Autosomal Dominant Nonsyndromic Hearing Loss 12

Mendelian MONDO:0011102 Pathograph 14 Show in embeddings browser Autosomal Dominant Nonsyndromic Hearing Loss Hereditary Hearing Loss

Autosomal dominant nonsyndromic hearing loss 12 (DFNA8/12) is caused by heterozygous pathogenic TECTA variants affecting alpha-tectorin, a major non-collagenous component of the cochlear tectorial membrane. DFNA8 and DFNA12 were mapped independently in Austrian and Belgian families before both were linked to TECTA. The primary lesion affects an extracellular matrix required for efficient hair-cell stimulation and cochlear amplification. A dominant-negative mechanism is supported by human segregation and allele-matched mouse studies, but normal secretion and incorporation of every mutant protein have not been demonstrated. Mouse models also reveal secondary hair-cell vulnerability under experimental exposure; the disease cannot be characterized as universally free of cellular injury. Hearing loss can be congenital, prelingual or later-onset, stable or progressive, with mid-frequency, high-frequency or flatter configurations. Protein domain and residue help interpret a variant but do not determine an individual audiogram or course. Some alleles associated with human progression produce stable mouse thresholds over the studied intervals. Preserved speech recognition in selected patients supports hearing rehabilitation but does not establish universal preservation of the auditory nerve or dominant TECTA-specific implant efficacy.

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1
Inheritance
6
Pathophys.
6
Phenotypes
2
Hypotheses
3
Gaps
14
Pathograph
1
Genes
4
Medical Actions
2
Differentials
4
Models
4
References
1
Deep Research
🏷

Classifications

Harrison's Part
NEUROLOGIC
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
Heterozygous pathogenic TECTA variants can be transmitted through multiple generations. Each child of a heterozygous parent has a 50% chance of inheriting the variant; onset, severity and progression cannot be predicted precisely from transmission alone. Many dominant alleles are missense or splice-altering variants; allele-specific interpretation distinguishes DFNA8/12 from recessive DFNB21.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:9590290 SUPPORT Human Clinical
"In both families, mutation analysis revealed missense mutations which replace conserved amino-acid residues within the zona pellucida domain of TECTA."
Establishes heterozygous missense variants as the cause in the two founding dominant families.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Individuals with autosomal dominant hearing loss have a 50% chance of transmitting the pathogenic variant to each child."
GeneReviews provides the general autosomal dominant transmission probability, not an allele-specific penetrance estimate.
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Mechanistic Hypotheses

2
Dominant-negative disruption of tectorial membrane organization
dominant_negative_tectorin_incorporation CANONICAL
Evidence balance 3 support
The contrast between unaffected heterozygous carriers of a recessive TECTA allele and dominant missense families supports a dominant-negative model. Allele-matched mice show matrix defects distinct from simple heterozygous null states. These findings do not prove normal secretion, abundance or physical incorporation for every dominant mutant protein. For c.5999G>A, patient RNA shows abnormal in-frame splicing without reduced total transcript abundance; the protein-level mechanism remains inferred.
Show evidence (3 references)
PMID:9949200 SUPPORT Human Clinical
"Comparison of the phenotype of the DFNB21 heterozygous carriers with that of DFNA8/12-affected individuals supports the hypothesis that the TECTA mutations which cause the dominant form of deafness have a dominant-negative effect."
States the carrier-versus-patient comparison that grounds the dominant-negative model.
PMID:9949200 SUPPORT INDIRECT Human Clinical
"The present results provide genetic evidence for alpha-tectorin forming homo- or heteromeric structures."
The authors infer homo- or heteromeric assembly from genetic observations; this is not a direct protein interaction assay.
PMID:40583560 SUPPORT INDIRECT Human Clinical
"Quantitative real-time polymerase chain reaction revealed no significant reduction in mRNA levels in lymphoblasts derived from individuals harboring the TECTA c.5999G > A (p.Gly2000Glu) variant"
Total RNA abundance was not reduced, but the study lacked direct protein-expression and matrix-incorporation measurements. This supports the authors' proposed mechanism indirectly and does not exclude a protein-level dosage effect.
Tectorial membrane regulation of calcium near hair-cell transduction channels
tectorial_membrane_calcium_adaptation EMERGING
Evidence balance 1 support
Tecta/Tectb double-knockout mice retain mature hair-cell properties but lose long-lasting emission adaptation. The authors propose that the membrane regulates calcium near transduction channels. This extends membrane function beyond mechanical coupling; calcium regulation and its relevance to dominant human TECTA alleles remain unproven.
Show evidence (1 reference)
PMID:33559882 SUPPORT INDIRECT PRIMARY RESULT Model Organism
"repetitive acoustic stimulation fails to produce adaptation of MET-dependent otoacoustic emissions in vivo in the Tecta/Tectb-/- mice."
A double-knockout mouse result supports the adaptation hypothesis indirectly for dominant DFNA8/12; no local calcium concentration was directly measured in patients.
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Discussions and Knowledge Gaps

3
Why do allele-matched Tecta mice not show the progression seen in the patients carrying the same substitution, and can any mouse be used to study progression in this disease?
HUMAN MODEL MISMATCH mouse_does_not_progress
Attached to
animal_models#Tecta C1619S/+ mouse (ZA domain) animal_models#Tecta C1509G/+ mouse pathophysiology#Secondary Outer Hair Cell Vulnerability animal_models#Tecta C1837G/+ mouse (ZP domain)
C1619S and C1837G mice lacked progressive threshold deterioration over the studied intervals despite progression in corresponding human families. C1509G emission thresholds were stable in quiet through six months; after noise, recovery and cell-loss distribution differed from wild type without greater total loss in the sampled region. Lifespan, genetic background and cumulative exposure are candidate explanations, not established causes of the mismatch. The studied conditions lack a spontaneous progression endpoint.
Show evidence (2 references)
PMID:24363064 SUPPORT Model Organism
"The phenotypes are stable and no evidence has been found for a progressive deterioration in TM structure or auditory function."
The direct statement of absent progression in the allele-matched mice.
PMID:10196713 SUPPORT Human Clinical
"The present study reports linkage to DFNA12 in a new family with autosomal dominant high frequency hearing loss progressing from mild to moderate severity."
Establishes that the human phenotype for a ZA-domain allele does progress, which is the half of the mismatch the mouse fails to reproduce.
Do Tecta mutations confer any central auditory phenotype in humans, given that all three allele-matched mouse models develop audiogenic seizures?
OPEN QUESTION audiogenic_seizure_in_tecta_mice
Attached to
animal_models#Tecta L1820F,G1824D/+ mouse (ZP domain) animal_models#Tecta C1619S/+ mouse (ZA domain) animal_models#Tecta C1837G/+ mouse (ZP domain)
C1619S, C1837G and L1820F/G1824D mice exhibited wild running predictive of seizures at low sound levels. The authors stopped stimulation early and could not complete the planned high-noise experiments. Central adaptation and other mechanisms remain hypotheses; a corresponding human phenotype was not established. This result cannot be assigned to the separate C1509G experiment.
Show evidence (1 reference)
PMID:24363064 SUPPORT Model Organism
"Despite elevated auditory thresholds, the Tecta mutant mice all exhibit an enhanced tendency to have audiogenic seizures in response to white noise stimuli at low sound pressure levels (≤84 dB SPL), revealing a previously unrecognised consequence of Tecta mutations."
Reports the unexpected central phenotype in all three models.
How much of the audiogram configuration does the mutated alpha-tectorin domain actually predict?
KNOWLEDGE GAP domain_audiogram_correlation_limits
Attached to
pathophysiology#Defective Tectorial Membrane Matrix Assembly phenotypes#Mid-Frequency Hearing Loss
Domain-associated structural differences in tested mice and human audiogram associations are useful but incomplete. Mid-frequency loss occurs outside the ZP domain, and cysteine/progression associations have exceptions. Both allelic effects and ascertainment matter; modifiers remain incompletely resolved. Domain location should inform interpretation without being presented as a deterministic prognosis.
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Pathophysiology

