Autosomal dominant nonsyndromic hearing loss 15

Summary

Autosomal dominant nonsyndromic hearing loss 15 (MONDO:0011226) is a disease caused by POU4F3 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: POU4F3 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 74

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant nonsyndromic hearing loss 15
Mondo ID	MONDO:0011226
MeSH	C566545
OMIM	602459
DOID	DOID:0110546
UMLS	C1865366
MedGen	355451
GARD	0018109
Is cancer (heuristic)	no

Also known as: autosomal dominant deafness 15 · autosomal dominant nonsyndromic deafness 15 · autosomal dominant nonsyndromic deafness caused by mutation in POU4F3 · autosomal dominant nonsyndromic deafness type 15 · deafness, autosomal dominant 15 · deafness, autosomal dominant type 15 · DFNA15 · POU4F3 autosomal dominant nonsyndromic deafness

Data availability: 74 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant nonsyndromic hearing loss › autosomal dominant nonsyndromic hearing loss 15

Related subtypes (75): autosomal dominant nonsyndromic hearing loss 1, autosomal dominant nonsyndromic hearing loss 2A, autosomal dominant nonsyndromic hearing loss 4A, autosomal dominant nonsyndromic hearing loss 6, autosomal dominant nonsyndromic hearing loss 5, autosomal dominant nonsyndromic hearing loss 10, autosomal dominant nonsyndromic hearing loss 11, autosomal dominant nonsyndromic hearing loss 9, autosomal dominant nonsyndromic hearing loss 7, autosomal dominant nonsyndromic hearing loss 12, autosomal dominant nonsyndromic hearing loss 3A, autosomal dominant nonsyndromic hearing loss 13, autosomal dominant nonsyndromic hearing loss 17, autosomal dominant nonsyndromic hearing loss 16, autosomal dominant nonsyndromic hearing loss 20, autosomal dominant nonsyndromic hearing loss 23, autosomal dominant nonsyndromic hearing loss 25, autosomal dominant nonsyndromic hearing loss 18, autosomal dominant nonsyndromic hearing loss 24, autosomal dominant nonsyndromic hearing loss 22, autosomal dominant nonsyndromic hearing loss 30, autosomal dominant nonsyndromic hearing loss 36, autosomal dominant nonsyndromic hearing loss 21, autosomal dominant nonsyndromic hearing loss 44, autosomal dominant nonsyndromic hearing loss 48, autosomal dominant nonsyndromic hearing loss 41, autosomal dominant nonsyndromic hearing loss 49, autosomal dominant nonsyndromic hearing loss 43, autosomal dominant nonsyndromic hearing loss 28, autosomal dominant nonsyndromic hearing loss 31, autosomal dominant nonsyndromic hearing loss 47, autosomal dominant auditory neuropathy 1, autosomal dominant nonsyndromic hearing loss 53, autosomal dominant nonsyndromic hearing loss 27, autosomal dominant nonsyndromic hearing loss 59, autosomal dominant nonsyndromic hearing loss 3B, autosomal dominant nonsyndromic hearing loss 2B, autosomal dominant nonsyndromic hearing loss 50, autosomal dominant nonsyndromic hearing loss 51, autosomal dominant nonsyndromic hearing loss 64, autosomal dominant nonsyndromic hearing loss 33, autosomal dominant nonsyndromic hearing loss 4B, autosomal dominant nonsyndromic hearing loss 56, autosomal dominant nonsyndromic hearing loss 54, autosomal dominant nonsyndromic hearing loss 58, autosomal dominant nonsyndromic hearing loss 65, autosomal dominant nonsyndromic hearing loss 67, autosomal dominant nonsyndromic hearing loss 40, autosomal dominant nonsyndromic hearing loss 69, autosomal dominant nonsyndromic hearing loss 68, autosomal dominant nonsyndromic hearing loss 70, autosomal dominant nonsyndromic hearing loss 66, hearing loss, autosomal dominant 74, hearing loss, autosomal dominant 77, hearing loss, autosomal dominant 81, hearing loss, autosomal dominant 82, hearing loss, autosomal dominant 83, hearing loss, autosomal dominant 84, hearing loss, autosomal dominant 80, hearing loss, autosomal dominant 37, hearing loss, autosomal dominant 75, hearing loss, autosomal dominant 76, hearing loss, autosomal dominant 71, hearing loss, autosomal dominant 72, hearing loss, autosomal dominant 73, hearing loss, autosomal dominant 34, with or without inflammation, hearing loss, autosomal dominant 78, hearing loss, autosomal dominant 79, hearing loss, autosomal dominant 85, hearing loss, autosomal dominant 86, hearing loss, autosomal dominant 87, hearing loss, autosomal dominant 88, hearing loss, autosomal dominant 89, hearing loss, autosomal dominant 90, autosomal dominant nonsyndromic hearing loss 91

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

74 retrieved; paginated sample, class counts are floors:

21 uncertain significance, 20 likely pathogenic, 17 pathogenic, 9 conflicting classifications of pathogenicity, 4 benign, 1 benign/likely benign, 1 not provided, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3336609	NM_002700.3(POU4F3):c.602del (p.Leu201fs)	POU4F3	Pathogenic	no assertion criteria provided
3336612	NM_002700.3(POU4F3):c.879C>A (p.Phe293Leu)	POU4F3	Pathogenic	no assertion criteria provided
3601695	NM_002700.3(POU4F3):c.592C>A (p.Arg198Ser)	POU4F3	Pathogenic	criteria provided, single submitter
3601700	NM_002700.3(POU4F3):c.976A>G (p.Arg326Gly)	POU4F3	Pathogenic	criteria provided, single submitter
372853	NM_002700.3(POU4F3):c.502del (p.Ala168fs)	POU4F3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4072367	NM_002700.3(POU4F3):c.288dup (p.Ile97fs)	POU4F3	Pathogenic	no assertion criteria provided
7079	NM_002700.3(POU4F3):c.865C>T (p.Leu289Phe)	POU4F3	Pathogenic	no assertion criteria provided
101525	NM_002700.3(POU4F3):c.662_675del (p.Gly221fs)	RBM27-POU4F3	Pathogenic	no assertion criteria provided
1334107	NM_002700.3(POU4F3):c.54del (p.Glu18fs)	RBM27-POU4F3	Pathogenic	criteria provided, single submitter
1334110	NM_002700.3(POU4F3):c.694G>T (p.Glu232Ter)	RBM27-POU4F3	Pathogenic	criteria provided, single submitter
1687177	NM_002700.3(POU4F3):c.66del (p.Ser23fs)	RBM27-POU4F3	Pathogenic	criteria provided, single submitter
1699941	NM_002700.3(POU4F3):c.37del (p.His13fs)	RBM27-POU4F3	Pathogenic	no assertion criteria provided
2502853	NM_002700.3(POU4F3):c.564dup (p.Ala189fs)	RBM27-POU4F3	Pathogenic	criteria provided, single submitter
3236702	NM_002700.3(POU4F3):c.823_842del (p.Lys275fs)	RBM27-POU4F3	Pathogenic	criteria provided, single submitter
7078	NM_002700.3(POU4F3):c.882_889del (p.Ile295fs)	RBM27-POU4F3	Pathogenic	no assertion criteria provided
7080	NM_002700.3(POU4F3):c.668T>C (p.Leu223Pro)	RBM27-POU4F3	Pathogenic	criteria provided, single submitter
96710	NM_002700.3(POU4F3):c.977G>A (p.Arg326Lys)	RBM27-POU4F3	Pathogenic	no assertion criteria provided
973500	NM_002700.3(POU4F3):c.184del (p.Ala62fs)	RBM27-POU4F3	Pathogenic	criteria provided, single submitter
1297744	NM_002700.3(POU4F3):c.952G>A (p.Val318Met)	POU4F3	Likely pathogenic	criteria provided, single submitter
3024075	NM_002700.3(POU4F3):c.494_497del (p.His165fs)	POU4F3	Likely pathogenic	no assertion criteria provided
3383007	NM_002700.3(POU4F3):c.337C>T (p.Gln113Ter)	POU4F3	Likely pathogenic	criteria provided, single submitter
3601692	NM_002700.3(POU4F3):c.296_297dup (p.Pro100fs)	POU4F3	Likely pathogenic	criteria provided, single submitter
3601694	NM_002700.3(POU4F3):c.413C>A (p.Ser138Ter)	POU4F3	Likely pathogenic	criteria provided, single submitter
3601696	NM_002700.3(POU4F3):c.592C>G (p.Arg198Gly)	POU4F3	Likely pathogenic	criteria provided, single submitter
3601702	NM_002700.3(POU4F3):c.97C>T (p.Arg33Ter)	POU4F3	Likely pathogenic	criteria provided, single submitter
1164004	NM_002700.3(POU4F3):c.886C>T (p.Gln296Ter)	RBM27-POU4F3	Likely pathogenic	criteria provided, single submitter
1705548	NM_002700.3(POU4F3):c.479del (p.Gly160fs)	RBM27-POU4F3	Likely pathogenic	criteria provided, single submitter
2502854	NM_002700.3(POU4F3):c.743T>C (p.Leu248Pro)	RBM27-POU4F3	Likely pathogenic	criteria provided, single submitter
2502855	NM_002700.3(POU4F3):c.879C>G (p.Phe293Leu)	RBM27-POU4F3	Likely pathogenic	criteria provided, single submitter
3362613	NM_002700.3(POU4F3):c.488del (p.His163fs)	RBM27-POU4F3	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
POU4F3	Definitive	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 15	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POU4F3	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA

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
POU4F3	HGNC:9220	ENSG00000091010	Q15319	POU domain, class 4, transcription factor 3	gencc,clinvar
RBM27-POU4F3	HGNC:58349	ENSG00000275740		RBM27-POU4F3 readthrough	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POU4F3	POU domain, class 4, transcription factor 3	Acts as a transcriptional activator.

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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POU4F3	Transcription factor	no		POU_dom, HD, Homeodomain-like_sf
RBM27-POU4F3	Other/Unknown	no

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)	1
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood vessel layer	1
choroid plexus epithelium	1
tendon of biceps brachii	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POU4F3	6	tissue_specific	yes	tendon of biceps brachii, blood vessel layer, choroid plexus epithelium
RBM27-POU4F3	106		marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POU4F3	1,175
RBM27-POU4F3	0

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
POU4F3	Q15319	65.58

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
vestibulocochlear nerve development	1	5617.3×	0.002	POU4F3
inner ear auditory receptor cell differentiation	1	1203.7×	0.005	POU4F3
retinal ganglion cell axon guidance	1	766.0×	0.005	POU4F3
axon extension	1	495.6×	0.006	POU4F3
neuromuscular process controlling balance	1	330.4×	0.006	POU4F3
inner ear morphogenesis	1	300.9×	0.006	POU4F3
neuron apoptotic process	1	185.2×	0.008	POU4F3
sensory perception of sound	1	100.9×	0.014	POU4F3
visual perception	1	79.5×	0.015	POU4F3
positive regulation of transcription by RNA polymerase II	1	14.9×	0.074	POU4F3
regulation of transcription by RNA polymerase II	1	11.7×	0.086	POU4F3

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
POU4F3	0	0
RBM27-POU4F3	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	POU4F3, RBM27-POU4F3

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)
POU4F3	0	—
RBM27-POU4F3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.