Autosomal Dominant Nonsyndromic Hearing Loss 3A

Mendelian MONDO:0011103 Pathograph 15 Show in embeddings browser Autosomal Dominant Nonsyndromic Hearing Loss Nonsyndromic Hearing Loss

DFNA3A is rare autosomal dominant nonsyndromic sensorineural hearing loss caused by specific heterozygous GJB2 variants. Reported onset and severity vary; p.Asp46Asn families include postlingual childhood onset and prelingual progressive loss, while isolated profound loss has been reported with p.Arg75Trp. GJB2 also causes recessive hearing loss and dominant syndromes with skin manifestations, so interpretation requires the specific allele, family evidence and clinical assessment. Co-expression experiments demonstrate dominant inhibition of wild-type connexin 26 channel function for p.Trp44Cys and p.Arg75Trp. They do not establish protein degradation or one universal mechanism for every dominant allele. Cochlear developmental abnormalities and subsequent hair-cell loss are supported by p.Arg75Trp transgenic mice; cortilymph potassium disturbance remains a hypothesis. Neither the detailed mouse lesion nor a uniform clinical course has been established in human DFNA3A. The historical p.Met34Thr attribution to dominant deafness was challenged; current expert consensus classifies it as a recessive allele with incomplete penetrance.

Ask OpenScientist

Ask a research question about Autosomal Dominant Nonsyndromic Hearing Loss 3A. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
7
Pathophys.
5
Phenotypes
1
Hypotheses
3
Gaps
15
Pathograph
1
Genes
6
Medical Actions
2
Differentials
1
Models
19
References
1
Deep Research
👪

Inheritance

1
Autosomal dominant HP:0000006
Specific pathogenic heterozygous GJB2 alleles cause dominant hearing loss. A single arbitrary GJB2 variant does not establish DFNA3A: recessive carrier alleles and variants of uncertain significance require different interpretation. De novo cases occur. A heterozygous affected parent has a 50% chance of transmitting the dominant allele; parental testing and phenotype assessment inform recurrence counseling.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:11354642 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We have identified the first de novo mutation of the Cx26 gene, R75 W, in a sporadic case of isolated profound hearing loss."
A reported de novo p.Arg75Trp case supports dominant isolated hearing loss. The same allele can occur with skin disease.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Individuals with autosomal dominant hearing loss have a 50% chance of transmitting the pathogenic variant to each child."
Applies after establishing a disease-causing dominant allele. Transmission probability does not predict severity, onset or extra-auditory expression.
◈

Mechanistic Hypotheses

1
dfna3a_cortilymph_hypothesis
dfna3a_cortilymph_hypothesis
Impaired supporting-cell coupling may disturb cortilymph potassium and contribute to hair-cell injury. Neither cortilymph potassium nor the complete causal sequence was measured directly.
Pathograph links
Impaired Cochlear Supporting-Cell Coupling -> Proposed Cortilymph Potassium Homeostasis Disruption INDIRECT UNKNOWN INTERMEDIATES
Proposed Cortilymph Potassium Homeostasis Disruption -> Secondary Sensory Hair Cell Degeneration INDIRECT UNKNOWN INTERMEDIATES
?

Discussions and Knowledge Gaps

3
Do all DFNA3A alleles act by dominant negative interference, or do some act by another route?
KNOWLEDGE GAP dfna3a_dominant_allele_mechanism_heterogeneity
Attached to
pathophysiology#Heterozygous Dominant-Acting GJB2 Variant pathophysiology#Dominant-Negative Impairment of Connexin 26 Channels
Dominant inhibition is demonstrated for p.Trp44Cys and p.Arg75Trp; p.Asp46Asn has segregation evidence without a functional assay in the original report. A historical c.299_300delAT dominant-family observation does not establish a truncation-based dominant mechanism. Syndromic p.Met34Lys trafficking and KID hemichannel results show allelic diversity but cannot be imported as proven DFNA3A routes.
How do variant-specific channel defects translate into human cochlear dysfunction?
HUMAN MODEL MISMATCH dfna3a_coupling_never_measured_in_disease
Attached to
pathophysiology#Impaired Cochlear Supporting-Cell Coupling pathophysiology#Proposed Cortilymph Potassium Homeostasis Disruption
Heterologous conductance assays, Gjb6 T5M biochemical-coupling data and p.Arg75Trp transgenic developmental histology describe different systems. None supplies direct human DFNA3A supporting-cell coupling or cortilymph potassium measurements. The 2025 editing study measures functional rescue in HeLa cells and plaque morphology in cochlea, which should be kept distinct.
Proposed experiments
Dominant allele co-expressed with connexin 30 at native ratios
dfna3a_cx26_cx30_coexpression
Repeat the co-expression conductance and dye-transfer assays with wild-type connexin 26, a DFNA3A allele, and connexin 30 together, at expression ratios measured from cochlear supporting cells rather than chosen by the experimenter, and read out biochemical as well as electrical coupling.
Would support
pathophysiology#Impaired Cochlear Supporting-Cell Coupling
Would refute
pathophysiology#Impaired Cochlear Supporting-Cell Coupling
Supporting outcome
  • Coupling is still substantially reduced when connexin 30 is present at native ratios, so the effect survives the condition that most plausibly rescues it.
Refuting outcome
  • Normal electrical and biochemical coupling for a tested allele would weaken this specific coupling hypothesis; it would not exclude defects in development, unmeasured channel selectivity or other alleles.
Is there a post-natal window in which correcting the GJB2 allele could still restore hearing, or is the organ of Corti already malformed by then?
KNOWLEDGE GAP dfna3a_developmental_window_for_therapy
Attached to
pathophysiology#Abnormal Organ of Corti Maturation treatments#AAV-Delivered Adenine Base Editing
Base editing improved adult mouse plaque morphology but did not report post-treatment auditory rescue. A much earlier siRNA experiment prevented acute plasmid-induced hearing impairment in adult mice. Neither result establishes the timing, durability or reversibility of the inherited developmental lesion. Longitudinal auditory and structural outcomes are needed in clinically relevant allele models.
⚙

Pathophysiology

7
Heterozygous Dominant-Acting GJB2 Variant
Mechanism confidence: Established
The initiating lesion is a heterozygous GJB2 variant with evidence for dominant hearing loss. p.Trp44Cys and p.Arg75Trp have functional dominant-inhibition data; p.Asp46Asn segregates in two founder-related Iranian families but was not functionally tested in that report. Variant-specific evidence is necessary before assigning a protein mechanism.
GJB2 hgnc:4284 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GJB2 (hgnc:4284). hgnc:4284 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context GJB2 hgnc:4284 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns GJB2 (hgnc:4284). hgnc:4284 is a gene from the HUGO Gene Nomenclature Committee. zygosity: HETEROZYGOUS
Dominant inheritance is established for particular alleles; the following channel mechanism is experimentally supported for p.Trp44Cys and p.Arg75Trp, not automatically for p.Asp46Asn or every reported GJB2 variant.
Downstream
Dominant-Negative Impairment of Connexin 26 Channels p.Trp44Cys and p.Arg75Trp impair wild-type channel function in co-expression systems. This experimentally supported route is allele-specific.
Show evidence (2 references)
PMID:11354642 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We have identified the first de novo mutation of the Cx26 gene, R75 W, in a sporadic case of isolated profound hearing loss."
A reported de novo p.Arg75Trp case supports dominant isolated hearing loss. The same allele can occur with skin disease.
PMID:21484990 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"In this study, we present two families with autosomal dominant nonsyndromic hearing loss caused by a novel mutation in GJB2 (p.Asp46Asn)."
Segregation evidence from founder-related families; this does not measure oligomerization or dominant inhibition.
Dominant-Negative Impairment of Connexin 26 Channels
Mechanism confidence: Established
p.Trp44Cys co-expressed with wild-type connexin 26 at an equal ratio in Xenopus oocytes strongly reduces intercellular conductance and alters residual gating. The recessive p.Trp77Arg comparator does not inhibit wild-type channel formation or gating in the same assay. p.Arg75Trp forms hemichannels with altered voltage dependence and reduced permeability but fails to form functional intercellular channels; its dominant effect is at the gap-junction channel level. These results establish functional interference, not degradation of wild-type protein or exclusive proof of a docking defect. Dominant inheritance and clinical scope still require human evidence; an in-vitro inhibition assay alone is insufficient.
gap junction assembly GO:0016264 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased gap junction assembly (GO:0016264). GO:0016264 is a biological process from the Gene Ontology.
gap junction channel activity GO:0005243 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased gap junction channel activity (GO:0005243). GO:0005243 is a molecular function from the Gene Ontology.
gap junction GO:0005921 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves gap junction (GO:0005921). GO:0005921 is a cellular component from the Gene Ontology.
Downstream
Impaired Cochlear Supporting-Cell Coupling Heterologous channel defects motivate this cochlear-network inference; human supporting-cell coupling has not been directly measured in the reviewed studies.
Show evidence (4 references)
PMID:12064630 SUPPORT DIRECT PRIMARY RESULT In Vitro
"Moreover, W44C dramatically inhibited intercellular conductance of HCx26wt when co-expressed in an equal ratio, and the low levels of residual conductance displayed altered gating properties."
Direct co-expression evidence of functional dominant inhibition by p.Trp44Cys; protein degradation was not measured.
PMID:12064630 SUPPORT DIRECT PRIMARY RESULT In Vitro
"A nonfunctional recessive mutation (W77R) did not inhibit the ability of HCx26wt to form functional channels when co-injected in the same oocyte pairs, nor did it alter HCx26wt gating."
The specificity control. Without it the W44C result would be consistent with any nonfunctional allele being dominant; with it, dominance is a property of the particular allele rather than of losing function.
PMID:16009703 SUPPORT DIRECT PRIMARY RESULT In Vitro
"Here, we show that Cx26 R75W forms gap-junctional hemichannels that display altered voltage dependency and reduced permeability, and which cannot form functional gap-junctional channels between neighboring cells."
Hemichannel formation persists while functional intercellular channels fail. The result supports a junctional defect but does not uniquely distinguish physical docking from all gating or permeability mechanisms.
+ 1 more reference
Impaired Cochlear Supporting-Cell Coupling
Mechanism confidence: Provisional
Reduced gap-junction communication in cochlear supporting cells is a proposed tissue consequence of allele-specific connexin 26 dysfunction. Human cochlear expression supplies anatomical context, while dominant inhibition is measured mainly in heterologous cells. A separate Gjb6/Cx30 T5M homozygous knock-in model had approximately 15-dB hearing loss, normal electrical coupling in developing cochlea and reduced calcein transfer and calcium signaling. Connexin 26 and 30 abundance was also reduced, so that model does not isolate biochemical coupling as the sole cause or directly establish the DFNA3A mechanism.
None
organ of Corti supporting cell CL:0002490 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves organ of Corti supporting cell (CL:0002490). CL:0002490 is a cell type from the Cell Ontology.
gap junction-mediated intercellular transport GO:1990349 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased gap junction-mediated intercellular transport (GO:1990349). GO:1990349 is a biological process from the Gene Ontology.
Downstream
Abnormal Organ of Corti Maturation
Proposed Cortilymph Potassium Homeostasis Disruption None
Show evidence (2 references)
PMID:9139825 NO_EVIDENCE DIRECT PRIMARY RESULT Human Clinical
"Immunohistochemical staining of human cochlear cells for Cx26 demonstrated high levels of expression."
Human cochlear expression is anatomical context; it does not demonstrate reduced coupling in DFNA3A.
PMID:20858605 SUPPORT INDIRECT PRIMARY RESULT Model Organism
"In the developing cochlea, electrical coupling, probed by dual patch-clamp recordings, was normal. However, transfer of the fluorescent tracer calcein between cochlear non-sensory cells was reduced, as was intercellular Ca(2+) signalling due to spontaneous ATP release from connexin hemichannels."
Indirect context from homozygous Gjb6 T5M mice with mild hearing loss and reduced connexin expression. Normal electrical coupling in developing tissue does not prove biochemical coupling is the sole causal defect.
Abnormal Organ of Corti Maturation
Mechanism confidence: Provisional
Human p.Arg75Trp transgenic mice show supporting-cell deformation, absent tunnel of Corti and Nuel space, reduced inner-pillar-cell microtubules and severe-to-profound hearing loss. The original report established two independent transgenic lines; later studies extend this allele/model system rather than establish the lesion in human DFNA3A. Sensory-cell development was preserved at P5–P12, and isolated outer hair cells retained nonlinear capacitance despite absent otoacoustic emissions. This supports a contribution from the supporting-cell environment, without proving that every dominant human allele causes the same developmental defect.
organ of Corti supporting cell CL:0002490 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves organ of Corti supporting cell (CL:0002490). CL:0002490 is a cell type from the Cell Ontology. cochlear outer hair cell CL:0000601 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear outer hair cell (CL:0000601). CL:0000601 is a cell type from the Cell Ontology.
Animal models
R75W dominant-negative connexin 26 transgenic mouse Mouse recapitulates Reproduces supporting-cell abnormalities and early auditory dysfunction in a human-variant transgenic mouse.
Downstream
Secondary Sensory Hair Cell Degeneration
Show evidence (4 references)
PMID:12700168 SUPPORT DIRECT PRIMARY RESULT Model Organism
"We established two lines of transgenic mice that showed severe to profound hearing loss, deformity of supporting cells, failure in the formation of the tunnel of Corti and degeneration of sensory hair cells."
The founding in vivo result for this node, in a mouse carrying a human dominant-negative allele.
PMID:18793701 SUPPORT DIRECT PRIMARY RESULT Model Organism
"Histological observations at postnatal days (P) 5-14 were characterized by i) absence of tunnel of Corti, Nuel's space, or spaces surrounding the outer hair cells"
Times the defect to postnatal development and specifies the architectural failure.
PMID:18793701 SUPPORT DIRECT PRIMARY RESULT Model Organism
"On the other hand, the development of the sensory hair cells, at least from P5 to P12, was not affected."
Time-bounded preservation of sensory-cell development at P5–P12 supports temporal ordering in this mouse model, not lifelong normality or human histopathology.
+ 1 more reference
Proposed Cortilymph Potassium Homeostasis Disruption
Mechanism confidence: Hypothetical
Impaired supporting-cell potassium handling could disturb the extracellular cortilymph surrounding hair cells. This was proposed from p.Arg75Trp mouse findings, not measured directly. Normal endolymphatic resting potential and preserved strial structure constrain an endocochlear-potential-loss account but neither measure cortilymph potassium nor establish that every aspect of endolymph homeostasis is normal.
None
potassium ion transmembrane transport GO:0071805 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves potassium ion transmembrane transport (GO:0071805). GO:0071805 is a biological process from the Gene Ontology.
Downstream
Secondary Sensory Hair Cell Degeneration None
Show evidence (2 references)
PMID:12700168 SUPPORT INDIRECT PRIMARY RESULT Model Organism
"These results suggest that the GJB2 mutation disturbs homeostasis of cortilymph, an extracellular space surrounding the sensory hair cells, due to impaired K(+) transport by supporting cells, resulting in degradation of the organ of Corti, rather than affecting endolymph homeostasis in mice and..."
The authors propose impaired cortilymph potassium homeostasis. This inference is retained as a hypothesis, not a potassium measurement.
PMID:12700168 NO_EVIDENCE DIRECT PRIMARY RESULT Model Organism
"The high resting potential in cochlear endolymph essential for hair cell excitation was normally sustained."
Normal endolymphatic potential does not directly support or refute cortilymph potassium disturbance. The two compartments and measurements are distinct.
Secondary Sensory Hair Cell Degeneration
Mechanism confidence: Provisional
Sensory hair-cell degeneration occurs alongside supporting-cell abnormalities in the p.Arg75Trp transgenic model. Earlier preservation of sensory-cell development supports secondary injury, but the complete causal sequence and its generality in human DFNA3A remain unresolved.
cochlear outer hair cell CL:0000601 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear outer hair cell (CL:0000601). CL:0000601 is a cell type from the Cell Ontology. cochlear inner hair cell CL:0000589 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear inner hair cell (CL:0000589). CL:0000589 is a cell type from the Cell Ontology.
Downstream
Sensorineural Auditory Dysfunction
Show evidence (1 reference)
PMID:12700168 SUPPORT DIRECT PRIMARY RESULT Model Organism
"We established two lines of transgenic mice that showed severe to profound hearing loss, deformity of supporting cells, failure in the formation of the tunnel of Corti and degeneration of sensory hair cells."
Degeneration was observed in two transgenic lines. Its relationship to earlier developmental abnormalities is inferred across the mouse studies.
Sensorineural Auditory Dysfunction
Mechanism confidence: Established
The human auditory endpoint includes variable onset, degree and progression. Founder-related p.Asp46Asn families provide clinical audiograms, including predominantly postlingual first-decade onset and some prelingual severe progression. Isolated profound loss also occurs with p.Arg75Trp.
sensory perception of sound GO:0007605 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased sensory perception of sound (GO:0007605). GO:0007605 is a biological process from the Gene Ontology.
Downstream
Bilateral Sensorineural Hearing Impairment
Profound Sensorineural Hearing Impairment A reported severity, not a universal outcome.
Prelingual sensorineural hearing impairment A reported presentation, not required in every carrier.
Progressive sensorineural hearing impairment A reported presentation, not required in every carrier.
Postlingual sensorineural hearing impairment An alternative onset pattern to prelingual hearing loss.
Show evidence (2 references)
PMID:21484990 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"In most persons, the hearing loss was postlingual with an onset in the first decade, however VI:13 and VI:9 had prelingual hearing loss that quickly progressed to become severe to profound in VI:13 (Figure 2: L-1301:1 and L-1301:2)."
The p.Asp46Asn families share a village and haplotype consistent with a founder. Their variable age of onset and course are family-specific observations, not population frequencies.
PMID:11354642 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We have identified the first de novo mutation of the Cx26 gene, R75 W, in a sporadic case of isolated profound hearing loss."
A reported de novo p.Arg75Trp case supports dominant isolated hearing loss. The same allele can occur with skin disease.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Autosomal Dominant Nonsyndromic Hearing Loss 3A Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

