Auriculocondylar syndrome

Summary

Auriculocondylar syndrome (MONDO:0000107) is a disease (an umbrella term covering 6 Mondo subtypes) with 4 cohort genes.

At a glance

• Prevalence: (Worldwide) [Orphanet-validated]
• Umbrella term: 6 Mondo subtypes
• Cohort genes: 4
• ClinVar variants: 2
• Phenotypes (HPO): 34

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		50	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

34 HPO clinical features (Orphanet curated; top 34 by frequency):

HPO ID	Term	Frequency
HP:0000377	Abnormal pinna morphology	Very frequent (80-99%)
HP:0007628	Mandibular condyle hypoplasia	Very frequent (80-99%)
HP:0009902	Cleft helix	Very frequent (80-99%)
HP:0000358	Posteriorly rotated ears	Frequent (30-79%)
HP:0000160	Narrow mouth	Frequent (30-79%)
HP:0000162	Glossoptosis	Frequent (30-79%)
HP:0000175	Cleft palate	Frequent (30-79%)
HP:0000183	Tongue muscle weakness	Frequent (30-79%)
HP:0000193	Bifid uvula	Frequent (30-79%)
HP:0000293	Full cheeks	Frequent (30-79%)
HP:0000324	Facial asymmetry	Frequent (30-79%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0000377	Abnormal pinna morphology	Frequent (30-79%)
HP:0000384	Preauricular skin tag	Frequent (30-79%)
HP:0000678	Dental crowding	Frequent (30-79%)
HP:0000689	Dental malocclusion	Frequent (30-79%)
HP:0002098	Respiratory distress	Frequent (30-79%)
HP:0002870	Obstructive sleep apnea	Frequent (30-79%)
HP:0008772	Aplasia/Hypoplasia of the external ear	Frequent (30-79%)
HP:0009895	Abnormality of the crus of the helix	Frequent (30-79%)
HP:0010754	Abnormality of the temporomandibular joint	Frequent (30-79%)
HP:0025267	Snoring	Frequent (30-79%)
HP:0030022	Question mark ear	Frequent (30-79%)
HP:0100277	Periauricular skin pits	Frequent (30-79%)
HP:0000171	Microglossia	Occasional (5-29%)
HP:0000256	Macrocephaly	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001290	Generalized hypotonia	Occasional (5-29%)
HP:0007627	Mandibular condyle aplasia	Occasional (5-29%)
HP:0011802	Hamartoma of tongue	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0030713	Vein of Galen aneurysmal malformation	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	auriculocondylar syndrome
Mondo ID	MONDO:0000107
MeSH	C538270
OMIM	602483
Orphanet	137888
ICD-11	1545895796
SNOMED CT	702443003
UMLS	C1865295
MedGen	355953
GARD	0009798
Is cancer (heuristic)	no

Also known as: auriculo-condylar syndrome · dysgnathia complex · ears prominent and constricted · question mark ear · question mark ear syndrome · question-mark ear syndrome

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

Disease family

An umbrella term covering 6 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › ear malformation › auriculocondylar syndrome

Subtypes (6): auriculocondylar syndrome 1, question mark ears, isolated, auriculocondylar syndrome 2, auriculocondylar syndrome 3, auriculocondylar syndrome 4, auriculocondylar syndrome 2B

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

2 retrieved; paginated sample, class counts are floors:

1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
31639	NM_001377142.1(PLCB4):c.1898G>A (p.Arg633His)	PLCB4	Pathogenic	criteria provided, multiple submitters, no conflicts
3769206	NC_000020.10:g.(9319685_9343542)_(9346162_9351860)dup	PLCB4	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 22 · Orphanet: 3 · 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
GNAI3	Definitive	Autosomal dominant	auriculocondylar syndrome 1	6
EDN1	Strong	Autosomal recessive	auriculocondylar syndrome 3	7
PLCB4	Strong	Autosomal dominant	auriculocondylar syndrome 2	7
HDAC9	Limited	Autosomal dominant	auriculocondylar syndrome 4	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PLCB4	Orphanet:137888	Auriculocondylar syndrome
EDN1	Orphanet:137888	Auriculocondylar syndrome
GNAI3	Orphanet:137888	Auriculocondylar syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PLCB4	HGNC:9059	ENSG00000101333	Q15147	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4	gencc,clinvar
HDAC9	HGNC:14065	ENSG00000048052	Q9UKV0	Histone deacetylase 9	gencc
EDN1	HGNC:3176	ENSG00000078401	P05305	Endothelin-1	gencc
GNAI3	HGNC:4387	ENSG00000065135	P08754	Guanine nucleotide-binding protein G(i) subunit alpha-3	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PLCB4	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4	Activated phosphatidylinositol-specific phospholipase C enzymes catalyze the production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) involved in G-protein coupled receptor signaling pathways.
HDAC9	Histone deacetylase 9	Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4).
EDN1	Endothelin-1	Endothelins are endothelium-derived vasoconstrictor peptides.
GNAI3	Guanine nucleotide-binding protein G(i) subunit alpha-3	Heterotrimeric guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

