA	Benign	criteria provided, multiple submitters, no conflicts
1654745	NM_001957.4(EDNRA):c.1034+19G>A	EDNRA	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
711201	NM_001957.4(EDNRA):c.1146A>G (p.Ser382=)	EDNRA	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
721740	NM_001957.4(EDNRA):c.354G>A (p.Leu118=)	EDNRA	Likely benign	criteria provided, multiple submitters, no conflicts
723006	NM_001957.4(EDNRA):c.549-10T>C	EDNRA	Likely benign	criteria provided, multiple submitters, no conflicts
745811	NM_001957.4(EDNRA):c.1110T>C (p.Tyr370=)	EDNRA	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
EDNRA	Definitive	Autosomal dominant	mandibulofacial dysostosis with alopecia	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EDNRA	Orphanet:443995	Mandibulofacial dysostosis with alopecia
EDNRA	Orphanet:586	Cystic fibrosis

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
EDNRA	HGNC:3179	ENSG00000151617	P25101	Endothelin-1 receptor	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EDNRA	Endothelin-1 receptor	Receptor for endothelin-1.

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
GPCR	1	23.9×	0.042

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EDNRA	GPCR	yes		GPCR_Rhodpsn, Endthln_rcpt, ETA_rcpt

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
cauda epididymis	1
seminal vesicle	1
visceral pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EDNRA	253	ubiquitous	marker	cauda epididymis, seminal vesicle, visceral pleura

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EDNRA	2,013

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EDNRA	P25101	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Peptide ligand-binding receptors	1	74.2×	0.017	EDNRA
G alpha (q) signalling events	1	57.4×	0.017	EDNRA

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
regulation of protein localization to cell leading edge	1	16852.0×	0.002	EDNRA
cellular response to human chorionic gonadotropin stimulus	1	8426.0×	0.002	EDNRA
podocyte apoptotic process	1	8426.0×	0.002	EDNRA
cardiac chamber formation	1	5617.3×	0.002	EDNRA
endothelin receptor signaling pathway involved in heart process	1	5617.3×	0.002	EDNRA
semaphorin-plexin signaling pathway involved in axon guidance	1	5617.3×	0.002	EDNRA
left ventricular cardiac muscle tissue morphogenesis	1	4213.0×	0.002	EDNRA
atrial cardiac muscle tissue development	1	4213.0×	0.002	EDNRA
neural crest cell fate commitment	1	4213.0×	0.002	EDNRA
sympathetic neuron axon guidance	1	4213.0×	0.002	EDNRA
positive regulation of cation channel activity	1	4213.0×	0.002	EDNRA
glomerular endothelium development	1	3370.4×	0.002	EDNRA
renal albumin absorption	1	3370.4×	0.002	EDNRA
heparin proteoglycan metabolic process	1	2808.7×	0.002	EDNRA
cellular response to luteinizing hormone stimulus	1	2808.7×	0.002	EDNRA
meiotic cell cycle process involved in oocyte maturation	1	2808.7×	0.002	EDNRA
cardiac neural crest cell migration involved in outflow tract morphogenesis	1	2407.4×	0.002	EDNRA
noradrenergic neuron differentiation	1	2407.4×	0.002	EDNRA
regulation of D-glucose transmembrane transport	1	2106.5×	0.002	EDNRA
developmental pigmentation	1	2106.5×	0.002	EDNRA
response to acetylcholine	1	2106.5×	0.002	EDNRA
artery smooth muscle contraction	1	1872.4×	0.002	EDNRA
axonogenesis involved in innervation	1	1685.2×	0.002	EDNRA
pharyngeal arch artery morphogenesis	1	1685.2×	0.002	EDNRA
endothelin receptor signaling pathway	1	1685.2×	0.002	EDNRA
vascular associated smooth muscle cell development	1	1685.2×	0.002	EDNRA
norepinephrine metabolic process	1	1532.0×	0.002	EDNRA
mesenchymal cell apoptotic process	1	1532.0×	0.002	EDNRA
cellular response to follicle-stimulating hormone stimulus	1	1404.3×	0.002	EDNRA
podocyte differentiation	1	1404.3×	0.002	EDNRA

Therapeutics

Drug target analysis

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

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

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
EDNRA	AMBRISENTAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EDNRA	31	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMBRISENTAN	4	EDNRA
GRAMICIDIN	4	EDNRA
NITAZOXANIDE	4	EDNRA
IRBESARTAN	4	EDNRA
ACYCLOVIR	4	EDNRA
MACITENTAN	4	EDNRA
APROCITENTAN	4	EDNRA
SITAXENTAN	4	EDNRA
FLUOXETINE	4	EDNRA
SULFATHIAZOLE	4	EDNRA
SULFISOXAZOLE	4	EDNRA
SUNITINIB	4	EDNRA
SPARSENTAN	4	EDNRA
PIOGLITAZONE	4	EDNRA
MELOXICAM	4	EDNRA
AMIODARONE	4	EDNRA
ENOXACIN	4	EDNRA
BOSENTAN	4	EDNRA
CLAZOSENTAN	3	EDNRA
ZIBOTENTAN	3	EDNRA
DARUSENTAN	3	EDNRA
AVOSENTAN	3	EDNRA
EXISULIND	3	EDNRA
TEZOSENTAN	3	EDNRA
ATRASENTAN	3	EDNRA
FANDOSENTAN	2	EDNRA
BQ-123	2	EDNRA
FELOPRENTAN	2	EDNRA
EDONENTAN	2	EDNRA
ENRASENTAN	2	EDNRA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
EDNRA	418	Binding:342, Functional:73, Toxicity:2, ADMET:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
EDNRA	418

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

30 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.

Compound	Max phase	Cohort target (bioactivity)
AMBRISENTAN	4	EDNRA
GRAMICIDIN	4	EDNRA
NITAZOXANIDE	4	EDNRA
IRBESARTAN	4	EDNRA
ACYCLOVIR	4	EDNRA
MACITENTAN	4	EDNRA
APROCITENTAN	4	EDNRA
SITAXENTAN	4	EDNRA
FLUOXETINE	4	EDNRA
SULFATHIAZOLE	4	EDNRA
SULFISOXAZOLE	4	EDNRA
SUNITINIB	4	EDNRA
SPARSENTAN	4	EDNRA
PIOGLITAZONE	4	EDNRA
MELOXICAM	4	EDNRA
AMIODARONE	4	EDNRA
ENOXACIN	4	EDNRA
BOSENTAN	4	EDNRA
CLAZOSENTAN	3	EDNRA
ZIBOTENTAN	3	EDNRA
DARUSENTAN	3	EDNRA
AVOSENTAN	3	EDNRA
EXISULIND	3	EDNRA
TEZOSENTAN	3	EDNRA
ATRASENTAN	3	EDNRA
FANDOSENTAN	2	EDNRA
BQ-123	2	EDNRA
FELOPRENTAN	2	EDNRA
EDONENTAN	2	EDNRA
ENRASENTAN	2	EDNRA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	EDNRA
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.