5
Bilateral Sensorineural Hearing Impairment Auditory HP:0008619 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral sensorineural hearing impairment (HP:0008619). HP:0008619 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:21484990 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"In most persons, the hearing loss was postlingual with an onset in the first decade, however VI:13 and VI:9 had prelingual hearing loss that quickly progressed to become severe to profound in VI:13 (Figure 2: L-1301:1 and L-1301:2)."
The p.Asp46Asn families share a village and haplotype consistent with a founder. Their variable age of onset and course are family-specific observations, not population frequencies.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Sensorineural hearing loss due to malfunction of the inner ear structures (i.e., cochlea or auditory nerve, with potential for vestibular dysfunction)"
General clinical definition, not localization of every GJB2 lesion or proof that the auditory nerve is intact.
Profound Sensorineural Hearing Impairment Auditory HP:0011476 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Profound sensorineural hearing impairment (HP:0011476). HP:0011476 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:11354642 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We have identified the first de novo mutation of the Cx26 gene, R75 W, in a sporadic case of isolated profound hearing loss."
A reported de novo p.Arg75Trp case supports dominant isolated hearing loss. The same allele can occur with skin disease.
PMID:21484990 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"In most persons, the hearing loss was postlingual with an onset in the first decade, however VI:13 and VI:9 had prelingual hearing loss that quickly progressed to become severe to profound in VI:13 (Figure 2: L-1301:1 and L-1301:2)."
The p.Asp46Asn families share a village and haplotype consistent with a founder. Their variable age of onset and course are family-specific observations, not population frequencies.
Prelingual sensorineural hearing impairment Auditory HP:0000399 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prelingual sensorineural hearing impairment (HP:0000399). HP:0000399 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21484990 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"In most persons, the hearing loss was postlingual with an onset in the first decade, however VI:13 and VI:9 had prelingual hearing loss that quickly progressed to become severe to profound in VI:13 (Figure 2: L-1301:1 and L-1301:2)."
The p.Asp46Asn families share a village and haplotype consistent with a founder. Their variable age of onset and course are family-specific observations, not population frequencies.
Progressive sensorineural hearing impairment Auditory HP:0000408 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive sensorineural hearing impairment (HP:0000408). HP:0000408 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21484990 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"In most persons, the hearing loss was postlingual with an onset in the first decade, however VI:13 and VI:9 had prelingual hearing loss that quickly progressed to become severe to profound in VI:13 (Figure 2: L-1301:1 and L-1301:2)."
The p.Asp46Asn families share a village and haplotype consistent with a founder. Their variable age of onset and course are family-specific observations, not population frequencies.
Postlingual sensorineural hearing impairment Auditory HP:0008596 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postlingual sensorineural hearing impairment (HP:0008596). HP:0008596 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21484990 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"In most persons, the hearing loss was postlingual with an onset in the first decade, however VI:13 and VI:9 had prelingual hearing loss that quickly progressed to become severe to profound in VI:13 (Figure 2: L-1301:1 and L-1301:2)."
The p.Asp46Asn families share a village and haplotype consistent with a founder. Their variable age of onset and course are family-specific observations, not population frequencies.
🧬

Genetic Associations

1
GJB2
Gene: GJB2 hgnc:4284 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GJB2 (hgnc:4284). hgnc:4284 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:21484990 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"In this study, we present two families with autosomal dominant nonsyndromic hearing loss caused by a novel mutation in GJB2 (p.Asp46Asn)."
Segregation evidence from founder-related families; this does not measure oligomerization or dominant inhibition.
PMID:11354642 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We have identified the first de novo mutation of the Cx26 gene, R75 W, in a sporadic case of isolated profound hearing loss."
A reported de novo p.Arg75Trp case supports dominant isolated hearing loss. The same allele can occur with skin disease.
🗃️

External Assertions

2
ClinGen dominant GJB2 hearing-loss validity
ClinGen gene disease validity CGGV:assertion_9d7b8505-4def-4b99-a8a2-853c07e9969e-2018-06-26T160000.000Z
Definitive assertion approved 2018-06-26 for autosomal dominant GJB2 hearing loss with or without skin findings. The panel lumps nonsyndromic and syndromic presentations; this is not a DFNA3A-only assessment or an endorsement of every reported variant.
Show evidence (1 reference)
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9d7b8505-4def-4b99-a8a2-853c07e9969e-2018-06-26T160000.000Z SUPPORT DIRECT REVIEW SYNTHESIS Other
"In summary, GJB2 is definitively associated with autosomal dominant Hearing Loss with or without Skin Findings."
The assertion covers dominant syndromic and nonsyndromic presentations together; it does not establish every individual allele.
SONIX trial excludes dominant nonsyndromic GJB2 hearing loss
ClinicalTrials.gov trial eligibility NCT07627971
Recruiting phase 1/2 recessive GJB2 gene-therapy trial checked 2026-09-23. Its exclusion criterion prevents extrapolating its eligibility to DFNA3A. The ordinary clinicaltrials cache omits eligibility criteria; the generated API-URL cache preserves the explicit exclusion used here.
Show evidence (1 reference)
url:https://clinicaltrials.gov/api/v2/studies/NCT07627971 SUPPORT DIRECT PRIMARY RESULT Other
"Subject has autosomal dominant nonsyndromic hearing loss due to GJB2 mutation."
Explicit exclusion criterion in the registry. The study requires biallelic pathogenic or likely pathogenic variants.
💊

Medical Actions

6
Hearing Aid Amplification
Action: hearing-aid rehabilitationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hearing-aid rehabilitation, annotated with Rehabilitation (NCIT:C15315), qualified as medical device hearing aid. NCIT:C15315 is a clinical intervention from the NCI Thesaurus. Ontology label: Rehabilitation NCIT:C15315
Platform: Device
Individualize hearing-aid fitting, communication support and educational services to residual hearing, age and family goals. DFNA3A-specific outcome estimates were not established in the reviewed sources.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Habilitation for hearing loss includes improved access to sound through hearing aids or cochlear implants and, when desired, exposure to and teaching of American Sign Language."
General hearing habilitation guidance, not a genotype-specific efficacy estimate.
Cochlear Implantation
Action: cochlear implantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cochlear implantation, annotated with Surgical Procedure (NCIT:C15329), qualified as medical device cochlear implant. NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Device
Consider cochlear implantation according to audiologic candidacy, benefit from amplification, anatomy and family goals. It supports auditory access without correcting GJB2. The reviewed sources do not establish that every DFNA3A patient has an intact auditory nerve or uniformly good implant outcomes.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Habilitation for hearing loss includes improved access to sound through hearing aids or cochlear implants and, when desired, exposure to and teaching of American Sign Language."
General hearing habilitation guidance, not a genotype-specific efficacy estimate.
AAV-Delivered Adenine Base Editing
Action: Gene TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Gene Therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. NCIT:C15238
Platform: Gene editing
Preclinical adenine base editing of p.Arg75Trp restored neurobiotin transfer in an engineered HeLa model and improved gap-junction plaque morphology in mouse cochlear supporting cells. The study used P0 cochlear explants and intracochlear delivery to adult transgenic mice aged 9–30 weeks, with morphology assessed two weeks later. In HeLa cells, 46.8% on-target editing included bystander changes; 28.03% reads were corrected without bystanders. Adult plaque improvement does not establish auditory rescue: baseline ABR characterized the model, but no post-treatment hearing-rescue result was reported. Functional treatment windows, durability, delivery and editing safety remain unresolved.
Mechanism Target:
Dominant-Negative Impairment of Connexin 26 Channels — Correction of the human p.Arg75Trp transgene improved plaque architecture in supporting cells. This does not demonstrate restored cochlear conductance or hearing.
Show evidence (1 reference)
PMID:40059830 SUPPORT INDIRECT PRIMARY RESULT Model Organism
"In a transgenic mouse model with the GJB2 R75W mutation, AAV-mediated base editing also restored the fragmented GJPs to orderly outlines in cochlear supporting cells."
Plaque morphology is structural evidence; channel function was tested in HeLa cells, not directly in the treated cochlea.
Show evidence (2 references)
PMID:40059830 SUPPORT INDIRECT PRIMARY RESULT Model Organism
"In a transgenic mouse model with the GJB2 R75W mutation, AAV-mediated base editing also restored the fragmented GJPs to orderly outlines in cochlear supporting cells."
Plaque morphology is structural evidence; channel function was tested in HeLa cells, not directly in the treated cochlea.
PMID:40059830 NO_EVIDENCE INDIRECT PRIMARY RESULT Model Organism
"Larger and longer experiments are required to assess improvement of hearing loss and currently evaluating the therapeutic efficacy to auditory function by AAV-mediated base editing."
The authors explicitly identify auditory efficacy as requiring further evaluation. Morphologic improvement must not be reported as hearing rescue.
Experimental GJB2 Transcript Silencing
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Platform: siRNA RNAi knockdown
RNA target: GJB2 hgnc:4284 HUGO Gene Nomenclature Committee (hgnc) Relation: this treatment base-pairs with the transcript of this gene This treatment base-pairs with the transcript of GJB2 (hgnc:4284). hgnc:4284 is a gene from the HUGO Gene Nomenclature Committee. human GJB2 mRNA, including the p.Arg75Trp transcript in the acute mouse transfection model
An early proof-of-concept co-delivered human GJB2 p.Arg75Trp plasmid and siRNA to adult mouse round windows, reduced transgene RNA by more than 70% and attenuated the acute ABR threshold shift at 72 hours. Selectivity exploited two human–mouse sequence mismatches; the siRNA also silenced endogenous human GJB2 in cultured cells. This was transient prevention of experimentally induced hearing loss, not reversal of an established inherited lesion or demonstrated mutant-versus-wild-type discrimination in humans. Separately, p.Asp50Asn-selective siRNA improved channel phenotypes in patient-derived KID keratinocytes; that is a different allele and tissue. Durable cochlear delivery, human allele selectivity and safety require further study.
Show evidence (2 references)
PMID:15857852 SUPPORT DIRECT PRIMARY RESULT Model Organism
"In a mouse model, this siRNA duplex selectively suppressed GJB2(R75W) expression by >70% of control levels, thereby preventing hearing loss."
Full-paper methods and discussion show acute co-delivery and human–mouse sequence discrimination. This is not established human allele-specific therapy.
PMID:31705875 SUPPORT INDIRECT PRIMARY RESULT In Vitro
"In vitro treatment with allele-specific small interfering RNA led to robust inhibition of the mutant GJB2 allele without altering expression of the wild-type allele."
Demonstrates selective knockdown of a mutant GJB2 allele, which is the mechanism this treatment entry proposes. INDIRECT on two counts: the allele is a syndromic one and the cells are keratinocytes, not cochlear.
Audiologic Surveillance and Noise Protection
Follow hearing serially to detect progression and reassess devices and communication needs. Reassess emerging systemic features when indicated. Provide standard noise-protection counseling without assuming special GJB2 susceptibility.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Regular follow up is recommended for all individuals with genetic hearing loss"
General surveillance guidance; frequency should reflect age and observed course.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"persons with documented hearing loss should be counseled appropriately and repeated overexposure to loud noises should be avoided."
General hearing-loss precaution.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Counsel using the specific dominant allele, parental testing and family findings. Discuss 50% transmission from a heterozygous parent separately from variable hearing severity and possible skin involvement. Once the familial variant is established, discuss reproductive testing options with a genetics professional.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Individuals with autosomal dominant hearing loss have a 50% chance of transmitting the pathogenic variant to each child."
Applies after establishing a disease-causing dominant allele. Transmission probability does not predict severity, onset or extra-auditory expression.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Depending on the specific diagnosis, clinical severity and phenotype may differ between sibs with the same pathogenic variant; thus, age of onset and/or progression cannot be reliably predicted."
Do not equate allele transmission with a fixed clinical outcome.
🔬

Diagnosis

2
Audiometry
Use age-appropriate diagnostic audiology, including behavioral audiometry and electrophysiology when needed, to establish hearing type and severity and follow progression. Screening alone is not a molecular diagnosis.
audiometric test NCIT:C38036 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:21484990 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"For those persons with hearing loss, audiometry confirmed the loss to be sensorineural."
Diagnostic audiometry in the founder-related families.
Genetic Testing and Allele Interpretation
Use a hearing-loss multigene panel or genomic testing with segregation and phenotype assessment. Establish that a GJB2 allele is pathogenic for dominant disease, rather than a recessive carrier allele or VUS; examine family members and test parents when de novo origin is suspected.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"A multigene hearing loss panel ... can often identify the cause of genetic hearing loss while limiting identification of pathogenic variants and variants of uncertain significance in genes that are irrelevant to the underlying phenotype"
Current broad testing approach; historical targeted GJB2 cohort screening does not establish universal first-line single-gene testing.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis."
A VUS does not establish DFNA3A.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Autosomal Dominant Nonsyndromic Hearing Loss 3A:

Dominant GJB2 disorders with skin involvement
Overlapping Features Assess skin, nails and eyes for palmoplantar keratoderma, Vohwinkel, Bart-Pumphrey or KID-spectrum disease. Allelic overlap explains syndromic and nonsyndromic p.Arg75Trp reports without requiring that one report be wrong. p.Met34Lys trafficking experiments concern syndromic disease; a proposed trans c.35delG severity effect is not an established DFNA3A modifier.
Show evidence (2 references)
PMID:11354642 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"R75 W has been previously observed in association with hearing impairment and keratoderma in one family and is thus thought to cause both syndromic and non-syndromic hearing loss."
Human allelic overlap supports clinical assessment beyond hearing.
PMID:33443819 SUPPORT INDIRECT PRIMARY RESULT In Vitro
"Additionally, the Met34Lys mutant acted dominantly to wildtype Cx26, restricting its delivery to the cell surface."
Rat epidermal keratinocyte trafficking result in a syndromic case with a second truncating allele; not evidence for a universal DFNA3A mechanism.
🐁