6
Heterozygous Pathogenic TECTA Variant
Heterozygous pathogenic variants occur across the entactin/NIDO, zonadhesin-like and zona pellucida domains of TECTA. The 2011 study screened a Spanish cohort without audiogram preselection and an American subset selected by audiogram. Dominant alleles include missense changes and coding variants that alter splicing: c.5999G>A produces two in-frame exon-20 deletions. A sequence-level missense annotation alone therefore does not identify the molecular consequence.
TECTA hgnc:11720 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TECTA (hgnc:11720). hgnc:11720 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context TECTA hgnc:11720 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns TECTA (hgnc:11720). hgnc:11720 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE
Includes missense and splice-altering alleles. Dominant-negative action is the prevailing model; variant-specific protein consequences require functional evidence.
Downstream
Defective Tectorial Membrane Matrix Assembly Dominant TECTA alleles alter matrix organization. Mutant-protein assembly effects are inferred from human genetics and supported by allele-matched mouse structural phenotypes, rather than measured for every human allele.
Show evidence (5 references)
PMID:9590290 SUPPORT Human Clinical
"In both families, mutation analysis revealed missense mutations which replace conserved amino-acid residues within the zona pellucida domain of TECTA."
The founding identification of TECTA missense variants in the DFNA8 and DFNA12 families.
PMID:21520338 SUPPORT Human Clinical
"Mutations lie in all domains of the α-tectorin protein, including those for the first time identified in the entactin domain, as well as the vWFD1, vWFD2, and vWFD3 repeats, and the D1-D2 and TIL2 connectors."
Establishes that the allelic spectrum spans the whole protein rather than being confined to the ZP and ZA domains.
PMID:10196713 SUPPORT Human Clinical
"This mutation abolishes the first of the vicinal cysteines (1619Cys-Gly-Leu- 1622Cys) present in the D4 von Willebrand factor (vWf) type D repeat."
Describes the cysteine-disrupting allele class and locates it in the zonadhesin-like domain.
+ 2 more references
Defective Tectorial Membrane Matrix Assembly
The tectorial membrane is built in the endolymph from type II collagen fibrils crosslinked by alpha- and beta-tectorin, adhering medially to the spiral limbus through a tectorin-rich matrix on the interdental cell membranes and contacting outer hair cell stereocilia at its lower surface. Mutant alpha-tectorin disturbs this assembly, and — the point that makes the genotype-phenotype correlation mechanistic rather than statistical — the ZP and ZA domains do so in structurally distinct ways, shown directly in mice carrying the human alleles.
tectorial membrane matrix assembly GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal tectorial membrane matrix assembly, annotated with extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ⚠ ABNORMAL
tectorial membrane UBERON:0002233 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in tectorial membrane, annotated with tectorial membrane of cochlea (UBERON:0002233). UBERON:0002233 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Tecta L1820F,G1824D/+ mouse (ZP domain) Mouse partially recapitulates Reproduces ZP-domain matrix abnormalities and elevated thresholds. Stable hearing is concordant with the human Belgian family for this allele.
Tecta C1619S/+ mouse (ZA domain) Mouse partially recapitulates Reproduces the ZA-domain structural lesion and threshold elevation, but the phenotype is stable where the human one progresses.
Tecta C1837G/+ mouse (ZP domain) Mouse partially recapitulates Reproduces ZP-domain matrix disruption and elevated thresholds, but not human progression.
Downstream
Impaired Mechanical Coupling to Outer Hair Cell Stereocilia A structurally abnormal or shortened membrane no longer loads the outer hair cell bundles correctly.
Show evidence (3 references)
PMID:24363064 SUPPORT Model Organism
"Mutations in the ZP and ZA domains generate distinctly different changes in the structure of the TM."
The tested ZP and ZA mouse alleles produced distinct structural phenotypes. Domain-level association does not establish an invariant human audiogram.
PMID:26806019 SUPPORT INDIRECT BACKGROUND Model Organism
"We observed that the TM adheres to the spiral limbus through a dense thin matrix enriched in α- and β-tectorin, both likely bound to the membranes of interdental cells."
Ultrastructural localization in rodent cochleae supports the normal anchoring role; it is indirect evidence for a pathogenic TECTA variant.
PMID:10196713 SUPPORT Human Clinical
"These results further support the involvement of TECTA mutations in autosomal dominant hearing impairment, and suggest that vicinal cysteines are involved in tectorial membrane matrix assembly."
Links the cysteine-disrupting allele class specifically to matrix assembly.
Impaired Mechanical Coupling to Outer Hair Cell Stereocilia
Abnormal matrix geometry reduces or redistributes tectorial-membrane contact with outer hair-cell bundles. In Tecta C1509G/+ mice, the shortened membrane contacts only the first outer hair-cell row. A computational model based on gerbil cochlear mechanics predicts increased shear on that row; the estimate is not a direct measurement in mice or patients.
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.
detection of mechanical stimulus involved in sensory perception of sound GO:0050910 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased detection of mechanical stimulus involved in sensory perception of sound (GO:0050910). GO:0050910 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Cochlear Amplifier Failure Without correct coupling the outer hair cell feedback loop loses gain and timing.
Secondary Outer Hair Cell Vulnerability Redistributed mechanical loading may increase injury susceptibility of remaining coupled cells under exposure; support comes from the C1509G model and associated mechanical simulation.
Show evidence (2 references)
PMID:21567249 SUPPORT Computational
"These analyses predicted that the shear force on the stereocilia is ~50% higher in the heterozygous condition."
A gerbil-based mechanical simulation imposed the shortened-membrane geometry. The approximately 50% increase is a model prediction, not a measured human effect.
PMID:21567249 SUPPORT Model Organism
"Together, these findings indicate that uncoupling the TM from some OHCs leads to partial hearing loss and places the remaining coupled OHCs at higher risk."
States the two consequences of uncoupling: immediate threshold elevation and secondary risk to the still-coupled cells.
Cochlear Amplifier Failure
Reduced or mistimed outer hair-cell feedback lowers cochlear sensitivity. Homozygous alpha-tectorin deletion mice have detached membranes and a 35 dB sensitivity reduction; this establishes normal membrane function indirectly for dominant DFNA8/12. Three assessed p.Y1870C family members had absent emissions with relatively preserved word recognition. Neither observation proves intact sensory cells and nerves in every patient or complete amplifier failure for every allele.
sensory perception of sound GO:0007605 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. ↓ DECREASED
organ of Corti UBERON:0002227 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in organ of Corti, annotated with spiral organ of cochlea (UBERON:0002227). UBERON:0002227 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Bilateral Sensorineural Hearing Loss Loss of amplification raises auditory thresholds in the affected band.
Show evidence (3 references)
PMID:11087000 SUPPORT INDIRECT Model Organism
"The basilar membranes of wild-type and alpha-tectorin mutant mice are tuned, but the alpha-tectorin mutants are 35 dB less sensitive."
Homozygous deletion-model physiology supports the membrane's contribution to amplification; this is not an allele-matched dominant model or human histopathology.
PMID:11087000 SUPPORT INDIRECT Model Organism
"Mice homozygous for a targeted deletion in a-tectorin have tectorial membranes that are detached from the cochlear epithelium and lack all noncollagenous matrix, but the architecture of the organ of Corti is otherwise normal."
Homozygous deletion-model physiology supports the membrane's contribution to amplification; this is not an allele-matched dominant model or human histopathology.
PMID:24636747 SUPPORT Human Clinical
"Although the missense p.Y1870C TECTA mutation leads to complete failure of the cochlear amplifier in humans, very high speech perception scores can be achieved with appropriate therapy."
The p.Y1870C family supports reduced amplification with usable speech perception; absence of emissions is not universal across TECTA variants.
Bilateral Sensorineural Hearing Loss
Bilateral sensorineural hearing loss has variable onset, severity, audiogram and course. Mid-frequency loss is common in reported families, but high-frequency and flatter patterns occur. Nonsyndromic presentation does not establish that every potential vestibular or subclinical feature has been excluded.
Downstream
Bilateral Sensorineural Hearing Impairment The clinical phenotype records the hearing loss represented by this terminal process.
Show evidence (1 reference)
PMID:9763681 SUPPORT Human Clinical
"The hearing loss was moderate to severe, a pure tone audiogram showing a U-shaped form with maximum loss at 2, 000 Hz."
Documents the audiometric configuration in the founding DFNA8 family.
Secondary Outer Hair Cell Vulnerability
In Tecta C1509G/+ mice, noise caused incompletely recovering emission thresholds and a redistribution of outer hair-cell loss toward the first row and more apical regions of the basal turn. Total loss in the sampled region did not significantly exceed wild type. Separately, electrical stimulation of excised cochleae produced greater reticular-lamina motion and membrane compromise. These experiments suggest exposure-dependent vulnerability; they do not demonstrate the cause of progression in human DFNA8/12 or every TECTA allele.
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
Tecta C1509G/+ mouse Mouse partially recapitulates Shows partial uncoupling and altered in-vivo noise recovery and injury distribution; mechanical simulations and separate ex-vivo electrical experiments support possible contributors.
Show evidence (2 references)
PMID:21567249 SUPPORT Model Organism
"However, noise exposure produced acute threshold shifts that fully recovered in Tecta (+/+) mice but only partially recovered in Tecta(C1509G/+) mice."
Demonstrates increased vulnerability to acoustic injury in the mutant.
PMID:21567249 SUPPORT INDIRECT In Vitro
"The increased movements were associated with a fourfold increase in OHC death as measured by vital dye staining."
This abstract statement refers to electrically stimulated excised cochleae with the membrane removed, assessed by propidium-iodide uptake. It is not fourfold cell death after in-vivo noise exposure.
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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 12 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

6
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:9763681 SUPPORT Human Clinical
"A four-generation family suffering from an autosomal-dominant, congenital, nonprogressive, nonsyndromic hearing loss was found in a rural region of Austria."
Documents the nonsyndromic dominant hearing loss in the founding family.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT INDIRECT REVIEW SYNTHESIS Other
"is not associated with visible abnormalities of the external ear or related medical findings; however, it can be associated with abnormalities of the middle ear and/or inner ear."
General clinical definition of nonsyndromic hearing loss, not a TECTA-specific onset or frequency claim.
Congenital Sensorineural Hearing Impairment Auditory HP:0008527 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital sensorineural hearing impairment (HP:0008527), qualified as congenital onset. HP:0008527 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (1 reference)
PMID:9763681 SUPPORT Human Clinical
"A four-generation family suffering from an autosomal-dominant, congenital, nonprogressive, nonsyndromic hearing loss was found in a rural region of Austria."
Documents the nonsyndromic dominant hearing loss in the founding family.
Mid-Frequency Hearing Loss Auditory HP:0012781 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mid-frequency hearing loss (HP:0012781). HP:0012781 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21520338 SUPPORT Human Clinical
"Specifically, mutations in the N-terminal region of α-tectorin (entactin domain, vWFD1, and vWFD2) lead to mid-frequency NSHL, a phenotype previously associated only with mutations in the ZP domain."
Documents mid-frequency loss and extends it beyond the ZP domain, which is the correction to the original correlation.
High-Frequency Hearing Impairment Auditory HP:0005101 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High-frequency hearing impairment (HP:0005101). HP:0005101 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10196713 SUPPORT Human Clinical
"The present study reports linkage to DFNA12 in a new family with autosomal dominant high frequency hearing loss progressing from mild to moderate severity."
Documents the high-frequency, progressive configuration in a ZA-domain family.
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), qualified as course progressive. HP:0000408 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (3 references)
PMID:10196713 SUPPORT Human Clinical
"The present study reports linkage to DFNA12 in a new family with autosomal dominant high frequency hearing loss progressing from mild to moderate severity."
Documents the high-frequency, progressive configuration in a ZA-domain family.
PMID:21520338 REFUTE DIRECT PRIMARY RESULT Human Clinical
"Serial audiograms from patient IV:1 in family S694 who carries the ZA region p.Cys1036Tyr mutation indicate a stable hearing loss"
A stable cysteine-substitution family limits a universal cysteine/progression rule.
PMID:21520338 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"the age-related typical audiograms (ARTA) analyses performed on the Belgian-K family, in which a cysteine is not mutated (p.Asn465Lys), indicate the hearing loss is progressive"
Progression in this non-cysteine allele limits a deterministic cysteine/progression rule.
Absent Otoacoustic Emissions with Preserved Word Recognition Auditory HP:6000182 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent otoacoustic emissions (HP:6000182). HP:6000182 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:24636747 SUPPORT Human Clinical
"Transient evoked and distortion product otoacoustic emissions were completely absent in all affected family members whereas word recognition scores were up to 95%."
Documents the dissociation between absent emissions and preserved speech discrimination.
PMID:21520338 REFUTE DIRECT PRIMARY RESULT Human Clinical
"The youngest mutation carrier, III:5, who was asymptomatic at the time of this study has normal TEOAEs in both ears."
Normal emissions in a young carrier limit extrapolation of the p.Y1870C phenotype.
🧬

Genetic Associations

1
TECTA
Gene: TECTA hgnc:11720 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TECTA (hgnc:11720). hgnc:11720 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (4 references)
PMID:9590290 SUPPORT Human Clinical
"These findings indicate that mutations in TECTA are responsible for hearing impairment in these families, and implicate a new type of protein in the pathogenesis of hearing impairment."
The founding gene-disease assignment.
PMID:21520338 SUPPORT Human Clinical
"Collectively, our results indicate that DFNA8/12 hearing loss is a frequent type of ADNSHL."
The selected Spanish and American cohorts establish an important contribution to ADNSHL, not a general-population prevalence or current global ranking.
PMID:21520338 SUPPORT Human Clinical
"Although the majority are private mutations, four of them-p.Cys1036Tyr, p.Cys1837Gly, p.Thr1866Met, and p.Arg1890Cys-were observed in more than one unrelated family. For two of these mutations founder effects were also confirmed."
Recurrence and founder analyses in the 2011 series; the full text supports a common founder for Cys1837Gly and shared haplotypes in some Arg1890Cys families. Recurrence does not establish progression.
+ 1 more reference
💊

