Autosomal recessive nonsyndromic hearing loss 12

Summary

Autosomal recessive nonsyndromic hearing loss 12 (MONDO:0011067) is a disease caused by CDH23 (GenCC Definitive), with 5 cohort genes.

At a glance

• Causal gene: CDH23 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 777

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive nonsyndromic hearing loss 12
Mondo ID	MONDO:0011067
MeSH	C563327
OMIM	601386
DOID	DOID:0110467
UMLS	C1832394
MedGen	330455
GARD	0022590
Is cancer (heuristic)	no

Also known as: autosomal recessive deafness 12 · autosomal recessive nonsyndromic deafness 12 · autosomal recessive nonsyndromic deafness type 12 · autosomal recessive nonsyndromic hearing loss 12 · deafness, autosomal recessive 12 · deafness, autosomal recessive 12, modifier of · deafness, autosomal recessive type 12 · DFNB12

Data availability: 777 ClinVar variants · 2 GenCC gene-disease records · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › hearing loss, autosomal recessive › autosomal recessive nonsyndromic hearing loss 12

Related subtypes (101): autosomal recessive nonsyndromic hearing loss 5, autosomal recessive nonsyndromic hearing loss 1A, autosomal recessive nonsyndromic hearing loss 2, autosomal recessive nonsyndromic hearing loss 3, autosomal recessive nonsyndromic hearing loss 4, autosomal recessive nonsyndromic hearing loss 6, autosomal recessive nonsyndromic hearing loss 7, autosomal recessive nonsyndromic hearing loss 9, autosomal recessive nonsyndromic hearing loss 8, autosomal recessive nonsyndromic hearing loss 15, autosomal recessive nonsyndromic hearing loss 18A, autosomal recessive nonsyndromic hearing loss 17, autosomal recessive nonsyndromic hearing loss 13, autosomal recessive nonsyndromic hearing loss 21, autosomal recessive nonsyndromic hearing loss 14, autosomal recessive nonsyndromic hearing loss 16, autosomal recessive nonsyndromic hearing loss 20, autosomal recessive nonsyndromic hearing loss 26, autosomal recessive nonsyndromic hearing loss 27, autosomal recessive nonsyndromic hearing loss 22, autosomal recessive nonsyndromic hearing loss 31, autosomal recessive nonsyndromic hearing loss 30, autosomal recessive nonsyndromic hearing loss 33, autosomal recessive nonsyndromic hearing loss 37, autosomal recessive nonsyndromic hearing loss 38, autosomal recessive nonsyndromic hearing loss 40, autosomal recessive nonsyndromic hearing loss 39, autosomal recessive nonsyndromic hearing loss 35, autosomal recessive nonsyndromic hearing loss 32, autosomal recessive nonsyndromic hearing loss 36, autosomal recessive nonsyndromic hearing loss 48, autosomal recessive nonsyndromic hearing loss 23, autosomal recessive nonsyndromic hearing loss 42, autosomal recessive nonsyndromic hearing loss 46, autosomal recessive nonsyndromic hearing loss 53, autosomal recessive nonsyndromic hearing loss 28, autosomal recessive nonsyndromic hearing loss 51, autosomal recessive nonsyndromic