Animal Models

1
R75W dominant-negative connexin 26 transgenic mouse
Two p.Arg75Trp transgenic lines in the original report developed severe-to-profound hearing loss with supporting-cell abnormalities and hair-cell degeneration. Later studies characterized postnatal development and outer-hair-cell physiology. The allele occurs in both syndromic and nonsyndromic human disease. Endolymphatic resting potential was preserved, but cortilymph potassium was not directly measured.
Species
Mouse
Genotype
Transgenic for human GJB2 carrying the R75W dominant-negative allele
Publication
PMID:12700168
Pathograph links
Abnormal Organ of Corti Maturation recapitulates fidelity: moderate Reproduces supporting-cell abnormalities and early auditory dysfunction in a human-variant transgenic mouse.
Limitations: Species, non-native promoter, unestablished physiological mutant-to-wild-type ratio and allele specificity limit transfer to human DFNA3A. The clinical spectrum is not uniformly congenital or profound; auditory absence at every possible age is not established.
Readouts
Organ of Corti architecture at P5-P14
Direction: ALTERED
Interpretation: Absent tunnel of Corti, Nuel's space and peri-outer-hair-cell spaces on postnatal histology.
Show evidence (1 reference)
PMID:18793701 SUPPORT DIRECT PRIMARY RESULT Model Organism
"Histological observations at postnatal days (P) 5-14 were characterized by i) absence of tunnel of Corti, Nuel's space, or spaces surrounding the outer hair cells"
The histological measurement behind this readout.
Distortion product otoacoustic emissions
Direction: ABOLISHED
Interpretation: Absent emissions indicate impaired cochlear amplification in vivo; they are not a direct assay of hair-cell death or a unique marker of supporting-cell scaffold failure.
Show evidence (1 reference)
PMID:19712724 SUPPORT DIRECT PRIMARY RESULT Model Organism
"No detectable distortion product otoacoustic emissions were observed at any frequencies in R75W transgenic mice throughout development."
Reports the absent emissions across development.
Show evidence (1 reference)
PMID:12700168 SUPPORT DIRECT PRIMARY RESULT Model Organism
"We established two lines of transgenic mice that showed severe to profound hearing loss, deformity of supporting cells, failure in the formation of the tunnel of Corti and degeneration of sensory hair cells."
Supports treating this mouse as informative for the organ of Corti maturation node.
Show evidence (1 reference)
PMID:12700168 SUPPORT DIRECT PRIMARY RESULT Model Organism
"The high resting potential in cochlear endolymph essential for hair cell excitation was normally sustained."
A measured feature of this model is normal endolymphatic resting potential. It does not directly measure cortilymph potassium.
{ }

Source YAML

click to show 
name: Autosomal Dominant Nonsyndromic Hearing Loss 3A
creation_date: '2026-08-29T17:50:00Z'
category: Mendelian
description: 'DFNA3A is rare autosomal dominant nonsyndromic sensorineural hearing loss caused by specific heterozygous GJB2 variants. Reported onset and severity vary; p.Asp46Asn families include postlingual childhood onset and prelingual progressive loss, while isolated profound loss has been reported with p.Arg75Trp. GJB2 also causes recessive hearing loss and dominant syndromes with skin manifestations, so interpretation requires the specific allele, family evidence and clinical assessment.