Medical Actions

4
Hearing amplification and auditory rehabilitation
Action: RehabilitationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Rehabilitation (NCIT:C15315), qualified as medical device hearing aid. NCIT:C15315 is a clinical intervention from the NCI Thesaurus. NCIT:C15315
Platform: Device
Individualized hearing aids and auditory habilitation can support communication. Benefit and communication goals are assessed per person; the small p.Y1870C series does not establish unusually high efficacy for all TECTA variants. Spoken language, sign language and combined approaches should reflect individual and family preferences.
Mechanism Target:
Cochlear Amplifier Failure — Amplification substitutes externally for the gain the tectorial membrane can no longer deliver, without repairing the matrix.
Show evidence (1 reference)
PMID:24636747 SUPPORT Human Clinical
"Although the missense p.Y1870C TECTA mutation leads to complete failure of the cochlear amplifier in humans, very high speech perception scores can be achieved with appropriate therapy."
The three-member p.Y1870C assessment supports useful speech perception; it is not a controlled comparison of rehabilitation strategies.
Show evidence (3 references)
PMID:24636747 SUPPORT INDIRECT Human Clinical
"Transient evoked and distortion product otoacoustic emissions were completely absent in all affected family members whereas word recognition scores were up to 95%."
The reported speech scores demonstrate retained function in this family, not a measured before/after treatment effect.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT INDIRECT REVIEW SYNTHESIS Other
"customized by an audiologist to the degree and frequency of hearing loss, can be used in individuals with mild-to-severe hearing loss."
General hearing-loss management guidance applicable to suitable TECTA presentations.
PMID:37927186 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"All the affected participants wore bilateral hearing aids from an early age."
Documents hearing-aid use in a dominant TECTA family; treatment efficacy was not comparatively measured.
Cochlear implantation
Action: cochlear device implantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cochlear device 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 specialist cochlear-implant evaluation for severe-to-profound loss with insufficient benefit from hearing aids, using individual audiologic and anatomic assessment. Electrical stimulation bypasses hair-cell transduction to activate auditory neurons. The cited 2013 TECTA implant case had biallelic DFNB21; it does not establish dominant DFNA8/12-specific outcomes or electric-acoustic stimulation efficacy.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months."
General pediatric candidacy guidance, not TECTA-specific efficacy.
PMID:24130743 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"We successfully identified four rare causative mutations in the MYO15A, TECTA, TMPRSS3, and ACTG1 genes in four patients who showed relatively good auditory performance with CI including EAS"
The full text identifies the TECTA patient as compound heterozygous for c.596delT and c.1471C>T (DFNB21), receiving CI at age two. The EAS cases had other genes; applicability to dominant TECTA disease is indirect.
Genetic counseling and prenatal diagnosis
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. NCIT:C15240
Discuss a 50% chance of transmitting the familial pathogenic variant with each pregnancy and the limits of predicting onset and severity. Familial-variant identification enables prenatal or preimplantation testing if desired. Reproductive testing and communication choices are personal decisions supported by nondirective counseling.
Show evidence (3 references)
PMID:40583560 SUPPORT Human Clinical
"we identified a novel aberrant splicing variant, c.5999G > A (p.Gly2000Glu), in TECTA as the cause of autosomal dominant hearing loss in five-generation kindred of Chinese descent and provided prenatal diagnosis for the family"
Documents prenatal diagnosis actually being provided in a DFNA8/12 family once the causative variant was identified.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Individuals with autosomal dominant hearing loss have a 50% chance of transmitting the pathogenic variant to each child."
GeneReviews provides the general autosomal dominant transmission probability, not an allele-specific penetrance estimate.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Once the pathogenic variant(s) have been identified in the family, prenatal and preimplantation genetic testing for genetic hearing loss are possible."
General reproductive-testing guidance after a molecular diagnosis.
Audiologic surveillance and noise protection
Repeat audiologic assessment to document stability or progression and adjust support. Tailor intervals to age, clinical course and needs; the GeneReviews table does not give a TECTA-specific schedule. Avoid repeated loud-noise overexposure as general hearing protection, without implying a quantified human TECTA-specific risk.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Regular follow up is recommended for all individuals with genetic hearing loss"
General surveillance recommendation; serial audiologic examinations assess stability and progression.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT INDIRECT REVIEW SYNTHESIS Other
"persons with documented hearing loss should be counseled appropriately and repeated overexposure to loud noises should be avoided."
General hearing-loss precaution; C1509G experiments provide preclinical context only.
🌍

Environmental Factors

1
Excessive noise exposure
excessive noise exposure ECTO:8000044 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is excessive noise exposure, annotated with exposure to sound radiation (ECTO:8000044). ECTO:8000044 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Noise is a potential modifier of inherited hearing loss. C1509G mouse experiments support altered recovery and spatial injury patterns, but do not quantify human TECTA-specific susceptibility or establish noise as the cause of human progression. General hearing-loss guidance supports avoiding repeated loud-noise overexposure.
Show evidence (1 reference)
PMID:21567249 SUPPORT Model Organism
"However, noise exposure produced acute threshold shifts that fully recovered in Tecta (+/+) mice but only partially recovered in Tecta(C1509G/+) mice."
Shows the mutant cochlea fails to recover from an acoustic insult that the wild-type recovers from fully, which is what makes noise a disease-relevant exposure here.
Mechanism Target:
EXACERBATES Secondary Outer Hair Cell Vulnerability — In the C1509G model, noise exposure changes emission-threshold recovery and the distribution of hair-cell injury. This exposure effect is model-specific.
Show evidence (1 reference)
PMID:21567249 SUPPORT Model Organism
"However, noise exposure produced acute threshold shifts that fully recovered in Tecta (+/+) mice but only partially recovered in Tecta(C1509G/+) mice."
Shows the mutant cochlea fails to recover from an acoustic insult that the wild-type recovers from fully, which is what makes noise a disease-relevant exposure here.
🔬

Diagnosis

3
Pure tone audiometry with otoacoustic emissions
Age-appropriate audiometry, speech testing and objective measures characterize severity, configuration and auditory function. Absent emissions with good word recognition can occur in TECTA disease but are neither universal nor sufficient for a molecular diagnosis. Other causes and syndromic features remain part of assessment.
Show evidence (1 reference)
PMID:24636747 SUPPORT Human Clinical
"Pure tone audiometry, brainstem evoked response audiometry, the Freiburger test for speech understanding and transient evoked and distortion product otoacoustic emissions were assessed in three available affected members bearing p.Y1870C."
Lists the test battery used to characterise affected family members.
Molecular testing and variant interpretation
A hearing-loss multigene panel or exome/genome analysis can identify a heterozygous pathogenic or likely pathogenic TECTA variant. Targeted testing is appropriate for a known familial variant. A VUS or domain location alone cannot confirm or exclude DFNA8/12; segregation and allele-specific functional information can refine interpretation.
Show evidence (5 references)
PMID:21520338 SUPPORT Human Clinical
"In an additional cohort of 835 American ADNSHL families, we preselected 73 probands for TECTA screening based on audiometric data."
Documents audiogram-guided selection for TECTA testing.
PMID:38224868 SUPPORT INDIRECT BACKGROUND Other
"There is increasing awareness of the importance of an etiologic diagnosis, and genetic testing with next-generation sequencing (NGS) has the highest diagnostic yield."
The general childhood hearing-loss review supports molecular testing; it does not itself specify a TECTA-only diagnostic strategy.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT INDIRECT REVIEW SYNTHESIS Other
"The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis."
General genetic-hearing-loss variant-interpretation guidance.
+ 2 more references
Evaluation of at-risk relatives
Offer hearing assessment and, when available, targeted familial-variant testing to relatives. A passed newborn screen does not exclude mild or later-onset hearing loss.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Permanent childhood hearing loss in a parent or sib increases the probability of hearing loss in other family members and warrants early complete diagnostic evaluation of hearing regardless of the family member's newborn hearing screening result."
General GeneReviews guidance for families with childhood genetic hearing loss.
PMID:40583560 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Individual V-3 passed newborn hearing screening; however, at the age of 6 years, she was diagnosed with HL and had used hearing aids since diagnosis."
A screened child subsequently had documented hearing loss; a passed newborn screen does not exclude familial TECTA hearing loss.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Autosomal Dominant Nonsyndromic Hearing Loss 12:

DFNB21, recessive TECTA deafness
Overlapping Features Biallelic TECTA variants cause DFNB21. Loss-of-function alleles often underlie recessive disease, but missense alleles can also be recessive, and sequence consequence alone cannot assign inheritance. The 2011 report noted a truncating allele in two members of a dominant pedigree but could not exclude incidental carrier status or a missed second allele. Assess zygosity, phase, segregation and variant-specific evidence.
Show evidence (1 reference)
PMID:9949200 SUPPORT Human Clinical
"Sequence analysis of the TECTA gene in the DFNB21-affected family revealed a G to A transition in the donor splice site (GT) of intron 9, predicted to lead to a truncated protein of 971 amino acids."
Documents the truncating allele class that produces the recessive disease.
Other autosomal dominant nonsyndromic hearing loss loci
Overlapping Features Many genetic hearing-loss disorders overlap with the DFNA8/12 audiogram. Mid-frequency loss can guide interpretation but is not specific; molecular testing and assessment for extra-auditory findings distinguish causes.
Show evidence (1 reference)
PMID:21520338 SUPPORT Human Clinical
"We therefore completed unbiased screening for TECTA mutations in a Spanish cohort of 372 probands from ADNSHL families."
Indicates that TECTA is identified within a large pool of otherwise similar dominant nonsyndromic hearing loss families, which is why sequencing rather than phenotype makes the assignment.
🐁

Animal Models

4
Tecta L1820F,G1824D/+ mouse (ZP domain)
One of three allele-matched mouse models built to test the human domain-to-audiogram correlation directly.
Species
Mouse
Genotype
Tecta(L1820F,G1824D/+), modelling the Belgian DFNA12 ZP-domain family
Publication
PMID:24363064
Pathograph links
Defective Tectorial Membrane Matrix Assembly partially recapitulates fidelity: moderate Reproduces ZP-domain matrix abnormalities and elevated thresholds. Stable hearing is concordant with the human Belgian family for this allele.
Limitations: Thresholds are elevated across 8-40 kHz rather than reproducing the human frequency map. Audiogenic seizure susceptibility was observed in these mice; a corresponding human TECTA phenotype is not established.
Readouts
Auditory brainstem response threshold, 8-40 kHz
Direction: INCREASED
Interpretation: Threshold elevation of 30-40 dB confirms functional hearing loss from a ZP-domain allele.
Show evidence (1 reference)
PMID:24363064 SUPPORT Model Organism
"Auditory brainstem response thresholds in the 8-40 kHz range are elevated by 30-40 dB in the ZP-domain mutants, whilst those in the ZA-domain mutant are elevated by 20-30 dB."
Gives the measured threshold elevation for both domain classes.
Show evidence (1 reference)
PMID:24363064 SUPPORT Model Organism
"Three mutant mice were created as models for human Tecta mutations; the Tecta(L1820F,G1824D/+) mouse for zona pellucida (ZP) domain mutations causing stable mid-frequency hearing loss in a Belgian family"
Establishes that this line was built to carry a specific human allele.
Tecta C1619S/+ mouse (ZA domain)
The allele-matched model for the progressive, high-frequency human phenotype — and the one that does not reproduce the progression.
Species
Mouse
Genotype
Tecta(C1619S/+), modelling the French DFNA12 zonadhesin-domain family
Publication
PMID:24363064
Pathograph links
Defective Tectorial Membrane Matrix Assembly partially recapitulates fidelity: moderate Reproduces the ZA-domain structural lesion and threshold elevation, but the phenotype is stable where the human one progresses.
Limitations: Thresholds were compared in different age groups through 11 months and remained stable despite human progression. The studied strain and interval provide no spontaneous progression endpoint; longer follow-up or different backgrounds were not excluded.
Readouts
Auditory thresholds across age groups and tectorial membrane structure
Direction: UNCHANGED
Interpretation: A genuine negative: no deterioration over time, against a progressive human course for the same allele.
Show evidence (1 reference)
PMID:24363064 SUPPORT Model Organism
"The phenotypes are stable and no evidence has been found for a progressive deterioration in TM structure or auditory function."
Reports the absence of progression in the mutant mice.
Show evidence (1 reference)
PMID:24363064 SUPPORT Model Organism
"the Tecta(C1619S/+) mouse for a zonadhesin-like (ZA) domain mutation responsible for progressive, high-frequency hearing loss in a French family"
Establishes the human allele this line was built to model.
Tecta C1837G/+ mouse (ZP domain)
ZP-domain model of a human progressive mid-frequency allele, with stable mouse thresholds through eight months.
Species
Mouse
Genotype
Tecta(C1837G/+), modelling a Spanish DFNA8/12 family
Publication
PMID:24363064
Pathograph links
Defective Tectorial Membrane Matrix Assembly partially recapitulates fidelity: moderate Reproduces ZP-domain matrix disruption and elevated thresholds, but not human progression.
Limitations: Thresholds were stable across age groups through eight months; audiogenic seizure susceptibility prevented planned high-noise progression experiments.
Readouts
Auditory thresholds across age groups and tectorial membrane structure
Direction: UNCHANGED
Interpretation: A genuine negative: no deterioration over time, against a progressive human course for the same allele.
Show evidence (1 reference)
PMID:24363064 SUPPORT Model Organism
"The phenotypes are stable and no evidence has been found for a progressive deterioration in TM structure or auditory function."
Reports the absence of progression in the mutant mice.
Show evidence (1 reference)
PMID:24363064 SUPPORT DIRECT PRIMARY RESULT Model Organism
"the Tecta(C1837G/+) mouse for a ZP-domain mutation underlying progressive mid-frequency hearing loss in a Spanish family"
Identifies the third allele studied in the three-mouse experiment.
Tecta C1509G/+ mouse
The model that supplies the biophysical account of secondary outer hair cell loss, through a shortened tectorial membrane that contacts only the first outer hair cell row.
Species
Mouse
Genotype
Tecta(C1509G/+) transgenic
Publication
PMID:21567249
Pathograph links
Secondary Outer Hair Cell Vulnerability partially recapitulates fidelity: moderate Shows partial uncoupling and altered in-vivo noise recovery and injury distribution; mechanical simulations and separate ex-vivo electrical experiments support possible contributors.
Limitations: Thresholds were stable in quiet through six months. Total hair-cell loss after noise was not significantly greater than wild type in the sampled region. Fourfold vital-dye labeling followed ex-vivo electrical stimulation, not noise. Human progression and exposure equivalence are unproven.
Readouts
Outer hair cell survival after noise exposure
Direction: DECREASED
Interpretation: Preferential loss in the first row, the row left mechanically coupled by the shortened membrane.
Show evidence (1 reference)
PMID:21567249 SUPPORT Model Organism
"While Tecta(+/+) mice lost OHCs primarily at the base and within all three rows, Tecta(C1509G/+) mice lost most of their OHCs in a more apical region of the cochlea and nearly completely within the first row."
The distribution of loss differs by row and cochlear location; this quote does not establish greater total cell loss.
Distortion product otoacoustic emission threshold in quiet
Direction: UNCHANGED
Interpretation: No spontaneous deterioration in a quiet environment to six months, which is what confines the model's claim to vulnerability rather than progression.
Show evidence (1 reference)
PMID:21567249 SUPPORT Model Organism
"Distortion product otoacoustic emission thresholds in a quiet environment did not change to 6 months of age."
Records the absence of spontaneous progression in the unexposed mutant.
Show evidence (1 reference)
PMID:21567249 SUPPORT INDIRECT BACKGROUND Human Clinical
"Humans with an autosomal dominant C1509G mutation in alpha-tectorin, a protein constituent of the TM, are born with a partial hearing loss that worsens over time."
Establishes that the modelled allele is a human disease allele.
{ }

