autosomal recessive nonsyndromic hearing loss 1A

disease

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Also known as autosomal recessive deafness 1Aautosomal recessive nonsyndromic deafness 1Aautosomal recessive nonsyndromic deafness type 1Aconnexin 26 deafnessdeafness nonsyndromic, connexin 26 linkeddeafness, autosomal recessive 1Adeafness, autosomal recessive 1a, autosomal recessive, digenic dominantdeafness, autosomal recessive type 1Adeafness, digenic GJB2/GJB6, Autosomal recessive, Digenic dominantdeafness, digenic, GJB2/GJB3deafness, digenic, GJB2/GJB3, Autosomal recessive, Digenic dominantdeafness, digenic, GJB2/GJB6DFNB1DFNB1AGJB2-related deafness

Summary

autosomal recessive nonsyndromic hearing loss 1A (MONDO:0009076) is a disease caused by GJB2 (GenCC Definitive), with 8 cohort genes and 1 clinical trial. The dominant Reactome pathway is Gap junction assembly (4 cohort genes).

At a glance

Causal gene: GJB2 (GenCC Definitive)
Cohort genes: 8
ClinVar variants: 451
Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive nonsyndromic hearing loss 1A
Mondo ID	MONDO:0009076
MeSH	C567134
OMIM	220290
DOID	DOID:0110475
NCIT	C129022
UMLS	C2673759
MedGen	388720
GARD	0001697
Is cancer (heuristic)	no

Also known as: autosomal recessive deafness 1A · autosomal recessive nonsyndromic deafness 1A · autosomal recessive nonsyndromic deafness type 1A · autosomal recessive nonsyndromic hearing loss 1A · connexin 26 deafness · deafness nonsyndromic, connexin 26 linked · deafness, autosomal recessive 1A · deafness, autosomal recessive 1a, autosomal recessive, digenic dominant · deafness, autosomal recessive type 1A · deafness, digenic GJB2/GJB6, Autosomal recessive, Digenic dominant · deafness, digenic, GJB2/GJB3 · deafness, digenic, GJB2/GJB3, Autosomal recessive, Digenic dominant · deafness, digenic, GJB2/GJB6 · DFNB1 · DFNB1A · GJB2-related deafness

Data availability: 451 ClinVar variants · 7 GenCC gene-disease records · 17 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 1A

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

451 retrieved; paginated sample, class counts are floors:

138 uncertain significance, 87 pathogenic, 64 conflicting classifications of pathogenicity, 53 pathogenic/likely pathogenic, 48 likely pathogenic, 29 likely benign, 21 benign/likely benign, 11 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
267367	NM_004004.5(GJB2):c.[134G>A;408C>A]		Pathogenic	criteria provided, single submitter
1073145	NM_004004.6(GJB2):c.41dup (p.Asn14fs)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1202621	NM_004004.6(GJB2):c.79_82delinsAGA (p.Val27fs)	GJB2	Pathogenic	criteria provided, single submitter
1297075	NM_004004.6(GJB2):c.157T>A (p.Cys53Ser)	GJB2	Pathogenic	no assertion criteria provided
1297076	NM_004004.6(GJB2):c.232G>A (p.Ala78Thr)	GJB2	Pathogenic	criteria provided, single submitter
1384271	NM_004004.6(GJB2):c.208C>G (p.Pro70Ala)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1446999	NM_004004.6(GJB2):c.28del (p.Leu10fs)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458348	NM_004004.6(GJB2):c.263C>T (p.Ala88Val)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
158605	NM_004004.6(GJB2):c.132G>A (p.Trp44Ter)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
158607	NM_004004.6(GJB2):c.298C>T (p.His100Tyr)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
158608	NM_004004.6(GJB2):c.632_633del (p.Cys211fs)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158609	NM_004004.6(GJB2):c.647_650del (p.Arg216fs)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
163514	NM_004004.6(GJB2):c.379C>T (p.Arg127Cys)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
167134	NM_004004.6(GJB2):c.250G>T (p.Val84Leu)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17000	NM_004004.6(GJB2):c.101T>C (p.Met34Thr)	GJB2	Pathogenic	reviewed by expert panel
17001	NM_004004.6(GJB2):c.231G>A (p.Trp77Ter)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17002	NM_004004.6(GJB2):c.71G>A (p.Trp24Ter)	GJB2	Pathogenic	reviewed by expert panel
17003	NM_004004.6(GJB2):c.229T>C (p.Trp77Arg)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17004	NM_004004.6(GJB2):c.35del (p.Gly12fs)	GJB2	Pathogenic	reviewed by expert panel
17005	NM_004004.6(GJB2):c.139G>T (p.Glu47Ter)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17006	NM_004004.6(GJB2):c.355GAG[1] (p.Glu120del)	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
17009	NM_004004.6(GJB2):c.427C>T (p.Arg143Trp)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17010	NM_004004.6(GJB2):c.167del (p.Leu56fs)	GJB2	Pathogenic	reviewed by expert panel
17011	NM_004004.6(GJB2):c.223C>T (p.Arg75Trp)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17013	NM_004004.6(GJB2):c.51_62delinsA (p.Thr18fs)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17014	NM_004004.6(GJB2):c.235del (p.Leu79fs)	GJB2	Pathogenic	reviewed by expert panel
17016	NM_004004.6(GJB2):c.269T>C (p.Leu90Pro)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17017	NM_004004.6(GJB2):c.428G>A (p.Arg143Gln)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17020	NM_004004.6(GJB2):c.148G>A (p.Asp50Asn)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 43 · Orphanet: 17 · 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
GJB2	Definitive	Autosomal dominant	hearing loss disorder	26
GJB3	Moderate	Autosomal dominant	autosomal recessive nonsyndromic hearing loss 1A	17