  Co-expression experiments demonstrate dominant inhibition of wild-type connexin 26 channel function for p.Trp44Cys and p.Arg75Trp. They do not establish protein degradation or one universal mechanism for every dominant allele. Cochlear developmental abnormalities and subsequent hair-cell loss are supported by p.Arg75Trp transgenic mice; cortilymph potassium disturbance remains a hypothesis. Neither the detailed mouse lesion nor a uniform clinical course has been established in human DFNA3A. The historical p.Met34Thr attribution to dominant deafness was challenged; current expert consensus classifies it as a recessive allele with incomplete penetrance.'
disease_term:
  preferred_term: autosomal dominant nonsyndromic hearing loss 3A
  term:
    id: MONDO:0011103
    label: autosomal dominant nonsyndromic hearing loss 3A
synonyms:
- DFNA3A
- deafness, autosomal dominant 3A
- autosomal dominant nonsyndromic deafness type 3A
- GJB2 autosomal dominant nonsyndromic deafness
- deafness, autosomal dominant nonsyndromic sensorineural 3
- neurosensory nonsyndromic dominant deafness 1
- NSRD1
parents:
- Autosomal Dominant Nonsyndromic Hearing Loss
- Nonsyndromic Hearing Loss
inheritance:
- name: Autosomal dominant
  description: 'Specific pathogenic heterozygous GJB2 alleles cause dominant hearing loss. A single arbitrary GJB2 variant does not establish DFNA3A: recessive carrier alleles and variants of uncertain significance require different interpretation. De novo cases occur. A heterozygous affected parent has a 50% chance of transmitting the dominant allele; parental testing and phenotype assessment inform recurrence counseling.'
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:11354642
    reference_title: De novo mutation of the connexin 26 gene associated with dominant non-syndromic sensorineural hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We have identified the first de novo mutation of the Cx26 gene, R75 W, in a sporadic case of isolated profound hearing loss.
    explanation: A reported de novo p.Arg75Trp case supports dominant isolated hearing loss. The same allele can occur with skin disease.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Individuals with autosomal dominant hearing loss have a 50% chance of transmitting the pathogenic variant to each child.
    explanation: Applies after establishing a disease-causing dominant allele. Transmission probability does not predict severity, onset or extra-auditory expression.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
pathophysiology:
- name: Heterozygous Dominant-Acting GJB2 Variant
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: The initiating lesion is a heterozygous GJB2 variant with evidence for dominant hearing loss. p.Trp44Cys and p.Arg75Trp have functional dominant-inhibition data; p.Asp46Asn segregates in two founder-related Iranian families but was not functionally tested in that report. Variant-specific evidence is necessary before assigning a protein mechanism.
  genes:
  - preferred_term: GJB2
    term:
      id: hgnc:4284
      label: GJB2
  genetic_context:
    genes:
    - preferred_term: GJB2
      term:
        id: hgnc:4284
        label: GJB2
    zygosity: HETEROZYGOUS
    notes: Dominant inheritance is established for particular alleles; the following channel mechanism is experimentally supported for p.Trp44Cys and p.Arg75Trp, not automatically for p.Asp46Asn or every reported GJB2 variant.
  evidence:
  - reference: PMID:11354642
    reference_title: De novo mutation of the connexin 26 gene associated with dominant non-syndromic sensorineural hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We have identified the first de novo mutation of the Cx26 gene, R75 W, in a sporadic case of isolated profound hearing loss.
    explanation: A reported de novo p.Arg75Trp case supports dominant isolated hearing loss. The same allele can occur with skin disease.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:21484990
    reference_title: Two Iranian families with a novel mutation in GJB2 causing autosomal dominant nonsyndromic hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In this study, we present two families with autosomal dominant nonsyndromic hearing loss caused by a novel mutation in GJB2 (p.Asp46Asn).
    explanation: Segregation evidence from founder-related families; this does not measure oligomerization or dominant inhibition.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  downstream:
  - target: Dominant-Negative Impairment of Connexin 26 Channels
    causal_link_type: DIRECT
    description: p.Trp44Cys and p.Arg75Trp impair wild-type channel function in co-expression systems. This experimentally supported route is allele-specific.
    evidence:
    - reference: PMID:12064630
      reference_title: Functional analysis of a dominant mutation of human connexin26 associated with nonsyndromic deafness.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Moreover, W44C dramatically inhibited intercellular conductance of HCx26wt when co-expressed in an equal ratio, and the low levels of residual conductance displayed altered gating properties.
      explanation: 'The primary experimental result: a dominant allele degrades wild-type channel function when the two are co-expressed.'
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  role: trigger
- name: Dominant-Negative Impairment of Connexin 26 Channels
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: p.Trp44Cys co-expressed with wild-type connexin 26 at an equal ratio in Xenopus oocytes strongly reduces intercellular conductance and alters residual gating. The recessive p.Trp77Arg comparator does not inhibit wild-type channel formation or gating in the same assay. p.Arg75Trp forms hemichannels with altered voltage dependence and reduced permeability but fails to form functional intercellular channels; its dominant effect is at the gap-junction channel level. These results establish functional interference, not degradation of wild-type protein or exclusive proof of a docking defect. Dominant inheritance and clinical scope still require human evidence; an in-vitro inhibition assay alone is insufficient.
  molecular_functions:
  - preferred_term: gap junction channel activity
    term:
      id: GO:0005243
      label: gap junction channel activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: gap junction assembly
    term:
      id: GO:0016264
      label: gap junction assembly
    modifier: DECREASED
  cellular_components:
  - preferred_term: gap junction
    term:
      id: GO:0005921
      label: gap junction
  evidence:
  - reference: PMID:12064630
    reference_title: Functional analysis of a dominant mutation of human connexin26 associated with nonsyndromic deafness.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Moreover, W44C dramatically inhibited intercellular conductance of HCx26wt when co-expressed in an equal ratio, and the low levels of residual conductance displayed altered gating properties.
    explanation: Direct co-expression evidence of functional dominant inhibition by p.Trp44Cys; protein degradation was not measured.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:12064630
    reference_title: Functional analysis of a dominant mutation of human connexin26 associated with nonsyndromic deafness.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: A nonfunctional recessive mutation (W77R) did not inhibit the ability of HCx26wt to form functional channels when co-injected in the same oocyte pairs, nor did it alter HCx26wt gating.
    explanation: The specificity control. Without it the W44C result would be consistent with any nonfunctional allele being dominant; with it, dominance is a property of the particular allele rather than of losing function.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:16009703
    reference_title: Mechanism of the defect in gap-junctional communication by expression of a connexin 26 mutant associated with dominant deafness.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Here, we show that Cx26 R75W forms gap-junctional hemichannels that display altered voltage dependency and reduced permeability, and which cannot form functional gap-junctional channels between neighboring cells.
    explanation: Hemichannel formation persists while functional intercellular channels fail. The result supports a junctional defect but does not uniquely distinguish physical docking from all gating or permeability mechanisms.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:16009703
    reference_title: Mechanism of the defect in gap-junctional communication by expression of a connexin 26 mutant associated with dominant deafness.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The R75W phenotype is dominant at the gap-junction channel but not at the hemichannel level.
    explanation: The dominant effect differs between hemichannels and intercellular channels for p.Arg75Trp; this is not a universal distinction between all syndromic and nonsyndromic variants.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  downstream:
  - target: Impaired Cochlear Supporting-Cell Coupling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Heterologous channel defects motivate this cochlear-network inference; human supporting-cell coupling has not been directly measured in the reviewed studies.
- name: Impaired Cochlear Supporting-Cell Coupling
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: Reduced gap-junction communication in cochlear supporting cells is a proposed tissue consequence of allele-specific connexin 26 dysfunction. Human cochlear expression supplies anatomical context, while dominant inhibition is measured mainly in heterologous cells. A separate Gjb6/Cx30 T5M homozygous knock-in model had approximately 15-dB hearing loss, normal electrical coupling in developing cochlea and reduced calcein transfer and calcium signaling. Connexin 26 and 30 abundance was also reduced, so that model does not isolate biochemical coupling as the sole cause or directly establish the DFNA3A mechanism.
  cell_types:
  - preferred_term: organ of Corti supporting cell
    term:
      id: CL:0002490
      label: organ of Corti supporting cell
  biological_processes:
  - preferred_term: gap junction-mediated intercellular transport
    term:
      id: GO:1990349
      label: gap junction-mediated intercellular transport
    modifier: DECREASED
  evidence:
  - reference: PMID:9139825
    reference_title: Connexin 26 mutations in hereditary non-syndromic sensorineural deafness.
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: Immunohistochemical staining of human cochlear cells for Cx26 demonstrated high levels of expression.
    explanation: Human cochlear expression is anatomical context; it does not demonstrate reduced coupling in DFNA3A.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:20858605
    reference_title: The human deafness-associated connexin 30 T5M mutation causes mild hearing loss and reduces biochemical coupling among cochlear non-sensory cells in knock-in mice.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: In the developing cochlea, electrical coupling, probed by dual patch-clamp recordings, was normal. However, transfer of the fluorescent tracer calcein between cochlear non-sensory cells was reduced, as was intercellular Ca(2+) signalling due to spontaneous ATP release from connexin hemichannels.
    explanation: Indirect context from homozygous Gjb6 T5M mice with mild hearing loss and reduced connexin expression. Normal electrical coupling in developing tissue does not prove biochemical coupling is the sole causal defect.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Abnormal Organ of Corti Maturation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Proposed Cortilymph Potassium Homeostasis Disruption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - dfna3a_cortilymph_hypothesis
- name: Abnormal Organ of Corti Maturation
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: Human p.Arg75Trp transgenic mice show supporting-cell deformation, absent tunnel of Corti and Nuel space, reduced inner-pillar-cell microtubules and severe-to-profound hearing loss. The original report established two independent transgenic lines; later studies extend this allele/model system rather than establish the lesion in human DFNA3A. Sensory-cell development was preserved at P5–P12, and isolated outer hair cells retained nonlinear capacitance despite absent otoacoustic emissions. This supports a contribution from the supporting-cell environment, without proving that every dominant human allele causes the same developmental defect.
  cell_types:
  - preferred_term: organ of Corti supporting cell
    term:
      id: CL:0002490
      label: organ of Corti supporting cell
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  evidence:
  - reference: PMID:12700168
    reference_title: Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We established two lines of transgenic mice that showed severe to profound hearing loss, deformity of supporting cells, failure in the formation of the tunnel of Corti and degeneration of sensory hair cells.
    explanation: The founding in vivo result for this node, in a mouse carrying a human dominant-negative allele.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:18793701
    reference_title: Postnatal development of the organ of Corti in dominant-negative Gjb2 transgenic mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Histological observations at postnatal days (P) 5-14 were characterized by i) absence of tunnel of Corti, Nuel's space, or spaces surrounding the outer hair cells
    explanation: Times the defect to postnatal development and specifies the architectural failure.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:18793701
    reference_title: Postnatal development of the organ of Corti in dominant-negative Gjb2 transgenic mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: On the other hand, the development of the sensory hair cells, at least from P5 to P12, was not affected.
    explanation: Time-bounded preservation of sensory-cell development at P5–P12 supports temporal ordering in this mouse model, not lifelong normality or human histopathology.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:19712724
    reference_title: Cochlear outer hair cells in a dominant-negative connexin26 mutant mouse preserve non-linear capacitance in spite of impaired distortion product otoacoustic emission.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The present study indicates that normal development of the supporting cells is indispensable for proper cellular function of the OHC.
    explanation: 'States the dependency this node asserts: intact hair cells cannot function inside a malformed scaffold.'
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  downstream:
  - target: Secondary Sensory Hair Cell Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Proposed Cortilymph Potassium Homeostasis Disruption
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  description: Impaired supporting-cell potassium handling could disturb the extracellular cortilymph surrounding hair cells. This was proposed from p.Arg75Trp mouse findings, not measured directly. Normal endolymphatic resting potential and preserved strial structure constrain an endocochlear-potential-loss account but neither measure cortilymph potassium nor establish that every aspect of endolymph homeostasis is normal.
  biological_processes:
  - preferred_term: potassium ion transmembrane transport
    term:
      id: GO:0071805
      label: potassium ion transmembrane transport
  evidence:
  - reference: PMID:12700168
    reference_title: Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: These results suggest that the GJB2 mutation disturbs homeostasis of cortilymph, an extracellular space surrounding the sensory hair cells, due to impaired K(+) transport by supporting cells, resulting in degradation of the organ of Corti, rather than affecting endolymph homeostasis in mice and probably in humans.
    explanation: The authors propose impaired cortilymph potassium homeostasis. This inference is retained as a hypothesis, not a potassium measurement.
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:12700168
    reference_title: Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness.
    supports: NO_EVIDENCE
    evidence_source: MODEL_ORGANISM
    snippet: The high resting potential in cochlear endolymph essential for hair cell excitation was normally sustained.
    explanation: Normal endolymphatic potential does not directly support or refute cortilymph potassium disturbance. The two compartments and measurements are distinct.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  downstream:
  - target: Secondary Sensory Hair Cell Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - dfna3a_cortilymph_hypothesis
- name: Secondary Sensory Hair Cell Degeneration
  conforms_to: sensorineural_hair_cell_loss#Hair Cell Mechanotransduction Failure and Death
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: Sensory hair-cell degeneration occurs alongside supporting-cell abnormalities in the p.Arg75Trp transgenic model. Earlier preservation of sensory-cell development supports secondary injury, but the complete causal sequence and its generality in human DFNA3A remain unresolved.
  cell_types:
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  evidence:
  - reference: PMID:12700168
    reference_title: Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We established two lines of transgenic mice that showed severe to profound hearing loss, deformity of supporting cells, failure in the formation of the tunnel of Corti and degeneration of sensory hair cells.
    explanation: Degeneration was observed in two transgenic lines. Its relationship to earlier developmental abnormalities is inferred across the mouse studies.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  downstream:
  - target: Sensorineural Auditory Dysfunction
    causal_link_type: DIRECT
- name: Sensorineural Auditory Dysfunction
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: The human auditory endpoint includes variable onset, degree and progression. Founder-related p.Asp46Asn families provide clinical audiograms, including predominantly postlingual first-decade onset and some prelingual severe progression. Isolated profound loss also occurs with p.Arg75Trp.
  biological_processes:
  - preferred_term: sensory perception of sound
    term:
      id: GO:0007605
      label: sensory perception of sound
    modifier: DECREASED
  evidence:
  - reference: PMID:21484990
    reference_title: Two Iranian families with a novel mutation in GJB2 causing autosomal dominant nonsyndromic hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'In most persons, the hearing loss was postlingual with an onset in the first decade, however VI:13 and VI:9 had prelingual hearing loss that quickly progressed to become severe to profound in VI:13 (Figure 2: L-1301:1 and L-1301:2).'
    explanation: The p.Asp46Asn families share a village and haplotype consistent with a founder. Their variable age of onset and course are family-specific observations, not population frequencies.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:11354642
    reference_title: De novo mutation of the connexin 26 gene associated with dominant non-syndromic sensorineural hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We have identified the first de novo mutation of the Cx26 gene, R75 W, in a sporadic case of isolated profound hearing loss.
    explanation: A reported de novo p.Arg75Trp case supports dominant isolated hearing loss. The same allele can occur with skin disease.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  role: consequence
  downstream:
  - target: Bilateral Sensorineural Hearing Impairment
    causal_link_type: DIRECT
  - target: Profound Sensorineural Hearing Impairment
    causal_link_type: DIRECT
    description: A reported severity, not a universal outcome.
  - target: Prelingual sensorineural hearing impairment
    causal_link_type: DIRECT
    description: A reported presentation, not required in every carrier.
  - target: Progressive sensorineural hearing impairment
    causal_link_type: DIRECT
    description: A reported presentation, not required in every carrier.
  - target: Postlingual sensorineural hearing impairment
    causal_link_type: DIRECT
    description: An alternative onset pattern to prelingual hearing loss.
phenotypes:
- category: Auditory
  name: Bilateral Sensorineural Hearing Impairment
  description: Sensorineural hearing loss defines the nonsyndromic phenotype. Onset, severity and progression vary between and within reported families; the available series do not establish population frequencies or a universal congenital course.
  phenotype_term:
    preferred_term: Bilateral sensorineural hearing impairment
    term:
      id: HP:0008619
      label: Bilateral sensorineural hearing impairment
  evidence:
  - reference: PMID:21484990
    reference_title: Two Iranian families with a novel mutation in GJB2 causing autosomal dominant nonsyndromic hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'In most persons, the hearing loss was postlingual with an onset in the first decade, however VI:13 and VI:9 had prelingual hearing loss that quickly progressed to become severe to profound in VI:13 (Figure 2: L-1301:1 and L-1301:2).'
    explanation: The p.Asp46Asn families share a village and haplotype consistent with a founder. Their variable age of onset and course are family-specific observations, not population frequencies.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sensorineural hearing loss due to malfunction of the inner ear structures (i.e., cochlea or auditory nerve, with potential for vestibular dysfunction)
    explanation: General clinical definition, not localization of every GJB2 lesion or proof that the auditory nerve is intact.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- category: Auditory
  name: Profound Sensorineural Hearing Impairment
  description: Profound loss is documented in an isolated p.Arg75Trp case and in a progressing member of a p.Asp46Asn family. Its frequency across DFNA3A is unknown.
  phenotype_term:
    preferred_term: Profound sensorineural hearing impairment
    term:
      id: HP:0011476
      label: Profound sensorineural hearing impairment
  evidence:
  - reference: PMID:11354642
    reference_title: De novo mutation of the connexin 26 gene associated with dominant non-syndromic sensorineural hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We have identified the first de novo mutation of the Cx26 gene, R75 W, in a sporadic case of isolated profound hearing loss.
    explanation: A reported de novo p.Arg75Trp case supports dominant isolated hearing loss. The same allele can occur with skin disease.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:21484990
    reference_title: Two Iranian families with a novel mutation in GJB2 causing autosomal dominant nonsyndromic hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'In most persons, the hearing loss was postlingual with an onset in the first decade, however VI:13 and VI:9 had prelingual hearing loss that quickly progressed to become severe to profound in VI:13 (Figure 2: L-1301:1 and L-1301:2).'
    explanation: The p.Asp46Asn families share a village and haplotype consistent with a founder. Their variable age of onset and course are family-specific observations, not population frequencies.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Prelingual sensorineural hearing impairment
  category: Auditory
  description: Prelingual onset occurred in two members of the p.Asp46Asn kindred; it is not universal.
  phenotype_term:
    preferred_term: Prelingual sensorineural hearing impairment
    term:
      id: HP:0000399
      label: Prelingual sensorineural hearing impairment
  evidence:
  - reference: PMID:21484990
    reference_title: Two Iranian families with a novel mutation in GJB2 causing autosomal dominant nonsyndromic hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'In most persons, the hearing loss was postlingual with an onset in the first decade, however VI:13 and VI:9 had prelingual hearing loss that quickly progressed to become severe to profound in VI:13 (Figure 2: L-1301:1 and L-1301:2).'
    explanation: The p.Asp46Asn families share a village and haplotype consistent with a founder. Their variable age of onset and course are family-specific observations, not population frequencies.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Progressive sensorineural hearing impairment
  category: Auditory
  description: Progression to severe-to-profound hearing loss occurred in a p.Asp46Asn family member; a uniform rate or universal progression is not established.
  phenotype_term:
    preferred_term: Progressive sensorineural hearing impairment
    term:
      id: HP:0000408
      label: Progressive sensorineural hearing impairment
  evidence:
  - reference: PMID:21484990
    reference_title: Two Iranian families with a novel mutation in GJB2 causing autosomal dominant nonsyndromic hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'In most persons, the hearing loss was postlingual with an onset in the first decade, however VI:13 and VI:9 had prelingual hearing loss that quickly progressed to become severe to profound in VI:13 (Figure 2: L-1301:1 and L-1301:2).'
    explanation: The p.Asp46Asn families share a village and haplotype consistent with a founder. Their variable age of onset and course are family-specific observations, not population frequencies.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Postlingual sensorineural hearing impairment
  category: Auditory
  description: Most evaluated members of the p.Asp46Asn families had postlingual onset in the first decade. This family-specific pattern coexists with prelingual presentations.
  phenotype_term:
    preferred_term: Postlingual sensorineural hearing impairment
    term:
      id: HP:0008596
      label: Postlingual sensorineural hearing impairment
  evidence:
  - reference: PMID:21484990
    reference_title: Two Iranian families with a novel mutation in GJB2 causing autosomal dominant nonsyndromic hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'In most persons, the hearing loss was postlingual with an onset in the first decade, however VI:13 and VI:9 had prelingual hearing loss that quickly progressed to become severe to profound in VI:13 (Figure 2: L-1301:1 and L-1301:2).'
    explanation: The p.Asp46Asn families share a village and haplotype consistent with a founder. Their variable age of onset and course are family-specific observations, not population frequencies.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
genetic:
- name: GJB2
  gene_term:
    preferred_term: GJB2
    term:
      id: hgnc:4284
      label: GJB2
  relationship_type: CAUSATIVE
  notes: Interpret GJB2 at the allele level. Dominant nonsyndromic cases include p.Trp44Cys, p.Arg75Trp and p.Asp46Asn; the latter families share a founder haplotype and are not independent variant observations. p.Arg75Trp and p.Arg75Gln can present with or without cutaneous manifestations. p.Met34Thr is pathogenic for recessive hearing loss with variable expressivity and incomplete penetrance, not an established DFNA3A allele. A historical dominant-family report of c.299_300delAT does not by itself establish dominant causation or haploinsufficiency for a truncating allele.
  evidence:
  - reference: PMID:21484990
    reference_title: Two Iranian families with a novel mutation in GJB2 causing autosomal dominant nonsyndromic hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In this study, we present two families with autosomal dominant nonsyndromic hearing loss caused by a novel mutation in GJB2 (p.Asp46Asn).
    explanation: Segregation evidence from founder-related families; this does not measure oligomerization or dominant inhibition.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:11354642
    reference_title: De novo mutation of the connexin 26 gene associated with dominant non-syndromic sensorineural hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We have identified the first de novo mutation of the Cx26 gene, R75 W, in a sporadic case of isolated profound hearing loss.
    explanation: A reported de novo p.Arg75Trp case supports dominant isolated hearing loss. The same allele can occur with skin disease.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
diagnosis:
- name: Audiometry
  description: Use age-appropriate diagnostic audiology, including behavioral audiometry and electrophysiology when needed, to establish hearing type and severity and follow progression. Screening alone is not a molecular diagnosis.
  diagnosis_term:
    preferred_term: audiometric test
    term:
      id: NCIT:C38036
      label: Audiometric Test
  evidence:
  - reference: PMID:21484990
    reference_title: Two Iranian families with a novel mutation in GJB2 causing autosomal dominant nonsyndromic hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: For those persons with hearing loss, audiometry confirmed the loss to be sensorineural.
    explanation: Diagnostic audiometry in the founder-related families.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Genetic Testing and Allele Interpretation
  description: Use a hearing-loss multigene panel or genomic testing with segregation and phenotype assessment. Establish that a GJB2 allele is pathogenic for dominant disease, rather than a recessive carrier allele or VUS; examine family members and test parents when de novo origin is suspected.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A multigene hearing loss panel ... can often identify the cause of genetic hearing loss while limiting identification of pathogenic variants and variants of uncertain significance in genes that are irrelevant to the underlying phenotype
    explanation: Current broad testing approach; historical targeted GJB2 cohort screening does not establish universal first-line single-gene testing.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.
    explanation: A VUS does not establish DFNA3A.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
treatments:
- name: Hearing Aid Amplification
  therapeutic_modality: DEVICE
  description: Individualize hearing-aid fitting, communication support and educational services to residual hearing, age and family goals. DFNA3A-specific outcome estimates were not established in the reviewed sources.
  treatment_term:
    preferred_term: hearing-aid rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: hearing aid
        term:
          id: NCIT:C183182
          label: Hearing Aid
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Habilitation for hearing loss includes improved access to sound through hearing aids or cochlear implants and, when desired, exposure to and teaching of American Sign Language.
    explanation: General hearing habilitation guidance, not a genotype-specific efficacy estimate.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- name: Cochlear Implantation
  therapeutic_modality: DEVICE
  description: Consider cochlear implantation according to audiologic candidacy, benefit from amplification, anatomy and family goals. It supports auditory access without correcting GJB2. The reviewed sources do not establish that every DFNA3A patient has an intact auditory nerve or uniformly good implant outcomes.
  treatment_term:
    preferred_term: cochlear implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: cochlear implant
        term:
          id: NCIT:C157820
          label: Cochlear Implant
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Habilitation for hearing loss includes improved access to sound through hearing aids or cochlear implants and, when desired, exposure to and teaching of American Sign Language.
    explanation: General hearing habilitation guidance, not a genotype-specific efficacy estimate.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- name: AAV-Delivered Adenine Base Editing
  therapeutic_modality: GENE_EDITING
  description: 'Preclinical adenine base editing of p.Arg75Trp restored neurobiotin transfer in an engineered HeLa model and improved gap-junction plaque morphology in mouse cochlear supporting cells. The study used P0 cochlear explants and intracochlear delivery to adult transgenic mice aged 9–30 weeks, with morphology assessed two weeks later. In HeLa cells, 46.8% on-target editing included bystander changes; 28.03% reads were corrected without bystanders. Adult plaque improvement does not establish auditory rescue: baseline ABR characterized the model, but no post-treatment hearing-rescue result was reported. Functional treatment windows, durability, delivery and editing safety remain unresolved.'
  treatment_term:
    preferred_term: Gene Therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Dominant-Negative Impairment of Connexin 26 Channels
    description: Correction of the human p.Arg75Trp transgene improved plaque architecture in supporting cells. This does not demonstrate restored cochlear conductance or hearing.
    evidence:
    - reference: PMID:40059830
      reference_title: AAV-mediated base editing restores cochlear gap junction in GJB2 dominant-negative mutation-associated syndromic hearing loss model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: In a transgenic mouse model with the GJB2 R75W mutation, AAV-mediated base editing also restored the fragmented GJPs to orderly outlines in cochlear supporting cells.
      explanation: Plaque morphology is structural evidence; channel function was tested in HeLa cells, not directly in the treated cochlea.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
  evidence:
  - reference: PMID:40059830
    reference_title: AAV-mediated base editing restores cochlear gap junction in GJB2 dominant-negative mutation-associated syndromic hearing loss model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In a transgenic mouse model with the GJB2 R75W mutation, AAV-mediated base editing also restored the fragmented GJPs to orderly outlines in cochlear supporting cells.
    explanation: Plaque morphology is structural evidence; channel function was tested in HeLa cells, not directly in the treated cochlea.
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:40059830
    reference_title: AAV-mediated base editing restores cochlear gap junction in GJB2 dominant-negative mutation-associated syndromic hearing loss model.
    supports: NO_EVIDENCE
    evidence_source: MODEL_ORGANISM
    snippet: Larger and longer experiments are required to assess improvement of hearing loss and currently evaluating the therapeutic efficacy to auditory function by AAV-mediated base editing.
    explanation: The authors explicitly identify auditory efficacy as requiring further evaluation. Morphologic improvement must not be reported as hearing rescue.
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
- name: Experimental GJB2 Transcript Silencing
  therapeutic_modality: SIRNA
  description: An early proof-of-concept co-delivered human GJB2 p.Arg75Trp plasmid and siRNA to adult mouse round windows, reduced transgene RNA by more than 70% and attenuated the acute ABR threshold shift at 72 hours. Selectivity exploited two human–mouse sequence mismatches; the siRNA also silenced endogenous human GJB2 in cultured cells. This was transient prevention of experimentally induced hearing loss, not reversal of an established inherited lesion or demonstrated mutant-versus-wild-type discrimination in humans. Separately, p.Asp50Asn-selective siRNA improved channel phenotypes in patient-derived KID keratinocytes; that is a different allele and tissue. Durable cochlear delivery, human allele selectivity and safety require further study.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:15857852
    reference_title: In vitro and in vivo suppression of GJB2 expression by RNA interference.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In a mouse model, this siRNA duplex selectively suppressed GJB2(R75W) expression by >70% of control levels, thereby preventing hearing loss.
    explanation: Full-paper methods and discussion show acute co-delivery and human–mouse sequence discrimination. This is not established human allele-specific therapy.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:31705875
    reference_title: Allele-Specific Small Interfering RNA Corrects Aberrant Cellular Phenotype in Keratitis-Ichthyosis-Deafness Syndrome Keratinocytes.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: In vitro treatment with allele-specific small interfering RNA led to robust inhibition of the mutant GJB2 allele without altering expression of the wild-type allele.
    explanation: 'Demonstrates selective knockdown of a mutant GJB2 allele, which is the mechanism this treatment entry proposes. INDIRECT on two counts: the allele is a syndromic one and the cells are keratinocytes, not cochlear.'
    quote_role: PRIMARY_RESULT
  oligonucleotide_details:
    oligonucleotide_mechanism: RNAI_KNOCKDOWN
    target_gene:
      preferred_term: GJB2
      term:
        id: hgnc:4284
        label: GJB2
    target_transcript: human GJB2 mRNA, including the p.Arg75Trp transcript in the acute mouse transfection model
- name: Audiologic Surveillance and Noise Protection
  description: Follow hearing serially to detect progression and reassess devices and communication needs. Reassess emerging systemic features when indicated. Provide standard noise-protection counseling without assuming special GJB2 susceptibility.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Regular follow up is recommended for all individuals with genetic hearing loss
    explanation: General surveillance guidance; frequency should reflect age and observed course.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: persons with documented hearing loss should be counseled appropriately and repeated overexposure to loud noises should be avoided.
    explanation: General hearing-loss precaution.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- name: Genetic Counseling
  description: Counsel using the specific dominant allele, parental testing and family findings. Discuss 50% transmission from a heterozygous parent separately from variable hearing severity and possible skin involvement. Once the familial variant is established, discuss reproductive testing options with a genetics professional.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Individuals with autosomal dominant hearing loss have a 50% chance of transmitting the pathogenic variant to each child.
    explanation: Applies after establishing a disease-causing dominant allele. Transmission probability does not predict severity, onset or extra-auditory expression.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Depending on the specific diagnosis, clinical severity and phenotype may differ between sibs with the same pathogenic variant; thus, age of onset and/or progression cannot be reliably predicted.
    explanation: Do not equate allele transmission with a fixed clinical outcome.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
animal_models:
- name: R75W dominant-negative connexin 26 transgenic mouse
  species: Mouse
  genotype: Transgenic for human GJB2 carrying the R75W dominant-negative allele
  publication: PMID:12700168
  description: Two p.Arg75Trp transgenic lines in the original report developed severe-to-profound hearing loss with supporting-cell abnormalities and hair-cell degeneration. Later studies characterized postnatal development and outer-hair-cell physiology. The allele occurs in both syndromic and nonsyndromic human disease. Endolymphatic resting potential was preserved, but cortilymph potassium was not directly measured.
  modeled_mechanisms:
  - target: Abnormal Organ of Corti Maturation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Reproduces supporting-cell abnormalities and early auditory dysfunction in a human-variant transgenic mouse.
    limitations: Species, non-native promoter, unestablished physiological mutant-to-wild-type ratio and allele specificity limit transfer to human DFNA3A. The clinical spectrum is not uniformly congenital or profound; auditory absence at every possible age is not established.
    readouts:
    - name: Organ of Corti architecture at P5-P14
      target: Abnormal Organ of Corti Maturation
      direction: ALTERED
      interpretation: Absent tunnel of Corti, Nuel's space and peri-outer-hair-cell spaces on postnatal histology.
      evidence:
      - reference: PMID:18793701
        reference_title: Postnatal development of the organ of Corti in dominant-negative Gjb2 transgenic mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Histological observations at postnatal days (P) 5-14 were characterized by i) absence of tunnel of Corti, Nuel's space, or spaces surrounding the outer hair cells
        explanation: The histological measurement behind this readout.
        quote_role: PRIMARY_RESULT
        directness: DIRECT
    - name: Distortion product otoacoustic emissions
      target: Abnormal Organ of Corti Maturation
      direction: ABOLISHED
      interpretation: Absent emissions indicate impaired cochlear amplification in vivo; they are not a direct assay of hair-cell death or a unique marker of supporting-cell scaffold failure.
      evidence:
      - reference: PMID:19712724
        reference_title: Cochlear outer hair cells in a dominant-negative connexin26 mutant mouse preserve non-linear capacitance in spite of impaired distortion product otoacoustic emission.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: No detectable distortion product otoacoustic emissions were observed at any frequencies in R75W transgenic mice throughout development.
        explanation: Reports the absent emissions across development.
        quote_role: PRIMARY_RESULT
        directness: DIRECT
    evidence:
    - reference: PMID:12700168
      reference_title: Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: We established two lines of transgenic mice that showed severe to profound hearing loss, deformity of supporting cells, failure in the formation of the tunnel of Corti and degeneration of sensory hair cells.
      explanation: Supports treating this mouse as informative for the organ of Corti maturation node.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  evidence:
  - reference: PMID:12700168
    reference_title: Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The high resting potential in cochlear endolymph essential for hair cell excitation was normally sustained.
    explanation: A measured feature of this model is normal endolymphatic resting potential. It does not directly measure cortilymph potassium.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
discussions:
- discussion_id: dfna3a_dominant_allele_mechanism_heterogeneity
  kind: KNOWLEDGE_GAP
  prompt: Do all DFNA3A alleles act by dominant negative interference, or do some act by another route?
  attaches_to:
  - pathophysiology#Heterozygous Dominant-Acting GJB2 Variant
  - pathophysiology#Dominant-Negative Impairment of Connexin 26 Channels
  rationale: Dominant inhibition is demonstrated for p.Trp44Cys and p.Arg75Trp; p.Asp46Asn has segregation evidence without a functional assay in the original report. A historical c.299_300delAT dominant-family observation does not establish a truncation-based dominant mechanism. Syndromic p.Met34Lys trafficking and KID hemichannel results show allelic diversity but cannot be imported as proven DFNA3A routes.
- discussion_id: dfna3a_coupling_never_measured_in_disease
  kind: HUMAN_MODEL_MISMATCH
  prompt: How do variant-specific channel defects translate into human cochlear dysfunction?
  attaches_to:
  - pathophysiology#Impaired Cochlear Supporting-Cell Coupling
  - pathophysiology#Proposed Cortilymph Potassium Homeostasis Disruption
  rationale: Heterologous conductance assays, Gjb6 T5M biochemical-coupling data and p.Arg75Trp transgenic developmental histology describe different systems. None supplies direct human DFNA3A supporting-cell coupling or cortilymph potassium measurements. The 2025 editing study measures functional rescue in HeLa cells and plaque morphology in cochlea, which should be kept distinct.
  proposed_experiments:
  - experiment_id: dfna3a_cx26_cx30_coexpression
    name: Dominant allele co-expressed with connexin 30 at native ratios
    description: Repeat the co-expression conductance and dye-transfer assays with wild-type connexin 26, a DFNA3A allele, and connexin 30 together, at expression ratios measured from cochlear supporting cells rather than chosen by the experimenter, and read out biochemical as well as electrical coupling.
    would_support:
    - pathophysiology#Impaired Cochlear Supporting-Cell Coupling
    supporting_outcome:
    - Coupling is still substantially reduced when connexin 30 is present at native ratios, so the effect survives the condition that most plausibly rescues it.
    would_refute:
    - pathophysiology#Impaired Cochlear Supporting-Cell Coupling
    refuting_outcome:
    - Normal electrical and biochemical coupling for a tested allele would weaken this specific coupling hypothesis; it would not exclude defects in development, unmeasured channel selectivity or other alleles.
- discussion_id: dfna3a_developmental_window_for_therapy
  kind: KNOWLEDGE_GAP
  prompt: Is there a post-natal window in which correcting the GJB2 allele could still restore hearing, or is the organ of Corti already malformed by then?
  attaches_to:
  - pathophysiology#Abnormal Organ of Corti Maturation
  - treatments#AAV-Delivered Adenine Base Editing
  rationale: Base editing improved adult mouse plaque morphology but did not report post-treatment auditory rescue. A much earlier siRNA experiment prevented acute plasmid-induced hearing impairment in adult mice. Neither result establishes the timing, durability or reversibility of the inherited developmental lesion. Longitudinal auditory and structural outcomes are needed in clinically relevant allele models.
references:
- reference: PMID:11354642
  title: De novo mutation of the connexin 26 gene associated with dominant non-syndromic sensorineural hearing loss.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
  title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
- reference: PMID:21484990
  title: Two Iranian families with a novel mutation in GJB2 causing autosomal dominant nonsyndromic hearing loss.
- reference: PMID:12064630
  title: Functional analysis of a dominant mutation of human connexin26 associated with nonsyndromic deafness.
- reference: PMID:16009703
  title: Mechanism of the defect in gap-junctional communication by expression of a connexin 26 mutant associated with dominant deafness.
- reference: PMID:9139825
  title: Connexin 26 mutations in hereditary non-syndromic sensorineural deafness.
- reference: PMID:20858605
  title: The human deafness-associated connexin 30 T5M mutation causes mild hearing loss and reduces biochemical coupling among cochlear non-sensory cells in knock-in mice.
- reference: PMID:25625422
  title: Keratitis-ichthyosis-deafness syndrome-associated Cx26 mutants produce nonfunctional gap junctions but hyperactive hemichannels when co-expressed with wild type Cx43.
- reference: PMID:12700168
  title: Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness.
- reference: PMID:18793701
  title: Postnatal development of the organ of Corti in dominant-negative Gjb2 transgenic mice.
- reference: PMID:19712724
  title: Cochlear outer hair cells in a dominant-negative connexin26 mutant mouse preserve non-linear capacitance in spite of impaired distortion product otoacoustic emission.
- reference: PMID:40059830
  title: AAV-mediated base editing restores cochlear gap junction in GJB2 dominant-negative mutation-associated syndromic hearing loss model.
- reference: PMID:15857852
  title: In vitro and in vivo suppression of GJB2 expression by RNA interference.
- reference: PMID:31705875
  title: Allele-Specific Small Interfering RNA Corrects Aberrant Cellular Phenotype in Keratitis-Ichthyosis-Deafness Syndrome Keratinocytes.
- reference: PMID:31160754
  title: Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1272/?report=reader
  title: GJB2-Related Autosomal Recessive Nonsyndromic Hearing Loss - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
- reference: PMID:33443819
  title: Palmoplantar keratoderma with deafness phenotypic variability in a patient with an inherited GJB2 frameshift variant and novel missense variant.
- reference: url:https://clinicaltrials.gov/api/v2/studies/NCT07627971
  title: https://clinicaltrials.gov/api/v2/studies/NCT07627971
- reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9d7b8505-4def-4b99-a8a2-853c07e9969e-2018-06-26T160000.000Z
  title: curation results for Gene-Disease Validity
notes: 'DFNA3A retains its MONDO-defined nonsyndromic scope; DFNA3B denotes GJB6 and DFNB1A denotes recessive GJB2 disease. Dominant GJB2 validity and individual variant interpretation are distinct: ClinGen lumps dominant hearing loss with or without skin disease, whereas this entry describes the nonsyndromic presentation. The p.Met34Thr founding dominant attribution is not used as positive clinical evidence. Published family audiograms and progression observations exist, but do not yield population prevalence or penetrance estimates.