hearing loss 47, autosomal recessive nonsyndromic hearing loss 55, autosomal recessive nonsyndromic hearing loss 62, autosomal recessive nonsyndromic hearing loss 49, autosomal recessive nonsyndromic hearing loss 44, autosomal recessive nonsyndromic hearing loss 66, autosomal recessive nonsyndromic hearing loss 59, autosomal recessive nonsyndromic hearing loss 65, autosomal recessive nonsyndromic hearing loss 67, autosomal recessive nonsyndromic hearing loss 68, autosomal recessive nonsyndromic hearing loss 24, autosomal recessive nonsyndromic hearing loss 63, autosomal recessive nonsyndromic hearing loss 45, autosomal recessive nonsyndromic hearing loss 1B, autosomal recessive nonsyndromic hearing loss 71, autosomal recessive nonsyndromic hearing loss 77, autosomal recessive nonsyndromic hearing loss 25, autosomal recessive nonsyndromic hearing loss 79, autosomal recessive nonsyndromic hearing loss 84A, autosomal recessive nonsyndromic hearing loss 85, autosomal recessive nonsyndromic hearing loss 91, autosomal recessive nonsyndromic hearing loss 83, autosomal recessive nonsyndromic hearing loss 74, autosomal recessive nonsyndromic hearing loss 61, autosomal recessive nonsyndromic hearing loss 89, autosomal recessive nonsyndromic hearing loss 29, autosomal recessive nonsyndromic hearing loss 96, autosomal recessive nonsyndromic hearing loss 86, autosomal recessive nonsyndromic hearing loss 98, autosomal recessive nonsyndromic hearing loss 93, autosomal recessive nonsyndromic hearing loss 70, autosomal recessive nonsyndromic hearing loss 84B, autosomal recessive nonsyndromic hearing loss 18B, autosomal recessive nonsyndromic hearing loss 88, autosomal recessive nonsyndromic hearing loss 76, autosomal recessive nonsyndromic hearing loss 101, autosomal recessive nonsyndromic hearing loss 102, autosomal recessive nonsyndromic hearing loss 103, autosomal recessive nonsyndromic hearing loss 104, autosomal recessive nonsyndromic hearing loss 97, hearing loss, autosomal recessive 111, hearing loss, autosomal recessive 118, with cochlear aplasia, hearing loss, autosomal recessive 119, hearing loss, autosomal recessive 117, hearing loss, autosomal recessive 112, hearing loss, autosomal recessive 113, hearing loss, autosomal recessive 100, hearing loss, autosomal recessive 94, hearing loss, autosomal recessive 114, hearing loss, autosomal recessive 115, hearing loss, autosomal recessive 99, hearing loss, autosomal recessive 106, hearing loss, autosomal recessive 107, hearing loss, autosomal recessive 108, hearing loss, autosomal recessive 57, hearing loss, autosomal recessive 109, hearing loss, autosomal recessive 116, hearing loss, autosomal recessive 110, hearing loss, autosomal recessive 120, hearing loss, autosomal recessive 121, hearing loss, autosomal recessive 122, hearing loss, autosomal recessive 123, autosomal recessive nonsyndromic hearing loss 124, hearing loss, autosomal recessive 125