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare 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
GJB3	Orphanet:139512	Neuropathy with hearing impairment
GJB3	Orphanet:317	Erythrokeratodermia variabilis
GJB3	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
GJB3	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
OTOA	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
GJB4	Orphanet:317	Erythrokeratodermia variabilis
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

8 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GJB2	HGNC:4284	ENSG00000165474	P29033	Gap junction beta-2 protein	gencc,clinvar
GJB3	HGNC:4285	ENSG00000188910	O75712	Gap junction beta-3 protein	gencc,clinvar
OTOA	HGNC:16378	ENSG00000155719	Q7RTW8	Otoancorin	clinvar
CRYL1	HGNC:18246	ENSG00000165475	Q9Y2S2	Lambda-crystallin homolog	clinvar
MIR4499	HGNC:41739	ENSG00000263978		microRNA 4499	clinvar
GJB4	HGNC:4286	ENSG00000189433	Q9NTQ9	Gap junction beta-4 protein	clinvar
GJB6	HGNC:4288	ENSG00000121742	O95452	Gap junction beta-6 protein	clinvar
CCDST	HGNC:55988	ENSG00000236427		cervical cancer associated DHX9 suppressive transcript	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GJB2	Gap junction beta-2 protein	Structural component of gap junctions.
GJB3	Gap junction beta-3 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.
OTOA	Otoancorin	May act as an adhesion molecule.
CRYL1	Lambda-crystallin homolog	Catalyzes the conversion of L-gulonate to 3-dehydro-L-gulonate.
GJB4	Gap junction beta-4 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: 0 · Unknown: 8 · 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
Other/Unknown	8	1.8×	0.009

Per-gene assignment

Symbol	Family	Druggable?	InterPro (top 3)
GJB2	Other/Unknown	no	Connexin, Connexin26, Connexin_N
GJB3	Other/Unknown	no	Connexin, Connexin31, Connexin_N
OTOA	Other/Unknown	no	Stereocilin-rel
CRYL1	Other/Unknown	no	3HC_DH_C, 3-OHacyl-CoA_DH_NAD-bd, 3-OHacyl-CoA_DH_CS
MIR4499	Other/Unknown	no
GJB4	Other/Unknown	no	Connexin, Connexin-30.3, Connexin_N
GJB6	Other/Unknown	no	Connexin, Connexin_N, Connexin_CS
CCDST	Other/Unknown	no