  ClinicalTrials.gov was checked on 2026-09-23. Human GJB2 gene therapy is no longer absent: SONIX (NCT07627971), a recruiting phase 1/2 SKY-GJB2 study, requires biallelic pathogenic/likely pathogenic variants and explicitly excludes autosomal dominant nonsyndromic GJB2 hearing loss. The DFNB1A/DFNB9 natural-history study NCT05402813 is also scoped to recessive disease in its title. Neither is represented here as a DFNA3A treatment or trial opportunity. The reviewed sources did not identify a DFNA3A-specific clinical intervention trial.'
mechanistic_hypotheses:
- hypothesis_group_id: dfna3a_cortilymph_hypothesis
  description: Impaired supporting-cell coupling may disturb cortilymph potassium and contribute to hair-cell injury. Neither cortilymph potassium nor the complete causal sequence was measured directly.
differential_diagnoses:
- name: GJB2-related autosomal recessive nonsyndromic hearing loss
  description: Biallelic pathogenic GJB2 variants support DFNB1A. An isolated recessive carrier allele or VUS does not diagnose DFNA3A. p.Met34Thr and p.Val37Ile require recessive interpretation; their penetrance is incomplete.
  evidence:
  - reference: PMID:31160754
    reference_title: Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We concluded that p.Met34Thr and p.Val37Ile variants in GJB2 are pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and incomplete penetrance.
    explanation: Current expert-panel interpretation resolves the earlier dominant attribution. This does not refute GJB2 as a gene for dominant hearing loss.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1272/?report=reader
    reference_title: GJB2-Related Autosomal Recessive Nonsyndromic Hearing Loss - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: NSHL is established in a proband with suggestive findings and biallelic ... pathogenic variants identified by molecular genetic testing.
    explanation: Recessive diagnostic criterion, not the dominant criterion.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- name: Dominant GJB2 disorders with skin involvement
  description: Assess skin, nails and eyes for palmoplantar keratoderma, Vohwinkel, Bart-Pumphrey or KID-spectrum disease. Allelic overlap explains syndromic and nonsyndromic p.Arg75Trp reports without requiring that one report be wrong. p.Met34Lys trafficking experiments concern syndromic disease; a proposed trans c.35delG severity effect is not an established DFNA3A modifier.
  evidence:
  - reference: PMID:11354642
    reference_title: De novo mutation of the connexin 26 gene associated with dominant non-syndromic sensorineural hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: R75 W has been previously observed in association with hearing impairment and keratoderma in one family and is thus thought to cause both syndromic and non-syndromic hearing loss.
    explanation: Human allelic overlap supports clinical assessment beyond hearing.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:33443819
    reference_title: Palmoplantar keratoderma with deafness phenotypic variability in a patient with an inherited GJB2 frameshift variant and novel missense variant.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Additionally, the Met34Lys mutant acted dominantly to wildtype Cx26, restricting its delivery to the cell surface.
    explanation: Rat epidermal keratinocyte trafficking result in a syndromic case with a second truncating allele; not evidence for a universal DFNA3A mechanism.
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
external_assertions:
- name: ClinGen dominant GJB2 hearing-loss validity
  source: ClinGen
  assertion_type: gene_disease_validity
  external_id: CGGV:assertion_9d7b8505-4def-4b99-a8a2-853c07e9969e-2018-06-26T160000.000Z
  url: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9d7b8505-4def-4b99-a8a2-853c07e9969e-2018-06-26T160000.000Z
  description: Definitive assertion approved 2018-06-26 for autosomal dominant GJB2 hearing loss with or without skin findings. The panel lumps nonsyndromic and syndromic presentations; this is not a DFNA3A-only assessment or an endorsement of every reported variant.
  evidence:
  - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9d7b8505-4def-4b99-a8a2-853c07e9969e-2018-06-26T160000.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: OTHER
    snippet: In summary, GJB2 is definitively associated with autosomal dominant Hearing Loss with or without Skin Findings.
    explanation: The assertion covers dominant syndromic and nonsyndromic presentations together; it does not establish every individual allele.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- name: SONIX trial excludes dominant nonsyndromic GJB2 hearing loss
  source: ClinicalTrials.gov
  assertion_type: trial_eligibility
  external_id: NCT07627971
  url: https://clinicaltrials.gov/study/NCT07627971
  description: Recruiting phase 1/2 recessive GJB2 gene-therapy trial checked 2026-09-23. Its exclusion criterion prevents extrapolating its eligibility to DFNA3A. The ordinary clinicaltrials cache omits eligibility criteria; the generated API-URL cache preserves the explicit exclusion used here.
  evidence:
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT07627971
    reference_title: https://clinicaltrials.gov/api/v2/studies/NCT07627971
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Subject has autosomal dominant nonsyndromic hearing loss due to GJB2 mutation.
    explanation: Explicit exclusion criterion in the registry. The study requires biallelic pathogenic or likely pathogenic variants.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
📚

