X-linked mixed hearing loss with perilymphatic gusher

Summary

X-linked mixed hearing loss with perilymphatic gusher (MONDO:0010576) is a disease caused by POU3F4 (GenCC Strong), with 3 cohort genes and 94 clinical trials. Top therapeutic interventions include valganciclovir, anakinra, and deferiprone.

At a glance

• Causal gene: POU3F4 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 160
• Clinical trials: 94

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked mixed hearing loss with perilymphatic gusher
Mondo ID	MONDO:0010576
OMIM	304400
Orphanet	383
DOID	DOID:0111737
UMLS	C1844678
MedGen	336750
GARD	0004504
MedDRA	10040016
Is cancer (heuristic)	no

Also known as: central hearing loss · conductive deafness with stapes fixation · deafness 3 conductive with stapes fixation · deafness conductive with stapes fixation · deafness mixed with perilymphatic gusher · deafness mixed with perilymphatic gusher, X-linked · deafness, X-linked 2 · deafness, X-linked 2, X-linked recessive · deafness, X-linked type 2 · DFN 3 nonsyndromic hearing loss and deafness · DFN3 · DFNX2 · gusher syndrome · high frequency deafness · high frequency hearing loss · high-frequency hearing loss · Nance deafness · perceptive deafness · perceptive hearing loss · perceptive hearing loss or deafness (+8 more)

Data availability: 160 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › auditory system disorder › inner ear disorder › X-linked mixed hearing loss with perilymphatic gusher

Related subtypes (14): bilateral hyperactive labyrinth, labyrinthine bilateral reactive loss, labyrinthitis, labyrinthine unilateral reactive loss, unilateral hyperactive labyrinth, vestibular disorder, cochlear disorder, bilateral hypoactive labyrinth, unilateral hypoactive labyrinth, otosclerosis, motion sickness, autoimmune inner ear disease, enlarged vestibular aqueduct syndrome, inner ear neoplasm

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

160 retrieved; paginated sample, class counts are floors:

75 pathogenic, 26 uncertain significance, 25 likely pathogenic, 10 benign/likely benign, 7 pathogenic/likely pathogenic, 6 conflicting classifications of pathogenicity, 5 benign, 4 likely benign, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
163514	NM_004004.6(GJB2):c.379C>T (p.Arg127Cys)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17001	NM_004004.6(GJB2):c.231G>A (p.Trp77Ter)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17007	NM_004004.6(GJB2):c.551G>C (p.Arg184Pro)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17016	NM_004004.6(GJB2):c.269T>C (p.Leu90Pro)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17032	NM_004004.6(GJB2):c.250G>C (p.Val84Leu)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
188830	NM_004004.6(GJB2):c.131G>A (p.Trp44Ter)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
189051	NM_004004.6(GJB2):c.334_335del (p.Lys112fs)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
189070	NM_004004.6(GJB2):c.508_511dup (p.Ala171fs)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
225375	NM_004004.6(GJB2):c.583A>G (p.Met195Val)	GJB2	Pathogenic	reviewed by expert panel
265481	NM_004004.6(GJB2):c.506G>A (p.Cys169Tyr)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
44729	NM_004004.6(GJB2):c.1A>G (p.Met1Val)	GJB2	Pathogenic	reviewed by expert panel
44733	NM_004004.6(GJB2):c.279G>A (p.Met93Ile)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
44735	NM_004004.6(GJB2):c.283G>A (p.Val95Met)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
44736	NM_004004.6(GJB2):c.299_300del (p.His100fs)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
44749	NM_004004.6(GJB2):c.416G>A (p.Ser139Asn)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
44767	NM_004004.6(GJB2):c.9G>A (p.Trp3Ter)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
499513	NM_004004.6(GJB2):c.95G>T (p.Arg32Leu)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
550195	NM_004004.6(GJB2):c.94C>A (p.Arg32Ser)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
644162	NM_004004.6(GJB2):c.576del (p.Val193fs)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5545	NM_001110219.3(GJB6):c.263C>T (p.Ala88Val)	GJB6	Pathogenic	criteria provided, multiple submitters, no conflicts
11677	NM_000307.5(POU3F4):c.648del (p.Leu217fs)	POU3F4	Pathogenic	no assertion criteria provided
11678	NM_000307.5(POU3F4):c.604A>T (p.Lys202Ter)	POU3F4	Pathogenic	no assertion criteria provided
11679	NM_000307.5(POU3F4):c.950T>G (p.Leu317Trp)	POU3F4	Pathogenic	no assertion criteria provided
11681	NM_000307.5(POU3F4):c.862_865del (p.Val289fs)	POU3F4	Pathogenic	no assertion criteria provided
11682	NM_000307.5(POU3F4):c.935C>T (p.Ala312Val)	POU3F4	Pathogenic	no assertion criteria provided
11683	NM_000307.5(POU3F4):c.990A>T (p.Arg330Ser)	POU3F4	Pathogenic	no assertion criteria provided
11684	NM_000307.5(POU3F4):c.967C>G (p.Arg323Gly)	POU3F4	Pathogenic	no assertion criteria provided
1185600	NM_000307.5(POU3F4):c.65_66del (p.Ser22fs)	POU3F4	Pathogenic	no assertion criteria provided
1185618	NM_000307.5(POU3F4):c.669T>A (p.Tyr223Ter)	POU3F4	Pathogenic	no assertion criteria provided
1185660	NM_000307.5(POU3F4):c.609_610del (p.Arg204fs)	POU3F4	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 13 · 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
POU3F4	Definitive	X-linked	nonsyndromic genetic hearing loss	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POU3F4	Orphanet:1435	Xq21 microdeletion syndrome
POU3F4	Orphanet:90641	Rare mitochondrial non-syndromic sensorineural deafness
GJB2	Orphanet:166286	Porokeratotic eccrine ostial and dermal duct nevus
GJB2	Orphanet:2202	Palmoplantar keratoderma-deafness syndrome
GJB2	Orphanet:2698	Knuckle pads-leukonychia-sensorineural deafness-palmoplantar hyperkeratosis syndrome
GJB2	Orphanet:477	KID syndrome
GJB2	Orphanet:494	Keratoderma hereditarium mutilans
GJB2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
GJB2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
GJB6	Orphanet:189	Hidrotic ectodermal dysplasia
GJB6	Orphanet:477	KID syndrome
GJB6	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
GJB6	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
POU3F4	HGNC:9217	ENSG00000196767	P49335	POU domain, class 3, transcription factor 4	gencc,clinvar
GJB2	HGNC:4284	ENSG00000165474	P29033	Gap junction beta-2 protein	clinvar
GJB6	HGNC:4288	ENSG00000121742	O95452	Gap junction beta-6 protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POU3F4	POU domain, class 3, transcription factor 4	Probable transcription factor which exert its primary action widely during early neural development and in a very limited set of neurons in the mature brain.
GJB2	Gap junction beta-2 protein	Structural component of gap junctions.
GJB6	Gap junction beta-6 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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
Transcription factor	1	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POU3F4	Transcription factor	no		POU_dom, HD, Homeodomain-like_sf
GJB2	Other/Unknown	no		Connexin, Connexin26, Connexin_N
GJB6	Other/Unknown	no		Connexin, Connexin_N, Connexin_CS

Expression context

Cohort genes with no expression data: 0.

2 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gingiva	2
gingival epithelium	2
ganglionic eminence	1
nucleus accumbens	1
ventricular zone	1
penis	1
upper arm skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POU3F4	54	broad	yes	ganglionic eminence, ventricular zone, nucleus accumbens
GJB2	196	broad	marker	gingival epithelium, gingiva, penis
GJB6	187	broad	marker	upper arm skin, gingiva, gingival epithelium

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GJB2	1,391
GJB6	1,219
POU3F4	1,132

Intra-cohort edges

A	B	Sources
GJB2	GJB6	string_interaction
GJB2	POU3F4	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GJB2	P29033	24