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
Enzyme (other)	2	6.0×	0.074
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PLCB4	Enzyme (other)	yes	3.1.4.11	C2_dom, PLipase_C_PInositol-sp_X_dom, PI-PLC_fam
HDAC9	Enzyme (other)	yes	3.5.1.98	HDACs, Ureohydrolase_dom_sf, His_deacetylse_dom
EDN1	Other/Unknown	no		Endothln-like_toxin, Endothelin_toxin_CS, Endothelin
GNAI3	Other/Unknown	no		Gprotein_alpha_su, Gprotein_alpha_I, GproteinA_insert

Expression context

Cohort genes with no expression data: 0.

4 cohort genes 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lateral nuclear group of thalamus	1
parotid gland	1
sural nerve	1
monocyte	1
oocyte	1
secondary oocyte	1
buccal mucosa cell	1
lower lobe of lung	1
right lung	1
epithelium of esophagus	1
esophagus squamous epithelium	1
tongue squamous epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLCB4	273	ubiquitous	marker	parotid gland, lateral nuclear group of thalamus, sural nerve
HDAC9	277	ubiquitous	marker	oocyte, monocyte, secondary oocyte
EDN1	253	ubiquitous	marker	lower lobe of lung, buccal mucosa cell, right lung
GNAI3	289	ubiquitous	marker	esophagus squamous epithelium, epithelium of esophagus, tongue squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EDN1	3,756
HDAC9	3,047
GNAI3	2,992
PLCB4	1,595

Intra-cohort edges

A	B	Sources
GNAI3	PLCB4	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNAI3	P08754	27
EDN1	P05305	17
HDAC9	Q9UKV0	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PLCB4	Q15147	86.03

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Adenylate cyclase inhibitory pathway	1	190.3×	0.030	GNAI3
ADP signalling through P2Y purinoceptor 12	1	124.1×	0.030	GNAI3
Synthesis of IP3 and IP4 in the cytosol	1	105.7×	0.030	PLCB4
Notch-HLH transcription pathway	1	102.0×	0.030	HDAC9
PLC beta mediated events	1	66.4×	0.030	PLCB4
ADORA2B mediated anti-inflammatory cytokines production	1	63.4×	0.030	GNAI3
GPER1 signaling	1	62.1×	0.030	GNAI3
NOTCH1 Intracellular Domain Regulates Transcription	1	59.5×	0.030	HDAC9
G alpha (z) signalling events	1	58.3×	0.030	GNAI3
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	49.2×	0.030	HDAC9
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	49.2×	0.030	HDAC9
Transcriptional and post-translational regulation of MITF-M expression and activity	1	44.6×	0.030	EDN1
Extra-nuclear estrogen signaling	1	42.6×	0.030	GNAI3
G alpha (q) signalling events	2	28.7×	0.030	PLCB4, EDN1
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	1	36.6×	0.032	HDAC9
Peptide ligand-binding receptors	1	18.5×	0.057	EDN1
G alpha (s) signalling events	1	18.3×	0.057	GNAI3
G alpha (i) signalling events	1	9.7×	0.099	GNAI3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
rhythmic excitation	1	4213.0×	0.006	EDN1
regulation of striated muscle cell differentiation	1	4213.0×	0.006	HDAC9
phospholipase C-activating endothelin receptor signaling pathway	1	4213.0×	0.006	PLCB4
histamine secretion	1	2106.5×	0.006	EDN1
phospholipase D-activating G protein-coupled receptor signaling pathway	1	2106.5×	0.006	EDN1
cellular response to human chorionic gonadotropin stimulus	1	2106.5×	0.006	EDN1
positive regulation of chemokine-mediated signaling pathway	1	2106.5×	0.006	EDN1
response to prostaglandin F	1	1404.3×	0.006	EDN1
regulation of skeletal muscle fiber development	1	1404.3×	0.006	HDAC9
cellular response to mineralocorticoid stimulus	1	1404.3×	0.006	EDN1
endothelin receptor signaling pathway involved in heart process	1	1404.3×	0.006	EDN1
negative regulation of phospholipase C/protein kinase C signal transduction	1	1404.3×	0.006	EDN1
semaphorin-plexin signaling pathway involved in axon guidance	1	1404.3×	0.006	EDN1
neural crest cell fate commitment	1	1053.2×	0.006	EDN1
vein smooth muscle contraction	1	1053.2×	0.006	EDN1
positive regulation of renal sodium excretion	1	1053.2×	0.006	EDN1
positive regulation of cell growth involved in cardiac muscle cell development	1	1053.2×	0.006	EDN1
sympathetic neuron axon guidance	1	1053.2×	0.006	EDN1
positive regulation of cation channel activity	1	1053.2×	0.006	EDN1
response to ozone	1	842.6×	0.006	EDN1
nitric oxide transport	1	842.6×	0.006	EDN1
positive regulation of odontogenesis	1	842.6×	0.006	EDN1
leukocyte activation	1	842.6×	0.006	EDN1
maternal process involved in parturition	1	842.6×	0.006	EDN1
glomerular endothelium development	1	842.6×	0.006	EDN1
renal albumin absorption	1	842.6×	0.006	EDN1
positive regulation of artery morphogenesis	1	842.6×	0.006	EDN1
regulation of systemic arterial blood pressure by endothelin	1	702.2×	0.006	EDN1
peptide hormone secretion	1	702.2×	0.006	EDN1
heparin proteoglycan metabolic process	1	702.2×	0.006	EDN1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 2