Source YAML

click to show 
name: Autosomal Dominant Nonsyndromic Hearing Loss 12
creation_date: "2026-08-31T16:45:00Z"
category: Mendelian
synonyms:
- DFNA12
- DFNA8/12
- deafness, autosomal dominant 12
- TECTA-related autosomal dominant hearing loss
- alpha-tectorin deafness
description: >-
  Autosomal dominant nonsyndromic hearing loss 12 (DFNA8/12) is caused by heterozygous pathogenic TECTA
  variants affecting alpha-tectorin, a major non-collagenous component of the cochlear tectorial membrane.
  DFNA8 and DFNA12 were mapped independently in Austrian and Belgian families before both were linked
  to TECTA.

  The primary lesion affects an extracellular matrix required for efficient hair-cell stimulation and
  cochlear amplification. A dominant-negative mechanism is supported by human segregation and allele-matched
  mouse studies, but normal secretion and incorporation of every mutant protein have not been demonstrated.
  Mouse models also reveal secondary hair-cell vulnerability under experimental exposure; the disease
  cannot be characterized as universally free of cellular injury.

  Hearing loss can be congenital, prelingual or later-onset, stable or progressive, with mid-frequency,
  high-frequency or flatter configurations. Protein domain and residue help interpret a variant but do
  not determine an individual audiogram or course. Some alleles associated with human progression produce
  stable mouse thresholds over the studied intervals. Preserved speech recognition in selected patients
  supports hearing rehabilitation but does not establish universal preservation of the auditory nerve
  or dominant TECTA-specific implant efficacy.
disease_term:
  preferred_term: autosomal dominant nonsyndromic hearing loss 12
  term:
    id: MONDO:0011102
    label: autosomal dominant nonsyndromic hearing loss 12
parents:
- Autosomal Dominant Nonsyndromic Hearing Loss
- Hereditary Hearing Loss
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:40583560
      reference_title: "A novel splicing variant in TECTA associated with prelingual autosomal dominant nonsyndromic hearing loss via dominant-negative effect."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The TECTA gene encodes α-tectorin, the major non-collagenous glycoprotein
        of the tectorial membrane, and plays a critical role in intracochlear
        sound transmission.
      explanation: >-
        Characterises the disorder as one of intracochlear sound transmission,
        placing it among the special-sense and hereditary hearing disorders.
references:
- reference: PMID:20301607
  title: "Genetic Hearing Loss Overview."
  tags:
  - GeneReviews
- reference: PMID:9590290
  title: "Mutations in the human alpha-tectorin gene cause autosomal dominant non-syndromic hearing impairment."
- reference: PMID:24363064
  title: "Three deaf mice: mouse models for TECTA-based human hereditary deafness reveal domain-specific structural phenotypes in the tectorial membrane."
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
  title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
inheritance:
- name: Autosomal dominant inheritance
  description: >-
    Heterozygous pathogenic TECTA variants can be transmitted through multiple generations. Each child
    of a heterozygous parent has a 50% chance of inheriting the variant; onset, severity and progression
    cannot be predicted precisely from transmission alone. Many dominant alleles are missense or splice-altering
    variants; allele-specific interpretation distinguishes DFNA8/12 from recessive DFNB21.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:9590290
    reference_title: "Mutations in the human alpha-tectorin gene cause autosomal dominant non-syndromic hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In both families, mutation analysis revealed missense mutations which
      replace conserved amino-acid residues within the zona pellucida domain of
      TECTA.
    explanation: >-
      Establishes heterozygous missense variants as the cause in the two founding
      dominant families.
  - 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: OTHER
    snippet: >-
      Individuals with autosomal dominant hearing loss have a 50% chance of transmitting the pathogenic
      variant to each child.
    explanation: >-
      GeneReviews provides the general autosomal dominant transmission probability, not an allele-specific
      penetrance estimate.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
mechanistic_hypotheses:
- hypothesis_group_id: dominant_negative_tectorin_incorporation
  hypothesis_label: >-
    Dominant-negative disruption of tectorial membrane organization
  status: CANONICAL
  description: >-
    The contrast between unaffected heterozygous carriers of a recessive TECTA allele and dominant missense
    families supports a dominant-negative model. Allele-matched mice show matrix defects distinct from
    simple heterozygous null states. These findings do not prove normal secretion, abundance or physical
    incorporation for every dominant mutant protein. For c.5999G>A, patient RNA shows abnormal in-frame
    splicing without reduced total transcript abundance; the protein-level mechanism remains inferred.
  evidence:
  - reference: PMID:9949200
    reference_title: "An alpha-tectorin gene defect causes a newly identified autosomal recessive form of sensorineural pre-lingual non-syndromic deafness, DFNB21."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Comparison of the phenotype of the DFNB21 heterozygous carriers with that
      of DFNA8/12-affected individuals supports the hypothesis that the TECTA
      mutations which cause the dominant form of deafness have a dominant-negative
      effect.
    explanation: >-
      States the carrier-versus-patient comparison that grounds the
      dominant-negative model.
  - reference: PMID:9949200
    reference_title: "An alpha-tectorin gene defect causes a newly identified autosomal recessive form of sensorineural pre-lingual non-syndromic deafness, DFNB21."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The present results provide genetic evidence for alpha-tectorin forming
      homo- or heteromeric structures.
    explanation: >-
      The authors infer homo- or heteromeric assembly from genetic observations; this is not a direct
      protein interaction assay.
    directness: INDIRECT
  - reference: PMID:40583560
    reference_title: "A novel splicing variant in TECTA associated with prelingual autosomal dominant nonsyndromic hearing loss via dominant-negative effect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Quantitative real-time polymerase chain reaction revealed no significant
      reduction in mRNA levels in lymphoblasts derived from individuals
      harboring the TECTA c.5999G > A (p.Gly2000Glu) variant
    explanation: >-
      Total RNA abundance was not reduced, but the study lacked direct protein-expression and matrix-incorporation
      measurements. This supports the authors' proposed mechanism indirectly and does not exclude a protein-level
      dosage effect.
    directness: INDIRECT
- hypothesis_group_id: tectorial_membrane_calcium_adaptation
  hypothesis_label: Tectorial membrane regulation of calcium near hair-cell transduction channels
  status: EMERGING
  description: >-
    Tecta/Tectb double-knockout mice retain mature hair-cell properties but lose long-lasting emission
    adaptation. The authors propose that the membrane regulates calcium near transduction channels. This
    extends membrane function beyond mechanical coupling; calcium regulation and its relevance to dominant
    human TECTA alleles remain unproven.
  evidence:
  - reference: PMID:33559882
    reference_title: MET currents and otoacoustic emissions from mice with a detached tectorial membrane indicate the extracellular matrix regulates Ca(2+) near stereocilia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      repetitive acoustic stimulation fails to produce adaptation of MET-dependent otoacoustic emissions
      in vivo in the Tecta/Tectb-/- mice.
    explanation: >-
      A double-knockout mouse result supports the adaptation hypothesis indirectly for dominant DFNA8/12;
      no local calcium concentration was directly measured in patients.
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
pathophysiology:
- name: Heterozygous Pathogenic TECTA Variant
  biological_scale: MOLECULAR
  description: >-
    Heterozygous pathogenic variants occur across the entactin/NIDO, zonadhesin-like and zona pellucida
    domains of TECTA. The 2011 study screened a Spanish cohort without audiogram preselection and an American
    subset selected by audiogram. Dominant alleles include missense changes and coding variants that alter
    splicing: c.5999G>A produces two in-frame exon-20 deletions. A sequence-level missense annotation
    alone therefore does not identify the molecular consequence.
  genes:
  - preferred_term: TECTA
    term:
      id: hgnc:11720
      label: TECTA
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: DOMINANT_NEGATIVE
    gene:
      preferred_term: TECTA
      term:
        id: hgnc:11720
        label: TECTA
    notes: >-
      Includes missense and splice-altering alleles. Dominant-negative action is the prevailing model;
      variant-specific protein consequences require functional evidence.
  evidence:
  - reference: PMID:9590290
    reference_title: "Mutations in the human alpha-tectorin gene cause autosomal dominant non-syndromic hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In both families, mutation analysis revealed missense mutations which
      replace conserved amino-acid residues within the zona pellucida domain of
      TECTA.
    explanation: >-
      The founding identification of TECTA missense variants in the DFNA8 and
      DFNA12 families.
  - reference: PMID:21520338
    reference_title: "DFNA8/12 caused by TECTA mutations is the most identified subtype of nonsyndromic autosomal dominant hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations lie in all domains of the α-tectorin protein, including those for
      the first time identified in the entactin domain, as well as the vWFD1,
      vWFD2, and vWFD3 repeats, and the D1-D2 and TIL2 connectors.
    explanation: >-
      Establishes that the allelic spectrum spans the whole protein rather than
      being confined to the ZP and ZA domains.
  - reference: PMID:10196713
    reference_title: "Mutation in the zonadhesin-like domain of alpha-tectorin associated with autosomal dominant non-syndromic hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This mutation abolishes the first of the vicinal cysteines
      (1619Cys-Gly-Leu- 1622Cys) present in the D4 von Willebrand factor (vWf)
      type D repeat.
    explanation: >-
      Describes the cysteine-disrupting allele class and locates it in the
      zonadhesin-like domain.
  - reference: PMID:40583560
    reference_title: "A novel splicing variant in TECTA associated with prelingual autosomal dominant nonsyndromic hearing loss via dominant-negative effect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data demonstrated that the variant altered RNA splicing, specifically
      causing aberrant splicing of exon 20 and resulting in two in-frame
      deletions.
    explanation: >-
      Documents the splice-altering coding-variant class, which produces in-frame
      deletions rather than a residue substitution.
  - reference: PMID:40583560
    reference_title: "A novel splicing variant in TECTA associated with prelingual autosomal dominant nonsyndromic hearing loss via dominant-negative effect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      expands the mutational landscape of DFNA8/12 to include coding variants
      that alter RNA splicing, and underscores the importance of investigating
      splicing effects of coding variants
    explanation: >-
      States that the DFNA8/12 allelic spectrum includes coding variants acting
      through splicing, which is the practical warning for variant
      interpretation in this gene.
  downstream:
  - target: Defective Tectorial Membrane Matrix Assembly
    description: >-
      Dominant TECTA alleles alter matrix organization. Mutant-protein assembly effects are inferred from
      human genetics and supported by allele-matched mouse structural phenotypes, rather than measured
      for every human allele.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:9949200
      reference_title: "An alpha-tectorin gene defect causes a newly identified autosomal recessive form of sensorineural pre-lingual non-syndromic deafness, DFNB21."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Comparison of the phenotype of the DFNB21 heterozygous carriers with that
        of DFNA8/12-affected individuals supports the hypothesis that the TECTA
        mutations which cause the dominant form of deafness have a
        dominant-negative effect.
      explanation: >-
        Grounds the step from variant to matrix defect in the dominant-negative
        genetics rather than in reduced protein amount.
      directness: INDIRECT
    - reference: PMID:24363064
      reference_title: "Three deaf mice: mouse models for TECTA-based human hereditary deafness reveal domain-specific structural phenotypes in the tectorial membrane."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Mutations in the ZP and ZA domains generate distinctly different changes in
        the structure of the TM.
      explanation: >-
        Establishes that the domain a variant sits in determines the kind of
        structural damage, which is the mechanistic basis of the audiogram
        correlation.
- name: Defective Tectorial Membrane Matrix Assembly
  biological_scale: TISSUE
  description: >-