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GJB6	O95452	82.33
POU3F4	P49335	64.25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Gap junction assembly	2	292.8×	5e-05	GJB2, GJB6
Oligomerization of connexins into connexons	1	1903.3×	7e-04	GJB2
Transport of connexins along the secretory pathway	1	1903.3×	7e-04	GJB2
Transport of connexons to the plasma membrane	1	271.9×	0.004	GJB2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
gap junction-mediated intercellular transport	2	1872.4×	5e-06	GJB2, GJB6
gap junction assembly	2	1404.3×	5e-06	GJB2, GJB6
sensory perception of sound	3	100.9×	5e-06	POU3F4, GJB2, GJB6
transmembrane transport	2	112.3×	4e-04	GJB2, GJB6
ear morphogenesis	1	1404.3×	0.002	GJB6
cell-cell signaling	2	46.4×	0.002	GJB2, GJB6
negative regulation of mesenchymal cell apoptotic process	1	802.5×	0.003	POU3F4
sinoatrial node development	1	702.2×	0.003	GJB6
response to electrical stimulus	1	216.1×	0.009	GJB6
cochlea morphogenesis	1	193.7×	0.009	POU3F4
maintenance of blood-brain barrier	1	160.5×	0.010	GJB6
inner ear development	1	124.8×	0.011	GJB6
cellular response to glucose stimulus	1	89.2×	0.015	GJB6
response to lipopolysaccharide	1	41.6×	0.029	GJB6
brain development	1	26.5×	0.042	POU3F4
negative regulation of cell population proliferation	1	14.0×	0.074	GJB6
regulation of transcription by RNA polymerase II	1	3.9×	0.236	POU3F4

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
GJB2	KANAMYCIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GJB2	1	4
POU3F4	0	0
GJB6	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
KANAMYCIN	4	GJB2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GJB2	5	Binding:5

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
KANAMYCIN	4	GJB2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GJB2
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	POU3F4, GJB6