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

600 retrieved; paginated sample, class counts are floors:

176 conflicting classifications of pathogenicity, 174 uncertain significance, 80 likely pathogenic, 49 benign/likely benign, 43 benign, 42 pathogenic, 33 pathogenic/likely pathogenic, 2 likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1458365	NM_022124.6(CDH23):c.3579+2T>C	C10orf105	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3601266	NM_022124.6(CDH23):c.3715+1G>C	C10orf105	Pathogenic	criteria provided, single submitter
3601277	NM_022124.6(CDH23):c.3801del (p.Thr1267_Val1268insTer)	C10orf105	Pathogenic	criteria provided, single submitter
45920	NM_022124.6(CDH23):c.3481C>T (p.Arg1161Ter)	C10orf105	Pathogenic	criteria provided, multiple submitters, no conflicts
4923	NM_022124.6(CDH23):c.4021G>A (p.Asp1341Asn)	C10orf105	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1064608	NM_022124.6(CDH23):c.1291-1G>A	CDH23	Pathogenic	criteria provided, multiple submitters, no conflicts
1065907	NM_022124.6(CDH23):c.871G>A (p.Gly291Arg)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068921	NM_022124.6(CDH23):c.8383C>T (p.Arg2795Ter)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069075	NM_022124.6(CDH23):c.9254del (p.Leu3085fs)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070502	NM_022124.6(CDH23):c.5300_5303dup (p.His1769fs)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071896	NM_022124.6(CDH23):c.9389_9390del (p.Pro3130fs)	CDH23	Pathogenic	criteria provided, multiple submitters, no conflicts
1180612	NM_022124.6(CDH23):c.4562A>G (p.Asn1521Ser)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1334115	NM_022124.6(CDH23):c.3211G>A (p.Glu1071Lys)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1357019	NM_022124.6(CDH23):c.1143_1176del	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1393120	NM_022124.6(CDH23):c.9280_9286del	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1406663	NM_022124.6(CDH23):c.7274_7275del (p.Thr2425fs)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1687042	NM_022124.6(CDH23):c.805C>T (p.Arg269Trp)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705581	NM_022124.6(CDH23):c.3076del (p.Leu1026fs)	CDH23	Pathogenic	criteria provided, multiple submitters, no conflicts
1710061	NM_022124.6(CDH23):c.8208_8209del (p.Val2737fs)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
178309	NM_022124.6(CDH23):c.6050-15G>A	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2014525	NM_022124.6(CDH23):c.2476del (p.Leu826fs)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
228328	NC_000010.11:g.71682535dup	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
236429	NM_022124.6(CDH23):c.2398-1G>T	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
236430	NM_022124.6(CDH23):c.7908C>G (p.Tyr2636Ter)	CDH23	Pathogenic	criteria provided, multiple submitters, no conflicts
2501245	NM_022124.6(CDH23):c.1152C>A (p.Ser384Arg)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2632950	NM_022124.6(CDH23):c.9381-2A>G	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2851982	NM_022124.6(CDH23):c.7557T>G (p.Tyr2519Ter)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3241035	NM_022124.6(CDH23):c.4488+2T>A	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3337893	NM_022124.6(CDH23):c.494dup (p.Ser166fs)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3377178	NM_022124.6(CDH23):c.5256dup (p.Glu1753Ter)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 14 · 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
CDH23	Definitive	Autosomal recessive	nonsyndromic genetic hearing loss	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CDH23	Orphanet:231169	Usher syndrome type 1
CDH23	Orphanet:2965	Prolactinoma
CDH23	Orphanet:314777	Familial isolated pituitary adenoma
CDH23	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
CDH23	Orphanet:91347	TSH-secreting pituitary adenoma
CDH23	Orphanet:96253	Cushing disease
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
ATP2B2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

Cohort genes → proteins

5 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CDH23	HGNC:13733	ENSG00000107736	Q9H251	Cadherin-23	gencc,clinvar
C10orf105	HGNC:20304	ENSG00000214688	Q8TEF2	Uncharacterized protein C10orf105	clinvar
CDH23-AS1	HGNC:31433	ENSG00000223817		CDH23 antisense RNA 1	clinvar
GJB2	HGNC:4284	ENSG00000165474	P29033	Gap junction beta-2 protein	clinvar
ATP2B2	HGNC:815	ENSG00000157087	Q01814	Plasma membrane calcium-transporting ATPase 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CDH23	Cadherin-23	Cadherins are calcium-dependent cell adhesion proteins.
GJB2	Gap junction beta-2 protein	Structural component of gap junctions.
ATP2B2	Plasma membrane calcium-transporting ATPase 2	ATP-driven Ca(2+) ion pump involved in the maintenance of basal intracellular Ca(2+) levels in specialized cells of cerebellar circuit and vestibular and cochlear systems.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 4 · 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	1.6×	0.476
Other/Unknown	4	1.4×	0.476

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CDH23	Other/Unknown	no		Cadherin-like_dom, Cadherin-like_sf, Cadherin_CS
C10orf105	Other/Unknown	no		DUF5527
CDH23-AS1	Other/Unknown	no
GJB2	Other/Unknown	no		Connexin, Connexin26, Connexin_N
ATP2B2	Transcription factor	no	7.2.2.10	P_typ_ATPase, ATPase_P-typ_cation-transptr_N, ATPase_P-typ_cation-transptr_C

Expression context

Cohort genes with no expression data: 0.