    The tectorial membrane is built in the endolymph from type II collagen
    fibrils crosslinked by alpha- and beta-tectorin, adhering medially to the
    spiral limbus through a tectorin-rich matrix on the interdental cell
    membranes and contacting outer hair cell stereocilia at its lower surface.
    Mutant alpha-tectorin disturbs this assembly, and — the point that makes the
    genotype-phenotype correlation mechanistic rather than statistical — the ZP
    and ZA domains do so in structurally distinct ways, shown directly in mice
    carrying the human alleles.
  biological_processes:
  - preferred_term: tectorial membrane matrix assembly
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  locations:
  - preferred_term: tectorial membrane
    term:
      id: UBERON:0002233
      label: tectorial membrane of cochlea
  evidence:
  - reference: PMID:24363064
    reference_title: "Three deaf mice: mouse models for TECTA-based human hereditary deafness reveal domain-specific structural phenotypes in the tectorial membrane."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mutations in the ZP and ZA domains generate distinctly different changes in
      the structure of the TM.
    explanation: >-
      The tested ZP and ZA mouse alleles produced distinct structural phenotypes. Domain-level association
      does not establish an invariant human audiogram.
  - reference: PMID:26806019
    reference_title: "Tectorins crosslink type II collagen fibrils and connect the tectorial membrane to the spiral limbus."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      We observed that the TM adheres to the spiral limbus through a dense thin
      matrix enriched in α- and β-tectorin, both likely bound to the membranes of
      interdental cells.
    explanation: >-
      Ultrastructural localization in rodent cochleae supports the normal anchoring role; it is indirect
      evidence for a pathogenic TECTA variant.
    quote_role: BACKGROUND
  - reference: PMID:10196713
    reference_title: "Mutation in the zonadhesin-like domain of alpha-tectorin associated with autosomal dominant non-syndromic hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results further support the involvement of TECTA mutations in
      autosomal dominant hearing impairment, and suggest that vicinal cysteines
      are involved in tectorial membrane matrix assembly.
    explanation: >-
      Links the cysteine-disrupting allele class specifically to matrix assembly.
  downstream:
  - target: Impaired Mechanical Coupling to Outer Hair Cell Stereocilia
    description: >-
      A structurally abnormal or shortened membrane no longer loads the outer hair
      cell bundles correctly.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21567249
      reference_title: "Biophysical mechanisms underlying outer hair cell loss associated with a shortened tectorial membrane."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The Tecta(C1509/+) transgenic mouse with the same point mutation has
        partial hearing loss secondary to a shortened TM that only contacts the
        first row of OHCs.
      explanation: >-
        Shows the structural defect translating directly into altered contact
        with the outer hair cells.
- name: Impaired Mechanical Coupling to Outer Hair Cell Stereocilia
  biological_scale: TISSUE
  description: >-
    Abnormal matrix geometry reduces or redistributes tectorial-membrane contact with outer hair-cell
    bundles. In Tecta C1509G/+ mice, the shortened membrane contacts only the first outer hair-cell row.
    A computational model based on gerbil cochlear mechanics predicts increased shear on that row; the
    estimate is not a direct measurement in mice or patients.
  cell_types:
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  biological_processes:
  - preferred_term: detection of mechanical stimulus involved in sensory perception of sound
    modifier: DECREASED
    term:
      id: GO:0050910
      label: detection of mechanical stimulus involved in sensory perception of sound
  evidence:
  - reference: PMID:21567249
    reference_title: "Biophysical mechanisms underlying outer hair cell loss associated with a shortened tectorial membrane."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      These analyses predicted that the shear force on the stereocilia is ~50%
      higher in the heterozygous condition.
    explanation: >-
      A gerbil-based mechanical simulation imposed the shortened-membrane geometry. The approximately
      50% increase is a model prediction, not a measured human effect.
  - reference: PMID:21567249
    reference_title: "Biophysical mechanisms underlying outer hair cell loss associated with a shortened tectorial membrane."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Together, these findings indicate that uncoupling the TM from some OHCs
      leads to partial hearing loss and places the remaining coupled OHCs at
      higher risk.
    explanation: >-
      States the two consequences of uncoupling: immediate threshold elevation
      and secondary risk to the still-coupled cells.
  downstream:
  - target: Cochlear Amplifier Failure
    description: >-
      Without correct coupling the outer hair cell feedback loop loses gain and
      timing.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11087000
      reference_title: "A targeted deletion in alpha-tectorin reveals that the tectorial membrane is required for the gain and timing of cochlear feedback."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Thus, the tectorial membrane ensures that outer hair cells can effectively
        respond to basilar membrane motion and that feedback is delivered with the
        appropriate gain and timing required for amplification.
      explanation: >-
        States the membrane's role in amplifier gain and timing, whose loss is
        this node.
      directness: INDIRECT
  - target: Secondary Outer Hair Cell Vulnerability
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Redistributed mechanical loading may increase injury susceptibility of remaining coupled cells under
      exposure; support comes from the C1509G model and associated mechanical simulation.
    evidence:
    - reference: PMID:21567249
      reference_title: "Biophysical mechanisms underlying outer hair cell loss associated with a shortened tectorial membrane."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Together, these findings indicate that uncoupling the TM from some OHCs
        leads to partial hearing loss and places the remaining coupled OHCs at
        higher risk.
      explanation: >-
        States the two consequences of uncoupling: immediate threshold elevation
        and secondary risk to the still-coupled cells.
- name: Cochlear Amplifier Failure
  biological_scale: TISSUE
  description: >-
    Reduced or mistimed outer hair-cell feedback lowers cochlear sensitivity. Homozygous alpha-tectorin
    deletion mice have detached membranes and a 35 dB sensitivity reduction; this establishes normal membrane
    function indirectly for dominant DFNA8/12. Three assessed p.Y1870C family members had absent emissions
    with relatively preserved word recognition. Neither observation proves intact sensory cells and nerves
    in every patient or complete amplifier failure for every allele.
  biological_processes:
  - preferred_term: sensory perception of sound
    modifier: DECREASED
    term:
      id: GO:0007605
      label: sensory perception of sound
  locations:
  - preferred_term: organ of Corti
    term:
      id: UBERON:0002227
      label: spiral organ of cochlea
  evidence:
  - reference: PMID:11087000
    reference_title: "A targeted deletion in alpha-tectorin reveals that the tectorial membrane is required for the gain and timing of cochlear feedback."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The basilar membranes of wild-type and alpha-tectorin mutant mice are tuned,
      but the alpha-tectorin mutants are 35 dB less sensitive.
    explanation: >-
      Homozygous deletion-model physiology supports the membrane's contribution to amplification; this
      is not an allele-matched dominant model or human histopathology.
    directness: INDIRECT
  - reference: PMID:11087000
    reference_title: "A targeted deletion in alpha-tectorin reveals that the tectorial membrane is required for the gain and timing of cochlear feedback."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mice homozygous for a targeted deletion in a-tectorin have tectorial
      membranes that are detached from the cochlear epithelium and lack all
      noncollagenous matrix, but the architecture of the organ of Corti is
      otherwise normal.
    explanation: >-
      Homozygous deletion-model physiology supports the membrane's contribution to amplification; this
      is not an allele-matched dominant model or human histopathology.
    directness: INDIRECT
  - reference: PMID:24636747
    reference_title: "Despite a lack of otoacoustic emission, word recognition is not seriously influenced in a TECTA DFNA8/12 family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although the missense p.Y1870C TECTA mutation leads to complete failure of
      the cochlear amplifier in humans, very high speech perception scores can be
      achieved with appropriate therapy.
    explanation: >-
      The p.Y1870C family supports reduced amplification with usable speech perception; absence of emissions
      is not universal across TECTA variants.
  downstream:
  - target: Bilateral Sensorineural Hearing Loss
    description: >-
      Loss of amplification raises auditory thresholds in the affected band.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24636747
      reference_title: "Despite a lack of otoacoustic emission, word recognition is not seriously influenced in a TECTA DFNA8/12 family."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Pure tone audiometry showed U-shaped curves with moderate to severe
        degrees of hearing impairment confirmed by brainstem evoked response
        audiometry.
      explanation: >-
        Documents the resulting threshold elevation and its audiometric shape.
- name: Bilateral Sensorineural Hearing Loss
  biological_scale: ORGANISM
  description: >-
    Bilateral sensorineural hearing loss has variable onset, severity, audiogram and course. Mid-frequency
    loss is common in reported families, but high-frequency and flatter patterns occur. Nonsyndromic presentation
    does not establish that every potential vestibular or subclinical feature has been excluded.
  evidence:
  - reference: PMID:9763681
    reference_title: "Autosomal-dominant, prelingual, nonprogressive sensorineural hearing loss: localization of the gene (DFNA8) to chromosome 11q by linkage in an Austrian family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The hearing loss was moderate to severe, a pure tone audiogram showing a
      U-shaped form with maximum loss at 2, 000 Hz.
    explanation: >-
      Documents the audiometric configuration in the founding DFNA8 family.
  downstream:
  - target: Bilateral Sensorineural Hearing Impairment
    causal_link_type: DIRECT
    description: The clinical phenotype records the hearing loss represented by this terminal process.
    evidence:
    - reference: PMID:9763681
      reference_title: "Autosomal-dominant, prelingual, nonprogressive sensorineural hearing loss: localization of the gene (DFNA8) to chromosome 11q by linkage in an Austrian family."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The hearing loss was moderate to severe, a pure tone audiogram showing a
        U-shaped form with maximum loss at 2, 000 Hz.
      explanation: >-
        Documents the audiometric configuration in the founding DFNA8 family.
- name: Secondary Outer Hair Cell Vulnerability
  biological_scale: CELLULAR
  description: >-
    In Tecta C1509G/+ mice, noise caused incompletely recovering emission thresholds and a redistribution
    of outer hair-cell loss toward the first row and more apical regions of the basal turn. Total loss
    in the sampled region did not significantly exceed wild type. Separately, electrical stimulation of
    excised cochleae produced greater reticular-lamina motion and membrane compromise. These experiments
    suggest exposure-dependent vulnerability; they do not demonstrate the cause of progression in human
    DFNA8/12 or every TECTA allele.
  cell_types:
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  evidence:
  - reference: PMID:21567249
    reference_title: "Biophysical mechanisms underlying outer hair cell loss associated with a shortened tectorial membrane."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      However, noise exposure produced acute threshold shifts that fully recovered
      in Tecta (+/+) mice but only partially recovered in Tecta(C1509G/+) mice.
    explanation: >-
      Demonstrates increased vulnerability to acoustic injury in the mutant.
  - reference: PMID:21567249
    reference_title: "Biophysical mechanisms underlying outer hair cell loss associated with a shortened tectorial membrane."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The increased movements were associated with a fourfold increase in OHC
      death as measured by vital dye staining.
    explanation: >-
      This abstract statement refers to electrically stimulated excised cochleae with the membrane removed,
      assessed by propidium-iodide uptake. It is not fourfold cell death after in-vivo noise exposure.
    directness: INDIRECT
phenotypes:
- category: Auditory
  name: Bilateral Sensorineural Hearing Impairment
  description: >-
    Bilateral, often symmetric hearing loss ranging from mild to severe in reported families, with variable
    frequency configuration.
  phenotype_term:
    preferred_term: Bilateral sensorineural hearing impairment
    term:
      id: HP:0008619
      label: Bilateral sensorineural hearing impairment
  evidence:
  - reference: PMID:9763681
    reference_title: "Autosomal-dominant, prelingual, nonprogressive sensorineural hearing loss: localization of the gene (DFNA8) to chromosome 11q by linkage in an Austrian family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A four-generation family suffering from an autosomal-dominant, congenital,
      nonprogressive, nonsyndromic hearing loss was found in a rural region of
      Austria.
    explanation: >-
      Documents the nonsyndromic dominant hearing loss in the founding family.
  - 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: OTHER
    snippet: >-
      is not associated with visible abnormalities of the external ear or related medical findings; however,
      it can be associated with abnormalities of the middle ear and/or inner ear.
    explanation: >-
      General clinical definition of nonsyndromic hearing loss, not a TECTA-specific onset or frequency
      claim.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
- category: Auditory
  name: Congenital Sensorineural Hearing Impairment
  description: >-
    Congenital onset is documented in the founding Austrian family. Prelingual onset also occurs, but
    is not synonymous with presence at birth; childhood or later recognition and passage of newborn screening
    are documented in other families.
  phenotype_term:
    preferred_term: Congenital sensorineural hearing impairment
    term:
      id: HP:0008527
      label: Congenital sensorineural hearing impairment
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:9763681
    reference_title: "Autosomal-dominant, prelingual, nonprogressive sensorineural hearing loss: localization of the gene (DFNA8) to chromosome 11q by linkage in an Austrian family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A four-generation family suffering from an autosomal-dominant, congenital,
      nonprogressive, nonsyndromic hearing loss was found in a rural region of
      Austria.
    explanation: >-
      Documents the nonsyndromic dominant hearing loss in the founding family.
- category: Auditory
  name: Mid-Frequency Hearing Loss
  description: >-
    The classic DFNA8/12 audiogram, a U-shaped or saucer-shaped curve with the
    maximum loss in the mid frequencies. Originally attributed to zona pellucida
    domain variants and subsequently found with N-terminal entactin and vWFD
    variants as well.
  phenotype_term:
    preferred_term: Mid-frequency hearing loss
    term:
      id: HP:0012781
      label: Mid-frequency hearing loss
  evidence:
  - reference: PMID:21520338
    reference_title: "DFNA8/12 caused by TECTA mutations is the most identified subtype of nonsyndromic autosomal dominant hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Specifically, mutations in the N-terminal region of α-tectorin (entactin
      domain, vWFD1, and vWFD2) lead to mid-frequency NSHL, a phenotype previously
      associated only with mutations in the ZP domain.
    explanation: >-
      Documents mid-frequency loss and extends it beyond the ZP domain, which is
      the correction to the original correlation.
- category: Auditory
  name: High-Frequency Hearing Impairment
  description: >-
    The alternative configuration, associated with zonadhesin-domain variants,
    and in the reported family progressing from mild to moderate.
  phenotype_term:
    preferred_term: High-frequency hearing impairment
    term:
      id: HP:0005101
      label: High-frequency hearing impairment
  evidence:
  - reference: PMID:10196713
    reference_title: "Mutation in the zonadhesin-like domain of alpha-tectorin associated with autosomal dominant non-syndromic hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The present study reports linkage to DFNA12 in a new family with autosomal
      dominant high frequency hearing loss progressing from mild to moderate
      severity.
    explanation: >-
      Documents the high-frequency, progressive configuration in a ZA-domain
      family.
- category: Auditory
  name: Progressive Sensorineural Hearing Impairment
  description: >-
    Progression is allele- and family-dependent. Cysteine loss was an early association, but p.Cys1036Tyr
    can be stable and p.Asn465Lys progressive; introduction of a cysteine in p.Tyr1870Cys is associated
    with stable loss. Cross-sectional age comparisons are weaker than serial individual audiograms.
  phenotype_term:
    preferred_term: Progressive sensorineural hearing impairment
    term:
      id: HP:0000408
      label: Progressive sensorineural hearing impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:10196713
    reference_title: "Mutation in the zonadhesin-like domain of alpha-tectorin associated with autosomal dominant non-syndromic hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The present study reports linkage to DFNA12 in a new family with autosomal
      dominant high frequency hearing loss progressing from mild to moderate
      severity.
    explanation: >-
      Documents the high-frequency, progressive configuration in a ZA-domain
      family.
  - reference: PMID:21520338
    reference_title: DFNA8/12 caused by TECTA mutations is the most identified subtype of nonsyndromic autosomal dominant hearing loss.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Serial audiograms from patient IV:1 in family S694 who carries the ZA region p.Cys1036Tyr mutation
      indicate a stable hearing loss
    explanation: >-
      A stable cysteine-substitution family limits a universal cysteine/progression rule.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:21520338
    reference_title: DFNA8/12 caused by TECTA mutations is the most identified subtype of nonsyndromic autosomal dominant hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the age-related typical audiograms (ARTA) analyses performed on the Belgian-K family, in which a
      cysteine is not mutated (p.Asn465Lys), indicate the hearing loss is progressive
    explanation: >-
      Progression in this non-cysteine allele limits a deterministic cysteine/progression rule.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Auditory
  name: Absent Otoacoustic Emissions with Preserved Word Recognition
  description: >-
    In three assessed p.Y1870C family members, transient and distortion-product emissions were absent
    while word recognition reached up to 95%. This allele-specific dissociation does not prove complete
    amplifier failure or normal neural anatomy in all patients. A young p.Cys1837Gly carrier had normal
    transient emissions.
  phenotype_term:
    preferred_term: Absent otoacoustic emissions
    term:
      id: HP:6000182
      label: Absent otoacoustic emissions
  evidence:
  - reference: PMID:24636747
    reference_title: "Despite a lack of otoacoustic emission, word recognition is not seriously influenced in a TECTA DFNA8/12 family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Transient evoked and distortion product otoacoustic emissions were
      completely absent in all affected family members whereas word recognition
      scores were up to 95%.
    explanation: >-
      Documents the dissociation between absent emissions and preserved speech
      discrimination.
  - reference: PMID:21520338
    reference_title: DFNA8/12 caused by TECTA mutations is the most identified subtype of nonsyndromic autosomal dominant hearing loss.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The youngest mutation carrier, III:5, who was asymptomatic at the time of this study has normal
      TEOAEs in both ears.
    explanation: >-
      Normal emissions in a young carrier limit extrapolation of the p.Y1870C phenotype.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
genetic:
- name: TECTA
  notes: >-
    TECTA encodes the modular extracellular glycoprotein alpha-tectorin. Dominant and recessive disease
    must be distinguished using variant interpretation, zygosity, segregation and clinical findings; sequence
    consequence alone is insufficient. The 2011 study increased the then-known dominant alleles from 13
    to 33, a historical count rather than a current total. Most variants in that series were private.
    Founder evidence differed between recurrent alleles and populations. Penetrance is not quantified
    here. Unchanged total RNA for c.5999G>A does not demonstrate normal protein abundance or secretion.
  gene_term:
    preferred_term: TECTA
    term:
      id: hgnc:11720
      label: TECTA
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:9590290
    reference_title: "Mutations in the human alpha-tectorin gene cause autosomal dominant non-syndromic hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings indicate that mutations in TECTA are responsible for hearing
      impairment in these families, and implicate a new type of protein in the
      pathogenesis of hearing impairment.
    explanation: >-
      The founding gene-disease assignment.
  - reference: PMID:21520338
    reference_title: "DFNA8/12 caused by TECTA mutations is the most identified subtype of nonsyndromic autosomal dominant hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Collectively, our results indicate that DFNA8/12 hearing loss is a frequent
      type of ADNSHL.
    explanation: >-
      The selected Spanish and American cohorts establish an important contribution to ADNSHL, not a general-population
      prevalence or current global ranking.
  - reference: PMID:21520338
    reference_title: "DFNA8/12 caused by TECTA mutations is the most identified subtype of nonsyndromic autosomal dominant hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although the majority are private mutations, four of them-p.Cys1036Tyr,
      p.Cys1837Gly, p.Thr1866Met, and p.Arg1890Cys-were observed in more than one
      unrelated family. For two of these mutations founder effects were also
      confirmed.
    explanation: >-
      Recurrence and founder analyses in the 2011 series; the full text supports a common founder for
      Cys1837Gly and shared haplotypes in some Arg1890Cys families. Recurrence does not establish progression.
  - reference: PMID:21520338
    reference_title: "DFNA8/12 caused by TECTA mutations is the most identified subtype of nonsyndromic autosomal dominant hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In aggregate, we identified 23 TECTA mutations in this process. Remarkably,
      20 of these mutations are novel, more than doubling the number of reported
      TECTA ADNSHL mutations from 13 to 33.
    explanation: >-
      The number 33 is the cumulative count reported in 2011, not the current allelic spectrum.
environmental:
- name: Excessive noise exposure
  description: >-
    Noise is a potential modifier of inherited hearing loss. C1509G mouse experiments support altered
    recovery and spatial injury patterns, but do not quantify human TECTA-specific susceptibility or establish
    noise as the cause of human progression. General hearing-loss guidance supports avoiding repeated
    loud-noise overexposure.
  exposure_term:
    preferred_term: excessive noise exposure
    term:
      id: ECTO:8000044
      label: exposure to sound radiation
  evidence:
  - reference: PMID:21567249
    reference_title: "Biophysical mechanisms underlying outer hair cell loss associated with a shortened tectorial membrane."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      However, noise exposure produced acute threshold shifts that fully recovered
      in Tecta (+/+) mice but only partially recovered in Tecta(C1509G/+) mice.
    explanation: >-
      Shows the mutant cochlea fails to recover from an acoustic insult that the
      wild-type recovers from fully, which is what makes noise a
      disease-relevant exposure here.
  influences_mechanisms:
  - target: Secondary Outer Hair Cell Vulnerability
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >-
      In the C1509G model, noise exposure changes emission-threshold recovery and the distribution of
      hair-cell injury. This exposure effect is model-specific.
    evidence:
    - reference: PMID:21567249
      reference_title: "Biophysical mechanisms underlying outer hair cell loss associated with a shortened tectorial membrane."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        However, noise exposure produced acute threshold shifts that fully recovered
        in Tecta (+/+) mice but only partially recovered in Tecta(C1509G/+) mice.
      explanation: >-
        Shows the mutant cochlea fails to recover from an acoustic insult that the
        wild-type recovers from fully, which is what makes noise a
        disease-relevant exposure here.
animal_models:
- name: Tecta L1820F,G1824D/+ mouse (ZP domain)
  species: Mouse
  genotype: Tecta(L1820F,G1824D/+), modelling the Belgian DFNA12 ZP-domain family
  publication: PMID:24363064
  description: >-
    One of three allele-matched mouse models built to test the human
    domain-to-audiogram correlation directly.
  modeled_mechanisms:
  - target: Defective Tectorial Membrane Matrix Assembly
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces ZP-domain matrix abnormalities and elevated thresholds. Stable hearing is concordant
      with the human Belgian family for this allele.
    limitations: >-
      Thresholds are elevated across 8-40 kHz rather than reproducing the human frequency map. Audiogenic
      seizure susceptibility was observed in these mice; a corresponding human TECTA phenotype is not
      established.
    readouts:
    - name: Auditory brainstem response threshold, 8-40 kHz
      target: Defective Tectorial Membrane Matrix Assembly
      direction: INCREASED