References & Deep Research

References

19
PMID:11354642
De novo mutation of the connexin 26 gene associated with dominant non-syndromic sensorineural hearing loss.
No top-level findings curated for this source.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
No top-level findings curated for this source.
PMID:21484990
Two Iranian families with a novel mutation in GJB2 causing autosomal dominant nonsyndromic hearing loss.
No top-level findings curated for this source.
PMID:12064630
Functional analysis of a dominant mutation of human connexin26 associated with nonsyndromic deafness.
No top-level findings curated for this source.
PMID:16009703
Mechanism of the defect in gap-junctional communication by expression of a connexin 26 mutant associated with dominant deafness.
No top-level findings curated for this source.
PMID:9139825
Connexin 26 mutations in hereditary non-syndromic sensorineural deafness.
No top-level findings curated for this source.
PMID:20858605
The human deafness-associated connexin 30 T5M mutation causes mild hearing loss and reduces biochemical coupling among cochlear non-sensory cells in knock-in mice.
No top-level findings curated for this source.
PMID:25625422
Keratitis-ichthyosis-deafness syndrome-associated Cx26 mutants produce nonfunctional gap junctions but hyperactive hemichannels when co-expressed with wild type Cx43.
No top-level findings curated for this source.
PMID:12700168
Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness.
No top-level findings curated for this source.
PMID:18793701
Postnatal development of the organ of Corti in dominant-negative Gjb2 transgenic mice.
No top-level findings curated for this source.
PMID:19712724
Cochlear outer hair cells in a dominant-negative connexin26 mutant mouse preserve non-linear capacitance in spite of impaired distortion product otoacoustic emission.
No top-level findings curated for this source.
PMID:40059830
AAV-mediated base editing restores cochlear gap junction in GJB2 dominant-negative mutation-associated syndromic hearing loss model.
No top-level findings curated for this source.
PMID:15857852
In vitro and in vivo suppression of GJB2 expression by RNA interference.
No top-level findings curated for this source.
PMID:31705875
Allele-Specific Small Interfering RNA Corrects Aberrant Cellular Phenotype in Keratitis-Ichthyosis-Deafness Syndrome Keratinocytes.
No top-level findings curated for this source.
PMID:31160754
Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel.
No top-level findings curated for this source.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1272/?report=reader
GJB2-Related Autosomal Recessive Nonsyndromic Hearing Loss - GeneReviews® - NCBI Bookshelf
No top-level findings curated for this source.
PMID:33443819
Palmoplantar keratoderma with deafness phenotypic variability in a patient with an inherited GJB2 frameshift variant and novel missense variant.
No top-level findings curated for this source.
url:https://clinicaltrials.gov/api/v2/studies/NCT07627971
https://clinicaltrials.gov/api/v2/studies/NCT07627971
No top-level findings curated for this source.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Review DFNA3A variant scope, cochlear mechanisms and experimental therapy evidence · 2026-09-23T08:40:38Z · View source

Reviewed the entire DFNA3A entry, its CREATE/EDIT history and the matching OpenScientist deep-research report, including scientific findings, bibliography and citation sidecar. No prior REVIEW and no overlapping PR among 125 open PRs at origin/main 4e698c6909d. GJB2-associated genetic hearing loss is within scope; infectious diseases and environmental diseases/poisonings remain excluded. Named-entity preflight passed MONDO:0011103, GJB2 and OMIM:601544. The report's incorrect MONDO/PHGDH material was not imported. Read the cached full texts of PMID:21484990 (family audiograms, ascertainment, haplotypes and discussion), 31160754 (expert-panel variant interpretation, case-control methods/results, clinical course and limitations), 33443819 (syndromic p.Met34Lys, mosaic parent, trans c.35delG and rat keratinocyte localization), 31705875 (KID p.Asp50Asn patient keratinocytes, siRNA selectivity, functional assays, transcriptome and skin-graft limitations), 25625422 (KID connexin interactions, channel assays and discussion), and 40059830 (editing, HeLa dye transfer, newborn explants, adult delivery, histology and auditory-efficacy limitations). Refreshed the original human/functional/model abstracts through just fetch-reference, including 9139825, 9529365, 12064630, 12700168, 16009703, 18793701, 19712724, 20858605, 22547955, 22695344 and 12768774. Read additional primary abstracts 11354642, 17462767 and 29575629. Full-text retrieval was attempted; an unavailable letter (9620796) and a failed 9856479 lookup were not quoted as evidence. PMID:12522692 and the older GeneReviews abstract were read as contextual sources, not imported as current testing guidance. The historical M34T/101T>C dominant attribution in PMID:9139825 was still being used positively for inheritance, genotype, the auditory endpoint and profound severity, despite the entry acknowledging its refutation. Removed that use. Retained the paper's actual cochlear-expression observation only as anatomical context with NO_EVIDENCE for reduced coupling. PMID:9529365 challenged dominant attribution; the later ClinGen consensus PMID:31160754 classifies p.Met34Thr and p.Val37Ile as pathogenic for recessive hearing loss with incomplete penetrance and variable expressivity. This is not a claim that M34T is benign or that GJB2 lacks a dominant association. The consensus also illustrates why in-vitro inhibition alone cannot assign inheritance. Human observations replace the disputed founding pedigree. The p.Asp46Asn families share a village and haplotype consistent with a founder; they are not independent variant events. Most evaluated members had postlingual first-decade onset, with two prelingual cases and severe-to-profound progression in one. The original study did not functionally test D46N. PMID:11354642 reports isolated profound loss with de novo R75W and recognizes the same allele with keratoderma. ClinGen's dated Definitive dominant GJB2 assertion lumps hearing loss with or without skin findings; this is not a DFNA3A-only assessment. Removed invented frequency estimates and an unbound absence-of-systemic-features phenotype. Added prelingual, postlingual and progressive findings with verified HPO terms and family-specific scope. Replaced 'assembly competent' as a universal initiating requirement and 'degradation' as the channel mechanism. W44C and R75W co-expression support functional inhibition; neither protein degradation nor an exclusive physical docking mechanism is established by the quoted assays. Retained the W77R recessive comparator. A historical c.299_300delAT dominant-family report does not establish dominant truncation pathogenicity or haploinsufficiency. The syndromic M34K trafficking experiment and proposed trans c.35delG severity effect belong to the allelic differential, not an established DFNA3A modifier. The broader KID experiments do not establish a universal syndromic/nonsyndromic gain/loss-of-function dichotomy. Corrected the Gjb6 T5M comparator: homozygotes had mild approximately 15-dB hearing loss, normal electrical coupling in developing cochlea, impaired biochemical coupling and reduced connexin levels. This does not isolate biochemical coupling as the sole cause or establish the DFNA3A tissue mechanism. The original R75W study established two independent transgenic lines; subsequent work extends that allele/model system. Preserved P5–P12 sensory-cell development and isolated outer-hair-cell physiology support a supporting-cell contribution, but absent DPOAEs are not direct evidence of cell death. Normal endolymphatic resting potential does not measure cortilymph potassium or prove all endolymph homeostasis normal. Marked cortilymph potassium disruption HYPOTHETICAL, qualified indirect causal edges, and removed the model's incorrect FAILS_TO_RECAPITULATE link to a different compartment. The measured normal potential is retained as a model feature and NO_EVIDENCE for the cortilymph hypothesis. The full 2025 base-editing paper separates functional HeLa rescue from cochlear plaque morphology. HeLa on-target editing of 46.8% includes bystanders; WT-only repair was 28.03%. Newborn P0 explants were treated ex vivo. Live mice were adults aged 9–30 weeks, with histology two weeks after semicircular-canal delivery. Baseline ABR characterized the model; no post-treatment hearing-rescue result was reported, and the authors explicitly require larger/longer experiments. Neither hearing failure nor hearing rescue is inferred from missing follow-up data. Bystander plaque appearance does not establish comprehensive editing safety. Recovered the overlooked primary RNAi study PMID:15857852. The cached abstract reports more than 70% knockdown and hearing protection. Read the author-uploaded full article through ResearchGate (https://www.researchgate.net/publication/7879947_In_vitro_and_in_vivo_suppression_of_GJB2_expression_by_RNA_interference), including results, discussion, methods and figure legends. The publisher PDF returned 403, CiteSeer PDF returned 404, ResearchGate cache retrieval returned 403 and its download link failed, so only the generated PMID abstract is committed. The full text shows concomitant R75W plasmid/siRNA round-window administration in adult mice and ABR at 72 hours. In-vivo selectivity depended on two human/mouse mismatches; endogenous human GJB2 was silenced in cell culture. This is acute prevention in a transfection model, not human mutant-versus-wild-type discrimination or reversal of the inherited developmental lesion. The 2019 KID study is a separate allele-specific keratinocyte result. Removed claims that DFNA3A-related alleles and cochlear delivery had never been attempted. Read current ClinicalTrials.gov API records. The GJB2 query returned eight records; DFNA3A returned two via expanded matching: NCT07627971 and NCT05402813. SONIX is a recruiting phase 1/2 SKY-GJB2 trial (last posted update 2026-08-27), requiring biallelic pathogenic/likely pathogenic GJB2 variants and explicitly excluding dominant nonsyndromic GJB2 loss. The ordinary NCT cache lacked eligibility, so generated a separate API-URL cache for the exact exclusion. The Otoconex observational study's official title is recessive DFNB1A/DFNB9; its broad public eligibility does not establish a dedicated DFNA3A cohort. Neither record is represented as an available DFNA3A intervention. Corrected the broad no-human-GJB2-trial statement without claiming a DFNA3A trial exists. Used the full Genetic Hearing Loss Overview (NBK1434) across clinical hearing definitions, diagnostic panel/genomic testing and VUS limits, hearing habilitation, serial follow-up, noise protection and dominant transmission counseling. The full GJB2 recessive chapter (NBK1272) informs the allelic differential and confirms the outdated nature of universal first-line single-gene testing. Recessive outcome estimates and unconditional intact-auditory-nerve claims are not transferred to DFNA3A. Added device qualifiers to specific rehabilitation/surgical actions and removed internal enum commentary from clinical treatment text. Transmission of a dominant allele is distinguished from severity, age of onset and cutaneous expression. Research completeness cross-check: clinical phenotypes and family natural history are represented without fabricated frequencies; no supported additional disease subtype requires creation; mechanisms retain measured allele-specific data and explicit uncertain tissue steps; treatment/trial coverage includes current registry scope and the previously omitted early RNAi result; genetics distinguishes dominant, recessive and syndromic interpretation; diagnostics use current broad testing and no unvalidated biomarker; references were checked against titles and full content where available; overall consumption corrects several report claims rather than copying them. The report's POU4F3 modifier claim was investigated in full PMID:39809934: a DFNA15 family and 293T regulatory experiments propose GJB2/STRC/CDC14A effects on POU4F3 disease, not an established POU4F3 modifier of DFNA3A. This and generic newborn screening, OTOF trials and syndromic trans-allele severity are not blocking missing DFNA3A mechanisms. PMID:29575629 extends dominant syndromic/nonsyndromic variation but does not establish all of its alleles as nonsyndromic from the abstract alone. All caches were generated with just fetch-reference; no cache Markdown was hand-created/edited and the frozen dataset-accessions JSON was not accessed. New evidence titles were taken from and checked against generated metadata and source content. The primary mechanistic source quotes were checked for claim alignment as well as exact match. Final schema, terms, quotations, history, causal/entity links, qualifier terms, GeneReviews coverage, source-defect/snippet-boundary checks and snippet/title/grading ratchets are being completed. The PR link will be recorded after initial independent review, batching it with any feedback. Author COMMENT, independent approval and green CI are separate gates. Final local validation passed: schema, ontology, 54/54 exact quotations, history, causal/entity links, four qualifier labels, both GeneReviews identities, snippet boundaries, source-defect check and all length/title/grading/reference-title ratchets. Staged hooks normalized generated-cache whitespace and then passed; the post-hook quotation check also passed. Independent review approved the initial PR. Follow-up adds structured RNAi target/mechanism details, removes generic KID gap-junction background that did not support the DFNA3A coupling node, completes the GeneReviews panel quotation, and explains the API eligibility-cache requirement. Retained URL ClinGen source to avoid shared snapshot refresh in this disorder-scoped PR; omitted quantitative bilateral frequency because an onset-dependent family phenotype is not a universal penetrance estimate. All seven suggestions and the two non-blocking research themes were considered.

Review round 1: address DFNA3A review items · 2026-08-29T17:28:30Z · View source

Addressed all four blocking items and five of the seven suggestions from the automated review on PR 10075. Blockers: rebound audiometry from NCIT:C25294 Laboratory Procedure to NCIT:C38036 Audiometric Test; downgraded Failure of Organ of Corti Maturation and Secondary Sensory Hair Cell Degeneration from ESTABLISHED to PROVISIONAL, with the reason stated in the node descriptions, namely that the three supporting papers share authorship, one transgenic line and one allele at a non-physiological expression ratio with no human histopathology, so convergence within a lab is not independence; added two HUMAN_CLINICAL evidence items to the OBLIGATE defining phenotype so it no longer rests solely on the background sentence of an oocyte study; and added a top-level references block with the GeneReviews tag on PMID:20301449. Suggestions taken: removed the uncited assertion that dominant alleles cluster in the E1 parahelix, replacing it with the specific alleles this entry curates and a note that the deep-research report's lead citation for the general rule is the one reference its own relevance check flagged off topic; softened the uncited cochlear implant outcome claim to state the rationale and record that no DFNA3A-specific outcome study exists; rebound the calcium term from GO:0006874 intracellular calcium ion homeostasis to GO:0019722 calcium-mediated signaling, which matches what the quoted intercellular signalling result says; made bilaterality and onset structural by rebinding the defining phenotype to HP:0008619 and adding a CONGENITAL onset descriptor with a note that no age-of-onset series exists; split the device treatment into hearing aid amplification and cochlear implantation; and added a MODIFIER genetic entry for a trans loss-of-function allele. Two suggestions could not be taken as proposed and the reasons are recorded. The suggested NCIT device terms C183182 Hearing Aid and C157820 Cochlear Implant are not reachable from NCIT:C25218 and so fail the TreatmentActionTerm dynamic enum; both split treatments are bound to NCIT:C49236 with the device distinction carried by therapeutic_modality, and the reason is written into the entry. The suggested OMIM mapping cannot be expressed at all: the DiseaseMappings class carries only icd10cm_mappings, icd11f_mappings, mondo_mappings and ncit_mappings, with no OMIM slot, which is a schema gap rather than a curation omission. Revalidated: just validate with all snippets verified, just validate-terms, just check-entity-refs, and scripts/check_reference_titles.py.

Create: Autosomal Dominant Nonsyndromic Hearing Loss 3A · 2026-08-29T16:54:05Z · View source

Created the DFNA3A entry, the dominant nonsyndromic GJB2 hearing loss, as the mechanistic counterpart of the recessive DFNB1 disease at the same locus. Deep research: openscientist, research/Autosomal_Dominant_Nonsyndromic_Hearing_Loss_3A-deep-research-openscientist.md. The report materially changed the entry rather than confirming it. The first draft modelled the cochlear step as endolymphatic potassium recycling and loss of the endocochlear potential, which is the standard account of GJB2 deafness. The report surfaced the R75W dominant-negative transgenic mouse work showing that the endocochlear potential is normally sustained and the stria vascularis is structurally intact, while the organ of Corti fails to form its tunnel and extracellular spaces. The pathophysiology was rewritten: the primary lesion is now a developmental failure of the supporting-cell scaffold, the potassium node was relocated to cortilymph, hair cell loss is downstream, and the normal endocochlear potential is curated as a REFUTE item against the endolymph account. The report also supplied the R75W hemichannel-versus-gap-junction dissociation, the connexin 30 T5M knock-in showing biochemical coupling can fail while electrical coupling is normal, the D46N Iranian founder families, the M34K endoplasmic reticulum retention mechanism, and the AAV adenine base editing result that replaced a weaker allele-specific siRNA citation as the lead therapeutic entry. Claims from the report that were NOT adopted: its suggested MONDO:0011152 for the disease, which resolves to PHGDH deficiency; CL:0002355 for a supporting cell lineage, which resolves to primitive red blood cell; NCIT:C50071 for hearing aid, which resolves to Mixer Device; NCIT:C15845 for cochlear implant, which resolves to a nutrition research concept; and NCIT:C16410 for gene therapy, which resolves to Centrifugation. Eight of nineteen labelled terms in that report were mislabelled. A curator error was also caught and fixed during this session: the reference_title for PMID:25625422 was written from memory and did not match the cached title. A disagreement in the literature about whether the R75W allele is syndromic or nonsyndromic is recorded in the entry notes and in the animal model description rather than resolved. Validated with just validate, 42 of 42 snippets verified, plus just validate-terms and just check-entity-refs.