Druggability breadth: 2 of 4 evidence-associated genes (50%) 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
HDAC9	CELECOXIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HDAC9	28	4
GNAI3	1	2
PLCB4	0	0
EDN1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CELECOXIB	4	HDAC9
PHENYLBUTANOIC ACID	4	HDAC9
SODIUM PHENYLBUTYRATE	4	HDAC9
ROMIDEPSIN	4	HDAC9
BELINOSTAT	4	HDAC9
PANOBINOSTAT	4	HDAC9
VORINOSTAT	4	HDAC9
GIVINOSTAT	4	HDAC9
CURCUMIN	3	HDAC9
CAFFEIC ACID	3	HDAC9
PRACINOSTAT	3	HDAC9
TACEDINALINE	3	HDAC9
ENTINOSTAT	3	HDAC9
TUCIDINOSTAT	3	HDAC9
ABEXINOSTAT	3	HDAC9
EBSELEN	3	HDAC9
NANATINOSTAT	2	HDAC9
AR-42	2	HDAC9
CHLOROGENIC ACID	2	HDAC9
DACINOSTAT	2	HDAC9
FIMEPINOSTAT	2	HDAC9
QUISINOSTAT	2	HDAC9
DOMATINOSTAT	2	HDAC9
MOLIBRESIB	2	GNAI3
PYROXAMIDE	1	HDAC9
CUDC-101	1	HDAC9
R-306465	1	HDAC9
GAMMA-AMINOBUTYRIC ACID	1	HDAC9
TRICHOSTATIN	1	HDAC9

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
HDAC9	1,625	Binding:1612, ADMET:8, Functional:4, Toxicity:1
GNAI3	11	Binding:7, Functional:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PLCB4	3.1.4.11	phosphoinositide phospholipase C
HDAC9	3.5.1.98	histone deacetylase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
HDAC9	1,625

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

29 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)
CELECOXIB	4	HDAC9
PHENYLBUTANOIC ACID	4	HDAC9
SODIUM PHENYLBUTYRATE	4	HDAC9
ROMIDEPSIN	4	HDAC9
BELINOSTAT	4	HDAC9
PANOBINOSTAT	4	HDAC9
VORINOSTAT	4	HDAC9
GIVINOSTAT	4	HDAC9
CURCUMIN	3	HDAC9
CAFFEIC ACID	3	HDAC9
PRACINOSTAT	3	HDAC9
TACEDINALINE	3	HDAC9
ENTINOSTAT	3	HDAC9
TUCIDINOSTAT	3	HDAC9
ABEXINOSTAT	3	HDAC9
EBSELEN	3	HDAC9
NANATINOSTAT	2	HDAC9
AR-42	2	HDAC9
CHLOROGENIC ACID	2	HDAC9
DACINOSTAT	2	HDAC9
FIMEPINOSTAT	2	HDAC9
QUISINOSTAT	2	HDAC9
DOMATINOSTAT	2	HDAC9
MOLIBRESIB	2	GNAI3
PYROXAMIDE	1	HDAC9
CUDC-101	1	HDAC9
R-306465	1	HDAC9
GAMMA-AMINOBUTYRIC ACID	1	HDAC9
TRICHOSTATIN	1	HDAC9

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	HDAC9
B	Phased (≥1) drug, not yet approved	1	GNAI3
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	PLCB4
E	Difficult family or no structure, no drug	1	EDN1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PLCB4	0	—
EDN1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.