      interpretation: >-
        Threshold elevation of 30-40 dB confirms functional hearing loss from a
        ZP-domain allele.
      evidence:
      - reference: PMID:24363064
        reference_title: "Three deaf mice: mouse models for TECTA-based human hereditary deafness reveal domain-specific structural phenotypes in the tectorial membrane."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Auditory brainstem response thresholds in the 8-40 kHz range are
          elevated by 30-40 dB in the ZP-domain mutants, whilst those in the
          ZA-domain mutant are elevated by 20-30 dB.
        explanation: >-
          Gives the measured threshold elevation for both domain classes.
  evidence:
  - reference: PMID:24363064
    reference_title: "Three deaf mice: mouse models for TECTA-based human hereditary deafness reveal domain-specific structural phenotypes in the tectorial membrane."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Three mutant mice were created as models for human Tecta mutations; the
      Tecta(L1820F,G1824D/+) mouse for zona pellucida (ZP) domain mutations
      causing stable mid-frequency hearing loss in a Belgian family
    explanation: >-
      Establishes that this line was built to carry a specific human allele.
- name: Tecta C1619S/+ mouse (ZA domain)
  species: Mouse
  genotype: Tecta(C1619S/+), modelling the French DFNA12 zonadhesin-domain family
  publication: PMID:24363064
  description: >-
    The allele-matched model for the progressive, high-frequency human phenotype
    — and the one that does not reproduce the progression.
  modeled_mechanisms:
  - target: Defective Tectorial Membrane Matrix Assembly
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the ZA-domain structural lesion and threshold elevation, but the
      phenotype is stable where the human one progresses.
    limitations: >-
      Thresholds were compared in different age groups through 11 months and remained stable despite human
      progression. The studied strain and interval provide no spontaneous progression endpoint; longer
      follow-up or different backgrounds were not excluded.
    readouts:
    - name: Auditory thresholds across age groups and tectorial membrane structure
      target: Defective Tectorial Membrane Matrix Assembly
      direction: UNCHANGED
      interpretation: >-
        A genuine negative: no deterioration over time, against a progressive
        human course for the same allele.
      evidence:
      - reference: PMID:24363064
        reference_title: "Three deaf mice: mouse models for TECTA-based human hereditary deafness reveal domain-specific structural phenotypes in the tectorial membrane."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          The phenotypes are stable and no evidence has been found for a
          progressive deterioration in TM structure or auditory function.
        explanation: >-
          Reports the absence of progression in the mutant mice.
  evidence:
  - reference: PMID:24363064
    reference_title: "Three deaf mice: mouse models for TECTA-based human hereditary deafness reveal domain-specific structural phenotypes in the tectorial membrane."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the Tecta(C1619S/+) mouse for a zonadhesin-like (ZA) domain mutation
      responsible for progressive, high-frequency hearing loss in a French family
    explanation: >-
      Establishes the human allele this line was built to model.
- name: Tecta C1837G/+ mouse (ZP domain)
  species: Mouse
  genotype: Tecta(C1837G/+), modelling a Spanish DFNA8/12 family
  publication: PMID:24363064
  description: >-
    ZP-domain model of a human progressive mid-frequency allele, with stable mouse thresholds through
    eight months.
  modeled_mechanisms:
  - target: Defective Tectorial Membrane Matrix Assembly
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces ZP-domain matrix disruption and elevated thresholds, but not human progression.
    limitations: >-
      Thresholds were stable across age groups through eight months; audiogenic seizure susceptibility
      prevented planned high-noise progression experiments.
    readouts:
    - name: Auditory thresholds across age groups and tectorial membrane structure
      target: Defective Tectorial Membrane Matrix Assembly
      direction: UNCHANGED
      interpretation: >-
        A genuine negative: no deterioration over time, against a progressive
        human course for the same allele.
      evidence:
      - reference: PMID:24363064
        reference_title: "Three deaf mice: mouse models for TECTA-based human hereditary deafness reveal domain-specific structural phenotypes in the tectorial membrane."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          The phenotypes are stable and no evidence has been found for a
          progressive deterioration in TM structure or auditory function.
        explanation: >-
          Reports the absence of progression in the mutant mice.
  evidence:
  - reference: PMID:24363064
    reference_title: "Three deaf mice: mouse models for TECTA-based human hereditary deafness reveal domain-specific structural phenotypes in the tectorial membrane."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the Tecta(C1837G/+) mouse for a ZP-domain mutation underlying progressive mid-frequency hearing
      loss in a Spanish family
    explanation: >-
      Identifies the third allele studied in the three-mouse experiment.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Tecta C1509G/+ mouse
  species: Mouse
  genotype: Tecta(C1509G/+) transgenic
  publication: PMID:21567249
  description: >-
    The model that supplies the biophysical account of secondary outer hair cell
    loss, through a shortened tectorial membrane that contacts only the first
    outer hair cell row.
  modeled_mechanisms:
  - target: Secondary Outer Hair Cell Vulnerability
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Shows partial uncoupling and altered in-vivo noise recovery and injury distribution; mechanical
      simulations and separate ex-vivo electrical experiments support possible contributors.
    limitations: >-
      Thresholds were stable in quiet through six months. Total hair-cell loss after noise was not significantly
      greater than wild type in the sampled region. Fourfold vital-dye labeling followed ex-vivo electrical
      stimulation, not noise. Human progression and exposure equivalence are unproven.
    readouts:
    - name: Outer hair cell survival after noise exposure
      target: Secondary Outer Hair Cell Vulnerability
      direction: DECREASED
      interpretation: >-
        Preferential loss in the first row, the row left mechanically coupled by
        the shortened membrane.
      evidence:
      - reference: PMID:21567249
        reference_title: "Biophysical mechanisms underlying outer hair cell loss associated with a shortened tectorial membrane."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          While Tecta(+/+) mice lost OHCs primarily at the base and within all
          three rows, Tecta(C1509G/+) mice lost most of their OHCs in a more
          apical region of the cochlea and nearly completely within the first row.
        explanation: >-
          The distribution of loss differs by row and cochlear location; this quote does not establish
          greater total cell loss.
    - name: Distortion product otoacoustic emission threshold in quiet
      target: Secondary Outer Hair Cell Vulnerability
      direction: UNCHANGED
      interpretation: >-
        No spontaneous deterioration in a quiet environment to six months, which
        is what confines the model's claim to vulnerability rather than
        progression.
      evidence:
      - reference: PMID:21567249
        reference_title: "Biophysical mechanisms underlying outer hair cell loss associated with a shortened tectorial membrane."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Distortion product otoacoustic emission thresholds in a quiet
          environment did not change to 6 months of age.
        explanation: >-
          Records the absence of spontaneous progression in the unexposed mutant.
  evidence:
  - reference: PMID:21567249
    reference_title: "Biophysical mechanisms underlying outer hair cell loss associated with a shortened tectorial membrane."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Humans with an autosomal dominant C1509G mutation in alpha-tectorin, a
      protein constituent of the TM, are born with a partial hearing loss that
      worsens over time.
    explanation: >-
      Establishes that the modelled allele is a human disease allele.
    quote_role: BACKGROUND
    directness: INDIRECT
diagnosis:
- name: Pure tone audiometry with otoacoustic emissions
  description: >-
    Age-appropriate audiometry, speech testing and objective measures characterize severity, configuration
    and auditory function. Absent emissions with good word recognition can occur in TECTA disease but
    are neither universal nor sufficient for a molecular diagnosis. Other causes and syndromic features
    remain part of assessment.
  evidence:
  - reference: PMID:24636747
    reference_title: "Despite a lack of otoacoustic emission, word recognition is not seriously influenced in a TECTA DFNA8/12 family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pure tone audiometry, brainstem evoked response audiometry, the Freiburger
      test for speech understanding and transient evoked and distortion product
      otoacoustic emissions were assessed in three available affected members
      bearing p.Y1870C.
    explanation: >-
      Lists the test battery used to characterise affected family members.
- name: Molecular testing and variant interpretation
  description: >-
    A hearing-loss multigene panel or exome/genome analysis can identify a heterozygous pathogenic or
    likely pathogenic TECTA variant. Targeted testing is appropriate for a known familial variant. A VUS
    or domain location alone cannot confirm or exclude DFNA8/12; segregation and allele-specific functional
    information can refine interpretation.
  evidence:
  - reference: PMID:21520338
    reference_title: "DFNA8/12 caused by TECTA mutations is the most identified subtype of nonsyndromic autosomal dominant hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In an additional cohort of 835 American ADNSHL families, we preselected 73
      probands for TECTA screening based on audiometric data.
    explanation: >-
      Documents audiogram-guided selection for TECTA testing.
  - reference: PMID:38224868
    reference_title: "Genetic diagnosis of childhood sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: >-
      There is increasing awareness of the importance of an etiologic diagnosis,
      and genetic testing with next-generation sequencing (NGS) has the highest
      diagnostic yield.
    explanation: >-
      The general childhood hearing-loss review supports molecular testing; it does not itself specify
      a TECTA-only diagnostic strategy.
    quote_role: BACKGROUND
  - 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: OTHER
    snippet: >-
      The identification of variant(s) of uncertain significance cannot be used to confirm or rule out
      the diagnosis.
    explanation: >-
      General genetic-hearing-loss variant-interpretation guidance.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  - 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: OTHER
    snippet: >-
      Single-gene testing (sequence analysis of a given gene, followed by gene-targeted deletion/duplication
      analysis) is rarely useful and typically NOT recommended.
    explanation: >-
      General testing strategy; familial variant testing remains a distinct use case.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  - reference: PMID:37927186
    reference_title: "Clinical relevance of the TECTA c.6183G>T variant identified in a family with autosomal dominant hearing loss: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This variant was not detected in the remaining five family members who did not have HL
    explanation: >-
      The family study used segregation with the phenotype to argue for reclassification of c.6183G>T;
      it did not provide a mutant-protein functional assay.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Evaluation of at-risk relatives
  description: >-
    Offer hearing assessment and, when available, targeted familial-variant testing to relatives. A passed
    newborn screen does not exclude mild or later-onset hearing loss.
  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: OTHER
    snippet: >-
      Permanent childhood hearing loss in a parent or sib increases the probability of hearing loss in
      other family members and warrants early complete diagnostic evaluation of hearing regardless of
      the family member's newborn hearing screening result.
    explanation: >-
      General GeneReviews guidance for families with childhood genetic hearing loss.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  - reference: PMID:40583560
    reference_title: A novel splicing variant in TECTA associated with prelingual autosomal dominant nonsyndromic hearing loss via dominant-negative effect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individual V-3 passed newborn hearing screening; however, at the age of 6 years, she was diagnosed
      with HL and had used hearing aids since diagnosis.
    explanation: >-
      A screened child subsequently had documented hearing loss; a passed newborn screen does not exclude
      familial TECTA hearing loss.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
treatments:
- name: Hearing amplification and auditory rehabilitation
  description: >-