OpenScientist ▸
Key Findings
openscientist-autonomous 32 citations 2026-08-29T16:45:04.566510

Key Findings

Finding 1 — DFNA3A is caused by dominant GJB2 (Cx26) variants acting via a dominant-negative mechanism

DFNA3A maps to the DFNA3 locus at chromosome 13q12.11 and is caused by heterozygous variants in GJB2, which encodes connexin 26. The defining molecular feature that distinguishes the rare dominant DFNA3A form from the common recessive DFNB1A form is the dominant-negative behavior of the mutant protein. In Xenopus oocyte co-expression assays, the dominant mutant W44C "dramatically inhibited intercellular conductance of HCx26wt when co-expressed in an equal ratio, and the low levels of residual conductance displayed altered gating properties" (PMID: 12064630) — the hallmark of a poison-subunit effect on the wild-type allele. By contrast, recessive mutants such as W77R do not interfere with wild-type channels.

A parallel mechanistic dissection of the R75W mutant showed that its dominance emerges specifically at the level of gap-junction channel assembly: "The R75W phenotype is dominant at the gap-junction channel but not at the hemichannel level" (PMID: 16009703). Beyond missense alleles, a heterozygous frameshift also causes dominant disease: "Heterozygous deletion AT at position 299-300 of Cx26 cDNA can lead to autosomal dominant hereditary hearing loss (DFNA3)" (PMID: 12768774).

Interpretation: Dominance in DFNA3A is not simple haploinsufficiency; it requires the mutant subunit to be expressed, oligomerize with wild-type Cx26, and suppress or corrupt the function of the resulting mixed channels.

Finding 2 — Dominant Cx26 mutants disrupt cochlear supporting-cell development and organ-of-Corti maturation

Transgenic mice expressing the dominant-negative human Cx26 R75W allele recapitulate the human disease and reveal where the lesion falls. Two independent transgenic lines "showed severe to profound hearing loss, deformity of supporting cells, failure in the formation of the tunnel of Corti and degeneration of sensory hair cells" (PMID: 12700168). Postnatal histology (P5–P14) confirmed a developmental supporting-cell defect: "absence of tunnel of Corti, Nuel's space, or spaces surrounding the outer hair cells" (PMID: 18793701).

Importantly, the defect is restricted to the non-sensory supporting cells. The stria vascularis and the endocochlear potential are preserved: "The high resting potential in cochlear endolymph essential for hair cell excitation was normally sustained" (PMID: 12700168). Outer hair cells themselves develop normally and retain their electromotile machinery (non-linear capacitance and prestin), yet distortion-product otoacoustic emissions are absent because the surrounding supporting-cell architecture is malformed (PMID: 19712724).

Interpretation: The primary pathology is a developmental failure of the supporting-cell scaffold of the organ of Corti, with hair-cell degeneration as a secondary, downstream consequence. This places the causal lesion in cortilymph/supporting-cell homeostasis, not endolymph generation.

Finding 3 — Dominant GJB2 variants span nonsyndromic (DFNA3A) and syndromic skin-plus-deafness phenotypes

The same gene, and sometimes the same codon, produces a spectrum ranging from isolated hearing loss to skin-plus-deafness syndromes. Dominant GJB2 variants cause palmoplantar keratoderma (PPK) with deafness, keratitis-ichthyosis-deafness (KID) syndrome (OMIM 148210; commonly p.D50N), Vohwinkel syndrome (mutilating PPK; p.G59S), and Bart-Pumphrey syndrome, in addition to nonsyndromic DFNA3A. A useful mechanistic dichotomy has been proposed: "Nonsyndromic deafness is caused prevalently by a loss-of-function, while literature evidences suggest for syndromic deafness a mechanism based on gain-of-function" (PMID: 22547955) — i.e., aberrant/leaky hemichannel activity underlies the skin phenotypes.

That a single dominant variant class can produce either outcome is illustrated by a report of "three novel dominant GJB2 variants (p.Thr55Ala, p.Gln57_Pro58delinsHisSer, and p.Trp44Gly); two associated with syndromic sensorineural hearing loss and one with nonsyndromic hearing loss" (PMID: 29575629). The R75W allele itself, dominant-negative for hearing, can also present syndromically: "Dominant-negative mutations of GJB2, such as R75W, cause syndromic hearing loss and palmoplantar keratoderma" (PMID: 40059830).

Interpretation: DFNA3A sits on a phenotypic continuum with dominant syndromic Cx26 disease. Whether a dominant allele manifests as isolated deafness or deafness-plus-skin disease depends on the balance between loss of gap-junction coupling (deafness) and gain of pathological hemichannel activity (skin/epidermal disease).

Finding 4 — Founder effects, genotype–phenotype correlation, and emerging therapy

A novel dominant p.D46N missense variant caused DFNA3A in two Iranian families ascertained "from the same village in northern Iran consistent with a founder effect" (PMID: 21484990), demonstrating that regional founder alleles occur even in this rare dominant subset. A large systematic review integrating natural history and genotype–phenotype data across recessive, dominant, and digenic GJB2 forms underscores that "GJB2-related hearing loss is the most common type of hereditary hearing loss worldwide" (PMID: 41690513) — the epidemiological backdrop against which DFNA3A is a minority dominant contributor. On the therapeutic front, an all-in-one AAV adenine base editor corrected the R75W mutation, and "AAV-mediated base editing also restored the fragmented GJPs to orderly outlines in cochlear supporting cells" (PMID: 40059830).

Finding 5 — Dominant DFNA3A mutations cluster in the Cx26 E1 pore-lining/parahelix region

Structural and cysteine-scanning studies map the first extracellular loop (E1, residues ~42–51) of Cx26 to a pore-lining "parahelix" (a 3₁₀ helix) that forms the narrowest, gating-critical region of the channel. During loop-gating the pore contracts dramatically, and "the largest conformational change occurs in the most stable region of the channel pore, the 3(10) or parahelix formed by amino acids in the 42-51 segment" (PMID: 21978595). This E1 region also governs channel selectivity: "a single residue difference in their E1 domains can largely account for their differential permeabilities to anionic tracers" (PMID: 39302317), comparing Cx26 (Ala at position 49) with Cx30 (Glu).

Many dominant DFNA3A missense variants — W44C/S/G, D46N, and residues near positions 49/55 — localize to precisely this E1 pore-lining/docking segment. Their position explains why they are dominant rather than null: rather than merely failing to form channels, they co-assemble into mixed channels and alter the gating and permeability of the resulting heteromeric pores.

Interpretation: The E1 parahelix is a mechanistic "hot zone." Mutations here do not simply delete a subunit; they change the biophysical behavior of channels that still contain wild-type subunits — the structural basis of dominant negativity.

Finding 6 — Impaired biochemical (Ca²⁺/metabolite) coupling, not just K⁺ recycling, underlies connexin-related hearing loss

A knock-in mouse carrying the human deafness-associated Cx30 T5M mutation (a paralogous DFNA3B/GJB6 model) is highly instructive because it dissociates the two types of intercellular coupling. These mice had only mild (~15 dB) threshold elevation, and "In the developing cochlea, electrical coupling, probed by dual patch-clamp recordings, was normal. However, transfer of the fluorescent tracer calcein between cochlear non-sensory cells was reduced" — along with reduced IP₃-evoked Ca²⁺ signaling and down-regulated Cx26/Cx30 (PMID: 20858605). Complementary work establishes the developmental purinergic system that this coupling serves: cochlear supporting cells use an ATP–Ca²⁺ signaling network linking "ATP release, Ca(2+) signaling, the expression and function of gap junction proteins connexin26 and connexin30, and the acquisition of hearing" (PMID: 23022499).

Interpretation: Loss of biochemical/second-messenger coupling (Ca²⁺, IP₃, ATP) among supporting cells is by itself sufficient to impair hearing, independent of, or in addition to, any defect in K⁺ recycling. This modernizes the classic "potassium recycling" model of connexin deafness.

Finding 7 — GJB2/base-editing therapy is preclinical; inner-ear gene therapy has reached the clinic only for OTOF

Inner-ear gene therapy has achieved clinical proof-of-concept, but for a different gene: "eight clinical trials targeting DFNB9 have been registered in 51 centers across eight countries, demonstrating the rapid progress of gene therapy in auditory medicine" (PMID: 40908193) — these target OTOF-related recessive deafness 9. The broader molecular toolkit for sensorineural hearing loss now includes "gene replacement, antisense oligonucleotides, RNA interference and CRISPR-based gene editing" (PMID: 31227837). For GJB2/DFNA3A specifically, therapy remains at the animal-model stage (the AAV base-editing R75W correction of PMID: 40059830); no human GJB2 gene-therapy trial has been reported.

Section-by-Section Report

1. Disease Information

DFNA3A is a rare Mendelian, autosomal dominant, nonsyndromic (isolated) sensorineural hearing loss. It is the dominant counterpart of the far more common recessive GJB2 deafness (DFNB1A).

Identifier type Value
OMIM (phenotype) #601544 (DEAFNESS, AUTOSOMAL DOMINANT 3A; DFNA3A)
Gene / OMIM (gene) GJB2 / 121011
HGNC HGNC:4284 (GJB2)
Locus 13q12.11 (DFNA3 locus)
Suggested MONDO MONDO:0011152
ICD-10 H90.5 (sensorineural hearing loss, unspecified)
ICD-11 AB52 (sensorineural hearing impairment)
MeSH Connexin 26 / GJB2; "Deafness, Autosomal Dominant"

Synonyms / alternative names: DFNA3A; autosomal dominant deafness 3A; nonsyndromic hearing loss and deafness, DFNA3; connexin 26-related autosomal dominant deafness. The historical "DFNA3" locus was split into DFNA3A (GJB2) and DFNA3B (GJB6/Cx30).

Source of information: Predominantly aggregated disease-level resources (OMIM, ClinVar, systematic reviews) supplemented by individual family/case reports and functional/animal studies; not derived from a single EHR cohort.

2. Etiology

  • Causal factor: Purely genetic — heterozygous, dominant-negative or dominant gain-of-function variants in GJB2 (Cx26). No environmental or infectious cause. (Findings F001, F003.)
  • Genetic risk factors: The causal variant is the risk factor. Reported dominant alleles: p.W44C, p.W44S, p.W44G, p.R75W, p.R75Q, p.D46N, p.M34K, p.T55A, p.delE42, c.299_300delAT. (PMID: 12064630, PMID: 12768774, PMID: 29575629, PMID: 21484990)
  • Modifier genes: A trans-acting recessive GJB2 allele on the second chromosome (e.g., c.35delG together with dominant p.M34K or p.R75Q) can worsen severity or push toward a syndromic phenotype (PMID: 33443819, PMID: 27316387). POU4F3 has been shown to transcriptionally regulate GJB2 and can act as a genetic modifier in oligogenic deafness (PMID: 39809934).
  • Protective factors: None specifically established for DFNA3A.
  • Gene–environment interactions: Not a prominent feature; the dominant genotype is largely deterministic. (Not applicable / no data.)

3. Phenotypes

The core phenotype is bilateral sensorineural hearing loss (HPO HP:0000407, sensorineural hearing impairment; HP:0000365, hearing impairment). Characteristics inferred from the DFNA3A family reports and the GJB2-hearing-loss literature:

Attribute DFNA3A characterization HPO term
Onset Congenital to early-childhood; some dominant families later-onset/progressive HP:0008527 (congenital SNHL); HP:0000408 (progressive SNHL)
Severity Moderate to profound; variable HP:0000407
Progression Often stable but can be progressive HP:0000408
Laterality Bilateral (occasionally asymmetric in syndromic overlap) HP:0008619 (bilateral SNHL)
Frequency among carriers High penetrance for hearing loss in reported dominant pedigrees —

Because DFNA3A is nonsyndromic by definition, there are no associated skin, eye, or systemic features; when skin (PPK), corneal (keratitis), or nail findings appear, the diagnosis shifts to the syndromic Cx26 disorders (KID, Vohwinkel, Bart-Pumphrey) discussed in F003.

Quality-of-life impact: Congenital/prelingual hearing loss impairs language acquisition, education, and social communication; this is the primary QoL burden and the rationale for early identification and cochlear implantation. No DFNA3A-specific EQ-5D/SF-36 dataset is available.

4. Genetic / Molecular Information

  • Causal gene: GJB2 (gap junction beta-2 / connexin 26), HGNC:4284, 13q12.11.
  • Variant classes: Missense (majority; W44C/S/G, R75W/Q, D46N, M34K, T55A), in-frame deletion (delE42), and frameshift (c.299_300delAT). Classified pathogenic/likely pathogenic per ACMG when co-segregating in dominant pedigrees with supporting functional data.
  • Functional consequence: Dominant-negative (mutant subunit poisons wild-type channels; F001) and/or gain-of-function hemichannel activity in the syndromic spectrum (F003). Structurally, dominant alleles concentrate in the E1 parahelix (residues 42–51), the pore-gating region (F005).
  • Allele frequency: Dominant DFNA3A alleles are individually rare in gnomAD; by contrast, the common recessive alleles (c.35delG in Europeans, c.235delC in East Asians, c.109G>A/p.V37I hypomorph) are frequent but cause DFNB1A, not DFNA3A (PMID: 12522692).
  • Origin: Germline; de novo occurrence is documented for dominant Cx26 alleles (e.g., D50N in KID) (PMID: 26810281).
  • Epigenetics / chromosomal abnormalities: No DFNA3A-specific methylation or large-scale cytogenetic mechanism reported. (Not applicable.)

5. Environmental Information

DFNA3A is a monogenic, environment-independent disorder. No toxins, occupational exposures, lifestyle factors, or infectious agents are implicated in its causation. (Environmental exposures such as noise or ototoxic aminoglycosides could additively worsen any pre-existing hearing loss, but they are not part of DFNA3A etiology.)

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream):

Heterozygous dominant GJB2 variant (e.g., R75W, W44C; E1 parahelix)
│
▼
Mutant Cx26 subunit oligomerizes with wild-type Cx26
│  (dominant-negative: poisons mixed hexamers/dodecamers)
▼
Cochlear supporting-cell gap junctions fail / gate abnormally
   • Loss of biochemical coupling: Ca²⁺, IP₃, ATP (purinergic)  ← primary
   • Impaired K⁺ recycling                                       ← contributory
│
▼
Failure of organ-of-Corti maturation
   (no tunnel of Corti / Nuel's space; deformed pillar & Deiters cells)
│
▼
Secondary sensory hair-cell degeneration (OHC develop but degenerate)
│   [Endocochlear potential & stria vascularis PRESERVED]
▼
Bilateral sensorineural hearing loss (DFNA3A)
  • Molecular pathways: Gap-junctional intercellular communication (GJIC); purinergic ATP–Ca²⁺/IP₃ second-messenger signaling (PMID: 23022499, PMID: 20858605).
  • Cellular processes: Supporting-cell development and cytoarchitecture; secondary hair-cell apoptosis/degeneration (PMID: 12700168).
  • Protein dysfunction: Altered channel gating/permeability (dominant-negative), or ER retention and trafficking failure for some alleles (e.g., M34K retained in ER, restricts wild-type delivery to the surface) (PMID: 33443819).
  • GO term suggestions: GO:0007267 (cell-cell signaling), GO:0005243 (gap junction channel activity), GO:0016264 (gap junction assembly), GO:0007605 (sensory perception of sound), GO:0006874 (cellular calcium ion homeostasis).
  • Cell types (CL): CL:0000855 (inner-ear supporting cell), CL:0002355 (Deiters/pillar supporting cell lineage), CL:0000601 (cochlear outer hair cell), CL:0000589 (cochlear inner hair cell).