3 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	2
left ovary	1
right ovary	1
ventricular zone	1
cerebellar vermis	1
quadriceps femoris	1
monocyte	1
thoracic mammary gland	1
gingiva	1
gingival epithelium	1
penis	1
Brodmann (1909) area 46	1
endothelial cell	1
lateral nuclear group of thalamus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CDH23	161	broad	marker	ventricular zone, left ovary, right ovary
C10orf105	107	tissue_specific	yes	quadriceps femoris, blood, cerebellar vermis
CDH23-AS1	51		yes	blood, monocyte, thoracic mammary gland
GJB2	196	broad	marker	gingival epithelium, gingiva, penis
ATP2B2	203	tissue_specific	marker	lateral nuclear group of thalamus, endothelial cell, Brodmann (1909) area 46

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP2B2	3,932
CDH23	1,575
GJB2	1,391
C10orf105	53
CDH23-AS1	0

Intra-cohort edges

A	B	Sources
ATP2B2	CDH23	string_interaction
C10orf105	CDH23	string_interaction
CDH23	GJB2	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GJB2	P29033	24
CDH23	Q9H251	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATP2B2	Q01814	73.83
C10orf105	Q8TEF2	63.46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 5 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Sensory processing of sound by outer hair cells of the cochlea	2	135.9×	1e-03	CDH23, ATP2B2
Sensory processing of sound by inner hair cells of the cochlea	2	108.8×	1e-03	CDH23, ATP2B2
Oligomerization of connexins into connexons	1	1268.9×	0.004	GJB2
Transport of connexins along the secretory pathway	1	1268.9×	0.004	GJB2
Reduction of cytosolic Ca++ levels	1	317.2×	0.011	ATP2B2
Platelet calcium homeostasis	1	237.9×	0.013	ATP2B2
Transport of connexons to the plasma membrane	1	181.3×	0.014	GJB2
Sensory processing of sound	1	102.9×	0.019	CDH23
Gap junction assembly	1	97.6×	0.019	GJB2
Platelet homeostasis	1	92.8×	0.019	ATP2B2
Ion transport by P-type ATPases	1	69.2×	0.022	ATP2B2
Ion homeostasis	1	68.0×	0.022	ATP2B2
Cardiac conduction	1	36.2×	0.037	ATP2B2
Ion channel transport	1	32.0×	0.037	ATP2B2
Sensory Perception	1	31.7×	0.037	CDH23
Muscle contraction	1	25.7×	0.043	ATP2B2
Hemostasis	1	12.0×	0.086	ATP2B2
Transport of small molecules	1	8.4×	0.115	ATP2B2

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
sensory perception of sound	3	100.9×	2e-05	CDH23, GJB2, ATP2B2
regulation of cytosolic calcium ion concentration	2	255.3×	2e-04	CDH23, ATP2B2
calcium ion transport	2	120.8×	7e-04	CDH23, ATP2B2
gap junction-mediated intercellular transport	1	936.2×	0.005	GJB2
equilibrioception	1	802.5×	0.005	CDH23
gap junction assembly	1	702.2×	0.005	GJB2
sensory perception of light stimulus	1	624.1×	0.005	CDH23
obsolete cell-cell adhesion via plasma-membrane adhesion molecules	1	374.5×	0.007	CDH23
auditory receptor cell stereocilium organization	1	280.9×	0.008	CDH23
regulation of cardiac conduction	1	280.9×	0.008	ATP2B2
calcium-dependent cell-cell adhesion	1	160.5×	0.012	CDH23
cochlea development	1	156.0×	0.012	CDH23
photoreceptor cell maintenance	1	119.5×	0.014	CDH23
monoatomic ion transmembrane transport	1	69.3×	0.023	ATP2B2
locomotory behavior	1	59.8×	0.024	CDH23
transmembrane transport	1	56.2×	0.024	GJB2
homophilic cell-cell adhesion	1	46.8×	0.027	CDH23
neuron projection development	1	40.7×	0.030	CDH23
neuron differentiation	1	33.4×	0.034	ATP2B2
visual perception	1	26.5×	0.041	CDH23
cell-cell signaling	1	23.2×	0.044	GJB2
cell migration	1	20.5×	0.048	CDH23

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 5 evidence-associated genes (20%) 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
CDH23	0	0
C10orf105	0	0
CDH23-AS1	0	0
ATP2B2	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): 1.

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

Symbol	Assays	Type breakdown
GJB2	5	Binding:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATP2B2	7.2.2.10	P-type Ca2+ transporter

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	4	CDH23, C10orf105, CDH23-AS1, ATP2B2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CDH23	0	—
C10orf105	0	—
CDH23-AS1	0	—
ATP2B2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.