X-linked external auditory canal atresia-dilated internal auditory canal-facial dysmorphism syndrome

Summary

X-linked external auditory canal atresia-dilated internal auditory canal-facial dysmorphism syndrome (MONDO:0044702) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 4

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	X-linked external auditory canal atresia-dilated internal auditory canal-facial dysmorphism syndrome
Mondo ID	MONDO:0044702
OMIM	301018
Orphanet	500188
DOID	DOID:0111738
UMLS	C4746975
MedGen	1648389
GARD	0017926
Is cancer (heuristic)	no

Also known as: deafness, X-linked 7 · deafness, X-linked 7, X-linked recessive · DFNX7

Data availability: 4 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 › hereditary otorhinolaryngologic disease › X-linked external auditory canal atresia-dilated internal auditory canal-facial dysmorphism syndrome

Related subtypes (20): otosclerosis, isolated congenital anosmia, second branchial cleft anomaly, familial congenital nasolacrimal duct obstruction, Meniere disease, motion sickness, familial thyroglossal duct cyst, bifid nose, autosomal recessive, X-linked mixed hearing loss with perilymphatic gusher, nasal dermoid cyst, short stature-auditory canal atresia-mandibular hypoplasia-skeletal anomalies syndrome, aural atresia, congenital, choanal atresia, BNAR syndrome, familial nasal acilia, tympanic paraganglioma, cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome, tonsillar lymphoma, benign paroxysmal positional vertigo, vertigo, benign recurrent, 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

4 retrieved; paginated sample, class counts are floors:

2 uncertain significance, 1 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
590781	NM_001004051.4(GPRASP2):c.1717_1718delinsAA (p.Ala573Asn)	ARMCX5-GPRASP2	Pathogenic	no assertion criteria provided
1806834	NM_001004051.4(GPRASP2):c.2363G>T (p.Ser788Ile)	ARMCX5-GPRASP2	Likely pathogenic	criteria provided, single submitter
1030276	NM_001004051.4(GPRASP2):c.1295G>A (p.Gly432Glu)	ARMCX5-GPRASP2	Uncertain significance	criteria provided, single submitter
3767322	NM_001004051.4(GPRASP2):c.383C>T (p.Ala128Val)	ARMCX5-GPRASP2	Uncertain significance	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
GPRASP2	Supportive	X-linked	X-linked external auditory canal atresia-dilated internal auditory canal-facial dysmorphism syndrome	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GPRASP2	Orphanet:500188	X-linked external auditory canal atresia-dilated internal auditory canal-facial dysmorphism syndrome

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GPRASP2	HGNC:25169	ENSG00000158301	Q96D09	G-protein coupled receptor-associated sorting protein 2	gencc
ARMCX5-GPRASP2	HGNC:42000	ENSG00000286237		ARMCX5-GPRASP2 readthrough	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GPRASP2	G-protein coupled receptor-associated sorting protein 2	May play a role in regulation of a variety of G-protein coupled receptors.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GPRASP2	Scaffold/PPI	no		ARM-rpt_dom, ARM-like, ARM-type_fold
ARMCX5-GPRASP2	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1
cortical plate	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GPRASP2	244	broad	yes	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
ARMCX5-GPRASP2	114	ubiquitous	yes	ventricular zone, cortical plate, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GPRASP2	1,979
ARMCX5-GPRASP2	0

Intra-cohort edges

A	B	Sources
ARMCX5-GPRASP2	GPRASP2	biogrid_interaction

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GPRASP2	Q96D09	50.21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 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
hematopoietic stem cell homeostasis	1	561.7×	0.002	GPRASP2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
GPRASP2	0	0
ARMCX5-GPRASP2	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	2	GPRASP2, ARMCX5-GPRASP2

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)
GPRASP2	0	—
ARMCX5-GPRASP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.