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)
POU3F4	0	GJB2
GJB6	0	GJB2

Clinical trials & evidence

Clinical trials

Clinical trials: 94.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	72
PHASE1/PHASE2	8
PHASE2	5
PHASE3	3
EARLY_PHASE1	3
PHASE2/PHASE3	2
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01655212	PHASE3	TERMINATED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment in a Randomized Controlled Trial
NCT02005822	PHASE3	COMPLETED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment
NCT02693704	PHASE2/PHASE3	COMPLETED	Evaluation of a Binaural Spatialization Method for Hearing Aids
NCT02882477	PHASE2/PHASE3	UNKNOWN	Treatment of Wolfram Syndrome Type 2 With the Chelator Deferiprone and Incretin Based Therapy
NCT03374514	PHASE3	UNKNOWN	Cochlear Electrical Impedance and the Effect of Topical Dexamethasone on Cochlear Implant Surgery
NCT03107871	PHASE2	ACTIVE_NOT_RECRUITING	Randomized Controlled Trial of Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants
NCT07032038	PHASE1/PHASE2	NOT_YET_RECRUITING	First In Human Randomised Trial of Rincell-1 in Adults With a Cochlear Implant
NCT07364747	PHASE2	RECRUITING	Protective Effect of Acetylcysteine Against Cisplatinum-Induced Ototoxicity: A Randomized Controlled Trial
NCT01267994	PHASE1/PHASE2	COMPLETED	A Clinical Trial of Anakinra for Steroid-Resistant Autoimmune Inner Ear Disease
NCT01902914	PHASE1/PHASE2	UNKNOWN	Effectiveness of P02 Digital Hearing Aids
NCT02038972	PHASE1/PHASE2	COMPLETED	Safety of Autologous Stem Cell Infusion for Children With Acquired Hearing Loss
NCT02497690	PHASE2	COMPLETED	Effectiveness of Therapy Via Telemedicine Following Cochlear Implants
NCT02616172	PHASE1/PHASE2	SUSPENDED	Autologous Bone Marrow Harvest and Transplant for Sensorineural Hearing Loss
NCT03616223	PHASE1/PHASE2	COMPLETED	FX-322 in Sensorineural Hearing Loss
NCT04120116	PHASE2	COMPLETED	FX-322 in Adults With Stable Sensorineural Hearing Loss
NCT04129775	PHASE1/PHASE2	COMPLETED	OTO-413 in Subjects With Speech-in-Noise Hearing Impairment
NCT04462198	PHASE1/PHASE2	COMPLETED	Phase I/IIa Study Evaluating Safety and Efficacy of an Intratympanic Dose of PIPE-505 in Subjects With Hearing Loss
NCT05061758	PHASE2	WITHDRAWN	A Trial of LY3056480 in Patients With SNLH
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT06707389	EARLY_PHASE1	NOT_YET_RECRUITING	Autologous Blood Monocyte Vesicles for the Treatment of Sudden Deafness
NCT07472023	EARLY_PHASE1	ENROLLING_BY_INVITATION	Regenerative Medicine and Stem Cell-Based Interventions for Inner Ear Trauma, Tinnitus, and Sensorineural Hearing Loss
NCT06025097	EARLY_PHASE1	COMPLETED	Intra-Tympanic Steroid With PRP Combination in Sensorineural Hearing Loss and Tinnitus.
NCT04733950	Not specified	RECRUITING	Cochlear Implanted Listening Effort and Hearing Attention
NCT05107466	Not specified	RECRUITING	Quantification of Visually Evoked Cortical Potentials in Individuals With Hearing Loss
NCT05402969	Not specified	RECRUITING	Evaluation of Electrode-modiolus Distance and Cochlear Fibrosis Using Depth Sounding and Spectroscopy Tools
NCT05634356	Not specified	RECRUITING	Social Influences on Sensorimotor Integration of Speech Production and Perception During Early Vocal Learning
NCT05670158	Not specified	RECRUITING	Immunity After Cochlear Implantation and Perilymph Molecular Profiles in Sensorineural Hearing Loss
NCT06053190	Not specified	RECRUITING	Effects of Clear Speech on Listening Effort and Memory in Sentence Processing
NCT06226558	Not specified	RECRUITING	Long-Term Outcomes of Children With Congenital CMV in New York State
NCT06229717	Not specified	RECRUITING	Vestibular and Postural Function in an Unselected Group of Children With Sensorineural Hearing Loss
NCT06434129	Not specified	RECRUITING	Role of Diffusion Tensor-magnetic Resonance Imaging in Investigating Sensorineural Hearing Loss
NCT06495268	Not specified	ACTIVE_NOT_RECRUITING	Healthy heaAring for Healthy Ageing: Data-driven Hearing Rehabilitation Intervention to Promote Healthy Hearing
NCT06507007	Not specified	RECRUITING	Genetic and Epigenetic Background of Inner Ear Dysfunction in Turner Syndrome
NCT06699797	Not specified	ACTIVE_NOT_RECRUITING	Pivotal Clinical Trial Evaluating the Safety and Efficacy of the Fully Implanted Acclaim Cochlear Implant
NCT06746038	Not specified	NOT_YET_RECRUITING	Evaluation of Extended Wear Hearing Aid for Mild Hearing Loss
NCT06936449	Not specified	RECRUITING	Long-term Follow-up of a Cochlear Implant With Dexamethasone Eluting Electrode Array
NCT06968702	Not specified	NOT_YET_RECRUITING	Project ICOPE Brazil: Assessment of Intrinsic Capacity in Brazilian Older Adults
NCT07023250	Not specified	NOT_YET_RECRUITING	Sensorineural Hearing Loss Imprint
NCT07039435	Not specified	RECRUITING	Perceptual Adaptation Following Cochlear Implantation (Aim 3a)
NCT07081542	Not specified	NOT_YET_RECRUITING	Comparative Analysis of Hearing Outcomes: Robotic vs. Manual Insertion of Cochlear Implants

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
VALGANCICLOVIR	4	3
ANAKINRA	4	1
DEFERIPRONE	4	1
GINKGO	4	1
SITAGLIPTIN	4	1
DISUFENTON SODIUM	3	1
SYRUP	3	1
RECOMBINANT METHIONYL HUMAN BRAIN-DERIVED NEUROTROPHIC FACTOR	1	1
CHEMBL5220618	0	1
GASTRODIN	0	1