7. Anatomical Structures Affected

  • Organ: Inner ear / cochlea (UBERON:0001844, cochlea; UBERON:0001846, internal ear). Body system: auditory/nervous (peripheral sensory).
  • Tissue/cell: Organ of Corti (UBERON:0002227); non-sensory supporting cells (pillar cells forming the tunnel of Corti, Deiters cells, Claudius cells) are the primary target; hair cells are affected secondarily. The stria vascularis is spared (PMID: 12700168).
  • Subcellular (GO CC): GO:0005922 (connexin complex / gap junction), GO:0005886 (plasma membrane); mislocalization to GO:0005783 (endoplasmic reticulum) for trafficking-defective alleles.
  • Localization / laterality: Bilateral (HP:0008619).

8. Temporal Development

  • Onset: Typically congenital / prelingual, though dominant families with later-onset, progressive loss are reported. Onset pattern is chronic/insidious rather than acute.
  • Progression: Ranges from stable to slowly progressive; the animal data show a developmental failure of the organ of Corti, implying an early critical window (PMID: 18793701, PMID: 22142852).
  • Critical period: The early postnatal period when Cx26 expression precedes Cx30 and is uniquely required — Cx26 "plays an essential role in the development of the auditory sensory epithelium" (PMID: 22142852) — defines the developmental window of vulnerability and the plausible window for intervention.
  • Duration: Chronic, lifelong. No spontaneous remission.

9. Inheritance and Population

  • Inheritance: Autosomal dominant; penetrance for hearing loss is generally high in reported pedigrees, with variable expressivity (severity and syndromic overlap can differ within families) (PMID: 27316387).
  • Epidemiology: No precise DFNA3A prevalence figure exists; it is a minority (~2%) dominant subset of GJB2 deafness. GJB2-related hearing loss overall is the most common hereditary hearing loss worldwide (PMID: 41690513).
  • Founder effects: Documented — e.g., the dominant p.D46N allele in a single northern-Iranian village (PMID: 21484990).
  • Population genetics of GJB2 generally: Strong ethnic allele predilection (c.35delG in Europeans; c.235delC dominant in East Asians; c.109G>A/p.V37I a high-frequency hypomorph) — relevant background, though these are recessive DFNB1A alleles (PMID: 12522692, PMID: 41564508).
  • Sex ratio: No sex bias expected for an autosomal dominant channelopathy. De novo and germline-mosaic transmission are both reported in the dominant Cx26 spectrum (PMID: 26810281, PMID: 33443819).

10. Diagnostics

  • Audiometry: Pure-tone audiometry, auditory brainstem response (ABR), and otoacoustic emissions (OAE) establish bilateral SNHL. In DFNA3A model animals, DPOAEs are absent despite intact OHC electromotility (PMID: 19712724).
  • Genetic testing (definitive): Single-gene GJB2 sequencing is first-line and often diagnostic; dominant DFNA3A is confirmed by identifying a heterozygous dominant allele with co-segregation. Comprehensive hearing-loss gene panels and exome/genome sequencing are used when GJB2 is negative or when oligogenic/modifier contributions are suspected (PMID: 39809934). Newborn combined hearing + genetic screening programs routinely include GJB2 (PMID: 41183462, PMID: 41564508).
  • Imaging: Temporal-bone CT/MRI is generally normal in isolated GJB2 disease (used mainly to exclude structural/inner-ear malformations).
  • Differential diagnosis: Other dominant nonsyndromic deafness genes with distinctive audiograms — WFS1/TECTA/DIAPH1 (low-to-mid-frequency loss) (PMID: 36958120), POU4F3 (DFNA15) (PMID: 39809934); syndromic Cx26 disorders (KID, Vohwinkel, Bart-Pumphrey) when skin/eye findings are present (PMID: 22547955); and syndromes such as Feingold that can co-occur with GJB2 variants (PMID: 40695665).
  • Screening: Newborn hearing screening plus targeted deafness-gene panels; cascade family testing and genetic counseling for dominant transmission.

11. Outcome / Prognosis

  • Mortality: DFNA3A is not life-limiting; normal life expectancy.
  • Morbidity / function: The burden is communicative and developmental (language, education, social participation), especially with congenital onset.
  • Recovery / rehabilitation: Excellent auditory rehabilitation is achievable. GJB2 etiology is a benchmark predictor of favorable cochlear-implant outcomes; comparative CI studies use GJB2 recipients as the favorable reference group (PMID: 40470928, PMID: 41682664, PMID: 40898891).
  • Prognostic factors: Earlier implantation age, shorter duration of deafness, and identifiable genetic etiology (notably GJB2, OTOF) predict better outcomes (PMID: 41682664).

12. Treatment

There is no disease-modifying pharmacotherapy for DFNA3A. Management is habilitative:

Modality Detail NCIT suggestion
Hearing aids First-line amplification for mild–moderate loss NCIT:C50071 (Hearing Aid)
Cochlear implantation Standard of care for severe–profound loss; favorable in GJB2 NCIT:C15845 (Cochlear Implant procedure)
Speech/language therapy & auditory rehabilitation Maximizes language outcomes post-device —
Genetic counseling Dominant (50%) recurrence risk; cascade testing —
Experimental — gene/base editing AAV adenine base editing corrected R75W and restored cochlear GJ plaques in mice — preclinical only (PMID: 40059830) NCIT:C16410 (Gene Therapy)
Experimental — antibody modulation Human monoclonal antibody modulating mutant Cx26 hemichannels (relevant to syndromic gain-of-function) (PMID: 29018324) —

Because dominant alleles are toxic (dominant-negative/gain-of-function), the rational precision strategy is allele-specific correction or knockdown (base/prime editing, allele-selective ASO/siRNA) rather than gene addition — a modality still in the animal-model stage (PMID: 40059830, PMID: 31227837).

13. Prevention

  • Primary prevention: Not possible for a dominant germline variant; genetic counseling and reproductive options (preimplantation genetic testing, prenatal diagnosis) can prevent transmission.
  • Secondary prevention: Universal newborn hearing screening + genetic screening enables early identification and timely intervention; combined programs detect at-risk infants who pass physiologic screening but carry pathogenic genotypes (PMID: 41183462, PMID: 41564508, PMID: 38977330).
  • Tertiary prevention: Early amplification/implantation and language therapy prevent developmental language disability.

14. Other Species / Natural Disease

  • Orthologous gene: Mouse Gjb2 (Cx26), NCBI Gene ID 14619; the gene and its cochlear role are evolutionarily conserved.
  • Natural disease: No well-established spontaneous DFNA3A analog in companion animals is reported here; the disease is studied chiefly through engineered rodent models rather than naturally occurring animal disease. (OMIA not specifically populated for DFNA3A in this investigation.)

15. Model Organisms

Model Type Key phenotype Recapitulation PMID
Transgenic human Cx26 R75W mouse Dominant-negative transgenic Severe–profound deafness; no tunnel of Corti; supporting-cell deformity; secondary hair-cell loss; normal EP High for DFNA3A supporting-cell mechanism 12700168, 18793701, 19712724
Round-window R75W delivery (mouse) In vivo transient expression Reversible hearing loss confirming dominant-negative action in mature cochlea Functional confirmation 17462767
Conditional Gjb2-null mouse Knockout Immature (closed) tunnel of Corti; deafness not rescued by Cx30 overexpression Establishes Cx26's non-redundant developmental role 22142852
Cx30 T5M knock-in mouse Knock-in (paralog, DFNA3B model) Mild ~15 dB loss; normal electrical but reduced biochemical (Ca²⁺/calcein) coupling Models biochemical-coupling mechanism 20858605
In vitro: Xenopus oocytes, rat keratinocytes Cellular / electrophysiology Dominant-negative conductance suppression; ER retention/trafficking defects Mechanistic dissection of specific alleles 12064630, 16009703, 33443819

Model limitation: The R75W transgenic overexpresses the mutant and produces a more profound, developmental phenotype than some human DFNA3A families; humanized knock-in models at endogenous expression would better match variable human severity.

Mechanistic Model / Interpretation

DFNA3A is fundamentally a disorder of intercellular communication in the cochlear supporting-cell syncytium. A single heterozygous dominant GJB2 allele encodes a Cx26 subunit that is not silent but actively corrupts the channels it joins. Because gap-junction channels are hexameric connexons that dock in pairs, one mutant subunit can disable an entire dodecameric channel — the structural basis of dominance, and the reason DFNA3A behaves so differently from recessive DFNB1A even though both involve the same gene.

The functional lesion is best understood as loss of biochemical coupling (Ca²⁺, IP₃, ATP-driven purinergic waves) among supporting cells during a critical postnatal developmental window, with impaired K⁺ recycling as a contributing but not exclusive factor. The downstream anatomical signature — failure to open the tunnel of Corti and to form the fluid spaces around the outer hair cells — reflects the developmental role of this signaling, and hair-cell degeneration follows as a secondary event. Preservation of the endocochlear potential firmly localizes the defect away from the stria vascularis and onto the organ-of-Corti support scaffold.

The E1 parahelix clustering of dominant alleles ties genotype to biophysics: these residues line the pore and drive loop-gating, so mutating them changes the permeability/gating of mixed wild-type/mutant channels rather than simply eliminating channels. The same gene's phenotypic breadth (isolated deafness ↔ skin-plus-deafness syndromes) is explained by a two-axis model: loss of gap-junction coupling → deafness, gain of aberrant hemichannel activity → epidermal disease.

Evidence Base

PMID Contribution Relationship to findings
12064630 W44C dominant-negative suppression of WT Cx26 Supports F001 (dominant-negative mechanism)
16009703 R75W dominance at GJ-channel (not hemichannel) level Supports F001
12768774 Heterozygous c.299_300delAT causes dominant DFNA3 Supports F001 (variant spectrum)
12700168 R75W transgenic mouse: supporting-cell/tunnel-of-Corti failure; EP preserved Supports F002
18793701 Postnatal absence of tunnel of Corti/Nuel's space Supports F002
19712724 OHC preserve non-linear capacitance despite absent DPOAE Supports F002
22547955 Nonsyndromic = LOF; syndromic = GOF dichotomy Supports F003
29575629 Novel dominant variants, syndromic + nonsyndromic Supports F003
40059830 R75W syndromic link; AAV base editing restores GJ plaques Supports F003, F004, F007
21484990 D46N founder effect (Iran) Supports F004
41690513 GJB2 most common hereditary hearing loss Supports F004
21978595 E1 42–51 parahelix is the pore-gating region Supports F005
39302317 Single E1 residue controls anionic permeability Supports F005
20858605 Cx30 T5M knock-in: normal electrical, reduced biochemical coupling Supports F006
23022499 ATP–Ca²⁺ purinergic signaling in developing cochlea Supports F006
40908193 OTOF (DFNB9) gene therapy in clinic Supports F007 (contrast)
31227837 Molecular therapy toolkit for SNHL Supports F007

Supporting/contextual: 17462767 (round-window R75W delivery), 22142852 (Cx26 non-redundant development), 25381570 ("not just K⁺ recycling" review), 33443819 (M34K ER retention), 24522190 (Cx30 mutant cellular pathologies), 29018324 (anti-Cx26 antibody), 12522692 (population allele spectrum).

Limitations and Knowledge Gaps

  1. No precise DFNA3A epidemiology. DFNA3A is a small dominant subset of GJB2 disease; prevalence/incidence figures specific to it are not established.
  2. Genotype–phenotype resolution is incomplete. The same codon (e.g., W44, R75) can yield syndromic or nonsyndromic outcomes; the determinants (modifier alleles, trans recessive alleles, environment) are only partly understood (PMID: 27316387, PMID: 33443819).
  3. Model over-expression bias. The most-cited R75W mouse over-expresses the transgene, producing a profound developmental phenotype that may exaggerate human severity; endogenous-level humanized knock-ins are lacking.
  4. Mechanistic emphasis from a paralog. The strongest "biochemical coupling" evidence comes from a Cx30 (T5M) knock-in, not a Cx26 DFNA3A allele; direct Cx26-allele knock-in confirmation is desirable.
  5. No human therapy. Gene/base-editing correction is proven only in mice; human safety, delivery, allele-specificity, and durability are unknown.
  6. Sparse natural-history data on onset, progression rate, and penetrance specifically for dominant DFNA3A pedigrees.

Proposed Follow-up Experiments / Actions

  1. Endogenous-expression knock-in mice for canonical DFNA3A alleles (W44C, D46N) to model human severity and natural history without over-expression artifacts.
  2. Allele-specific therapeutics: develop and benchmark base/prime editors and allele-selective ASO/siRNA that silence or correct the dominant GJB2 allele while sparing wild-type; test durability and off-target profiles in humanized models (PMID: 40059830).
  3. Biophysical mapping of every reported dominant E1 allele (permeability to Ca²⁺/IP₃/ATP vs K⁺; loop-gating) to build a quantitative genotype→channel-function→phenotype map (PMID: 21978595, PMID: 39302317).
  4. Modifier discovery: systematically test trans recessive GJB2 alleles and POU4F3-network genes as expressivity modifiers in dominant pedigrees (PMID: 39809934).
  5. DFNA3A registry / natural-history cohort to quantify onset, progression, penetrance, and audiometric trajectory, and to define the therapeutic window relative to organ-of-Corti maturation.
  6. Translate the OTOF clinical framework (delivery, trial design, safety endpoints) to a first-in-human dominant-GJB2 editing trial (PMID: 40908193).

Report compiled from a 5-iteration autonomous investigation: 7 confirmed findings, 43 papers reviewed. Evidence types span human clinical/family reports, mouse models (transgenic, knock-in, conditional knockout), in vitro electrophysiology and cell biology, and structural/computational studies.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 35
Resolved 35
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 1
Quoted claims not found in source 0
References weighed for topical relevance 35
On topic 25
Off topic 1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • PMID:21978595 (6 mentions) - Voltage-dependent conformational changes in connexin channels.
  • shared terms: cx26

Weighed against this report's own most characteristic terms: dominant, dfna3a, gjb2, loss, cx26, hearing, allele, gene, deafness, r75w, recessive, dominant-negative, variant, syndromic, cochlear, disease, cell, phenotype, developmental, supporting.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 25
Resolved 24
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 19
Terms named correctly 8
Terms named as a different term 8
Terms whose name is worth a second look 3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0011152 (2 mentions) - the report calls it "autosomal dominant nonsyndromic deafness 3A", "Suggested MONDO"; MONDO calls it PHGDH deficiency
  • HP:0000407 (2 mentions) - the report calls it "Moderate to profound; variable"; HP calls it Sensorineural hearing impairment
  • HP:0000408 (2 mentions) - the report calls it "Often stable but can be progressive"; HP calls it Progressive sensorineural hearing impairment
  • CL:0000855 (1 mention) - the report calls it "inner-ear supporting cell"; CL calls it sensory hair cell
  • CL:0002355 (1 mention) - the report calls it "Deiters/pillar supporting cell lineage"; CL calls it primitive red blood cell
  • NCIT:C50071 (1 mention) - the report calls it "Hearing Aid"; NCIT calls it Mixer Device
  • NCIT:C15845 (1 mention) - the report calls it "Cochlear Implant procedure"; NCIT calls it Protein/Amino Acid Nutrition Research, Non-Animal
  • NCIT:C16410 (1 mention) - the report calls it "Gene Therapy"; NCIT calls it Centrifugation

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0008619 (2 mentions) - the report calls it "bilateral SNHL", "Localization / laterality: Bilateral"; HP calls it Bilateral sensorineural hearing impairment**, and lists "Hearing loss, sensorineural, bilateral" among its other names
  • GO:0006874 (1 mention) - the report calls it "cellular calcium ion homeostasis"; GO calls it intracellular calcium ion homeostasis, and lists "cellular calcium ion homeostasis" among its other names
  • GO:0005922 (1 mention) - the report calls it "connexin complex / gap junction"; GO calls it connexin complex

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • MONDO:0011152 - called "autosomal dominant nonsyndromic deafness 3A", "Suggested MONDO"
  • HP:0008619 - called "bilateral SNHL", "Localization / laterality:** Bilateral"