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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gingiva	2
gingival epithelium	2
skin of abdomen	2
skin of leg	2
upper arm skin	2
adult mammalian kidney	2
penis	1
left testis	1
primordial germ cell in gonad	1
testis	1
C1 segment of cervical spinal cord	1
right lobe of liver	1
blood	1
liver	1
zone of skin	1
lower esophagus mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1
quadriceps femoris	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GJB2	196	broad	marker	gingival epithelium, gingiva, penis
GJB3	183	broad	marker	skin of abdomen, skin of leg, upper arm skin
OTOA	86		yes	primordial germ cell in gonad, left testis, testis
CRYL1	268	ubiquitous	marker	adult mammalian kidney, right lobe of liver, C1 segment of cervical spinal cord
MIR4499	74		yes	liver, blood, adult mammalian kidney
GJB4	70	tissue_specific	yes	skin of abdomen, zone of skin, skin of leg
GJB6	187	broad	marker	upper arm skin, gingiva, gingival epithelium
CCDST	111	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, lower esophagus mucosa, quadriceps femoris

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CRYL1	2,064
GJB2	1,391
GJB6	1,219
GJB3	782
GJB4	469
OTOA	435
MIR4499	0
CCDST	0

Intra-cohort edges

A	B	Sources
GJB2	GJB3	biogrid_interaction, string_interaction
GJB2	GJB6	string_interaction
GJB2	OTOA	string_interaction
GJB3	GJB4	string_interaction
GJB3	GJB6	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 4 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GJB2	P29033	24
CRYL1	Q9Y2S2	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
OTOA	Q7RTW8	84.12
GJB6	O95452	82.33
GJB3	O75712	79.29
GJB4	Q9NTQ9	78.75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 8 evidence-associated genes (6 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 6 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	4	195.2×	1e-08	GJB2, GJB3, GJB4, GJB6
Oligomerization of connexins into connexons	1	634.4×	0.004	GJB2
Transport of connexins along the secretory pathway	1	634.4×	0.004	GJB2
Formation of xylulose-5-phosphate	1	317.2×	0.006	CRYL1
Transport of connexons to the plasma membrane	1	90.6×	0.015	GJB2
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	1	46.4×	0.025	GJB3
Post-translational modification: synthesis of GPI-anchored proteins	1	28.0×	0.035	OTOA

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
gap junction-mediated intercellular transport	3	1404.3×	1e-08	GJB2, GJB4, GJB6
cell-cell signaling	4	46.4×	6e-06	GJB2, GJB3, GJB4, GJB6
gap junction assembly	2	702.2×	2e-05	GJB2, GJB6
sensory perception of sound	3	50.5×	1e-04	GJB2, OTOA, GJB6
transmembrane transport	2	56.2×	0.002	GJB2, GJB6
ear morphogenesis	1	702.2×	0.005	GJB6
obsolete D-glucuronate catabolic process to D-xylulose 5-phosphate	1	468.1×	0.006	CRYL1
sinoatrial node development	1	351.1×	0.007	GJB6
olfactory behavior	1	312.1×	0.007	GJB4
transmission of nerve impulse	1	108.0×	0.018	OTOA
response to electrical stimulus	1	108.0×	0.018	GJB6
maintenance of blood-brain barrier	1	80.2×	0.022	GJB6
placenta development	1	73.9×	0.022	GJB3
inner ear development	1	62.4×	0.024	GJB6
cellular response to glucose stimulus	1	44.6×	0.031	GJB6
fatty acid metabolic process	1	32.3×	0.040	CRYL1
cell-matrix adhesion	1	27.3×	0.044	OTOA
sensory perception of smell	1	26.0×	0.044	GJB4
multicellular organism growth	1	22.8×	0.048	OTOA
response to lipopolysaccharide	1	20.8×	0.049	GJB6
negative regulation of cell population proliferation	1	7.0×	0.134	GJB6

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 7

Druggability breadth: 1 of 8 evidence-associated genes (12%) 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
GJB3	0	0
OTOA	0	0
CRYL1	0	0
MIR4499	0	0
GJB4	0	0
GJB6	0	0
CCDST	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: 6; 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	7	GJB3, OTOA, CRYL1, MIR4499, GJB4, GJB6, CCDST

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GJB3	0	GJB2
GJB6	0	GJB2
OTOA	0	—
CRYL1	0	—
MIR4499	0	—
GJB4	0	—
CCDST	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05402813	Not specified	RECRUITING	Natural History in Children up to 16 Years With Mild to Profound Hearing Loss Due to Mutations in GJB2 / OTOF Genes

Cohort genes: GJB2, GJB3, OTOA, CRYL1, MIR4499, GJB4, GJB6, CCDST