    Individualized hearing aids and auditory habilitation can support communication. Benefit and communication
    goals are assessed per person; the small p.Y1870C series does not establish unusually high efficacy
    for all TECTA variants. Spoken language, sign language and combined approaches should reflect individual
    and family preferences.
  treatment_term:
    preferred_term: 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
  therapeutic_modality: DEVICE
  target_mechanisms:
  - target: Cochlear Amplifier Failure
    description: >-
      Amplification substitutes externally for the gain the tectorial membrane
      can no longer deliver, without repairing the matrix.
    evidence:
    - reference: PMID:24636747
      reference_title: "Despite a lack of otoacoustic emission, word recognition is not seriously influenced in a TECTA DFNA8/12 family."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Although the missense p.Y1870C TECTA mutation leads to complete failure of
        the cochlear amplifier in humans, very high speech perception scores can
        be achieved with appropriate therapy.
      explanation: >-
        The three-member p.Y1870C assessment supports useful speech perception; it is not a controlled
        comparison of rehabilitation strategies.
  evidence:
  - reference: PMID:24636747
    reference_title: "Despite a lack of otoacoustic emission, word recognition is not seriously influenced in a TECTA DFNA8/12 family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Transient evoked and distortion product otoacoustic emissions were
      completely absent in all affected family members whereas word recognition
      scores were up to 95%.
    explanation: >-
      The reported speech scores demonstrate retained function in this family, not a measured before/after
      treatment effect.
    directness: INDIRECT
  - 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: OTHER
    snippet: >-
      customized by an audiologist to the degree and frequency of hearing loss, can be used in individuals
      with mild-to-severe hearing loss.
    explanation: >-
      General hearing-loss management guidance applicable to suitable TECTA presentations.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  - reference: PMID:37927186
    reference_title: "Clinical relevance of the TECTA c.6183G>T variant identified in a family with autosomal dominant hearing loss: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All the affected participants wore bilateral hearing aids from an early age.
    explanation: >-
      Documents hearing-aid use in a dominant TECTA family; treatment efficacy was not comparatively measured.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Cochlear implantation
  description: >-
    Consider specialist cochlear-implant evaluation for severe-to-profound loss with insufficient benefit
    from hearing aids, using individual audiologic and anatomic assessment. Electrical stimulation bypasses
    hair-cell transduction to activate auditory neurons. The cited 2013 TECTA implant case had biallelic
    DFNB21; it does not establish dominant DFNA8/12-specific outcomes or electric-acoustic stimulation
    efficacy.
  treatment_term:
    preferred_term: cochlear device 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
  therapeutic_modality: DEVICE
  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: OTHER
    snippet: >-
      Cochlear implantation can be considered in children with severe-to-profound hearing loss who are
      older than age nine months.
    explanation: >-
      General pediatric candidacy guidance, not TECTA-specific efficacy.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  - reference: PMID:24130743
    reference_title: Massively parallel DNA sequencing successfully identifies new causative mutations in deafness genes in patients with cochlear implantation and EAS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We successfully identified four rare causative mutations in the MYO15A, TECTA, TMPRSS3, and ACTG1
      genes in four patients who showed relatively good auditory performance with CI including EAS
    explanation: >-
      The full text identifies the TECTA patient as compound heterozygous for c.596delT and c.1471C>T
      (DFNB21), receiving CI at age two. The EAS cases had other genes; applicability to dominant TECTA
      disease is indirect.
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
- name: Genetic counseling and prenatal diagnosis
  description: >-
    Discuss a 50% chance of transmitting the familial pathogenic variant with each pregnancy and the limits
    of predicting onset and severity. Familial-variant identification enables prenatal or preimplantation
    testing if desired. Reproductive testing and communication choices are personal decisions supported
    by nondirective counseling.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:40583560
    reference_title: "A novel splicing variant in TECTA associated with prelingual autosomal dominant nonsyndromic hearing loss via dominant-negative effect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified a novel aberrant splicing variant, c.5999G > A (p.Gly2000Glu),
      in TECTA as the cause of autosomal dominant hearing loss in five-generation
      kindred of Chinese descent and provided prenatal diagnosis for the family
    explanation: >-
      Documents prenatal diagnosis actually being provided in a DFNA8/12 family
      once the causative variant was identified.
  - 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: OTHER
    snippet: >-
      Individuals with autosomal dominant hearing loss have a 50% chance of transmitting the pathogenic
      variant to each child.
    explanation: >-
      GeneReviews provides the general autosomal dominant transmission probability, not an allele-specific
      penetrance estimate.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  - 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: OTHER
    snippet: >-
      Once the pathogenic variant(s) have been identified in the family, prenatal and preimplantation
      genetic testing for genetic hearing loss are possible.
    explanation: >-
      General reproductive-testing guidance after a molecular diagnosis.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
- name: Audiologic surveillance and noise protection
  description: >-
    Repeat audiologic assessment to document stability or progression and adjust support. Tailor intervals
    to age, clinical course and needs; the GeneReviews table does not give a TECTA-specific schedule.
    Avoid repeated loud-noise overexposure as general hearing protection, without implying a quantified
    human TECTA-specific risk.
  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: OTHER
    snippet: >-
      Regular follow up is recommended for all individuals with genetic hearing loss
    explanation: >-
      General surveillance recommendation; serial audiologic examinations assess stability and progression.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  - 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: OTHER
    snippet: >-
      persons with documented hearing loss should be counseled appropriately and repeated overexposure
      to loud noises should be avoided.
    explanation: >-
      General hearing-loss precaution; C1509G experiments provide preclinical context only.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
differential_diagnoses:
- name: DFNB21, recessive TECTA deafness
  description: >-
    Biallelic TECTA variants cause DFNB21. Loss-of-function alleles often underlie recessive disease,
    but missense alleles can also be recessive, and sequence consequence alone cannot assign inheritance.
    The 2011 report noted a truncating allele in two members of a dominant pedigree but could not exclude
    incidental carrier status or a missed second allele. Assess zygosity, phase, segregation and variant-specific
    evidence.
  evidence:
  - reference: PMID:9949200
    reference_title: "An alpha-tectorin gene defect causes a newly identified autosomal recessive form of sensorineural pre-lingual non-syndromic deafness, DFNB21."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequence analysis of the TECTA gene in the DFNB21-affected family revealed a
      G to A transition in the donor splice site (GT) of intron 9, predicted to
      lead to a truncated protein of 971 amino acids.
    explanation: >-
      Documents the truncating allele class that produces the recessive disease.
- name: Other autosomal dominant nonsyndromic hearing loss loci
  description: >-
    Many genetic hearing-loss disorders overlap with the DFNA8/12 audiogram. Mid-frequency loss can guide
    interpretation but is not specific; molecular testing and assessment for extra-auditory findings distinguish
    causes.
  evidence:
  - reference: PMID:21520338
    reference_title: "DFNA8/12 caused by TECTA mutations is the most identified subtype of nonsyndromic autosomal dominant hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We therefore completed unbiased screening for TECTA mutations in a Spanish
      cohort of 372 probands from ADNSHL families.
    explanation: >-
      Indicates that TECTA is identified within a large pool of otherwise similar
      dominant nonsyndromic hearing loss families, which is why sequencing rather
      than phenotype makes the assignment.
discussions:
- discussion_id: mouse_does_not_progress
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Why do allele-matched Tecta mice not show the progression seen in the
    patients carrying the same substitution, and can any mouse be used to study
    progression in this disease?
  attaches_to:
  - animal_models#Tecta C1619S/+ mouse (ZA domain)
  - animal_models#Tecta C1509G/+ mouse
  - pathophysiology#Secondary Outer Hair Cell Vulnerability
  - animal_models#Tecta C1837G/+ mouse (ZP domain)
  rationale: >-
    C1619S and C1837G mice lacked progressive threshold deterioration over the studied intervals despite
    progression in corresponding human families. C1509G emission thresholds were stable in quiet through
    six months; after noise, recovery and cell-loss distribution differed from wild type without greater
    total loss in the sampled region. Lifespan, genetic background and cumulative exposure are candidate
    explanations, not established causes of the mismatch. The studied conditions lack a spontaneous progression
    endpoint.
  evidence:
  - reference: PMID:24363064
    reference_title: "Three deaf mice: mouse models for TECTA-based human hereditary deafness reveal domain-specific structural phenotypes in the tectorial membrane."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The phenotypes are stable and no evidence has been found for a progressive
      deterioration in TM structure or auditory function.
    explanation: >-
      The direct statement of absent progression in the allele-matched mice.
  - reference: PMID:10196713
    reference_title: "Mutation in the zonadhesin-like domain of alpha-tectorin associated with autosomal dominant non-syndromic hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The present study reports linkage to DFNA12 in a new family with autosomal
      dominant high frequency hearing loss progressing from mild to moderate
      severity.
    explanation: >-
      Establishes that the human phenotype for a ZA-domain allele does progress,
      which is the half of the mismatch the mouse fails to reproduce.
- discussion_id: audiogenic_seizure_in_tecta_mice
  kind: OPEN_QUESTION
  prompt: >-
    Do Tecta mutations confer any central auditory phenotype in humans, given
    that all three allele-matched mouse models develop audiogenic seizures?
  attaches_to:
  - animal_models#Tecta L1820F,G1824D/+ mouse (ZP domain)
  - animal_models#Tecta C1619S/+ mouse (ZA domain)
  - animal_models#Tecta C1837G/+ mouse (ZP domain)
  rationale: >-
    C1619S, C1837G and L1820F/G1824D mice exhibited wild running predictive of seizures at low sound levels.
    The authors stopped stimulation early and could not complete the planned high-noise experiments. Central
    adaptation and other mechanisms remain hypotheses; a corresponding human phenotype was not established.
    This result cannot be assigned to the separate C1509G experiment.
  evidence:
  - reference: PMID:24363064
    reference_title: "Three deaf mice: mouse models for TECTA-based human hereditary deafness reveal domain-specific structural phenotypes in the tectorial membrane."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Despite elevated auditory thresholds, the Tecta mutant mice all exhibit an
      enhanced tendency to have audiogenic seizures in response to white noise
      stimuli at low sound pressure levels (≤84 dB SPL), revealing a previously
      unrecognised consequence of Tecta mutations.
    explanation: >-
      Reports the unexpected central phenotype in all three models.
- discussion_id: domain_audiogram_correlation_limits
  kind: KNOWLEDGE_GAP
  prompt: >-
    How much of the audiogram configuration does the mutated alpha-tectorin
    domain actually predict?
  attaches_to:
  - pathophysiology#Defective Tectorial Membrane Matrix Assembly
  - phenotypes#Mid-Frequency Hearing Loss
  rationale: >-
    Domain-associated structural differences in tested mice and human audiogram associations are useful
    but incomplete. Mid-frequency loss occurs outside the ZP domain, and cysteine/progression associations
    have exceptions. Both allelic effects and ascertainment matter; modifiers remain incompletely resolved.
    Domain location should inform interpretation without being presented as a deterministic prognosis.
notes: >-
  DFNA8 and DFNA12 denote the same TECTA-related dominant disease. Protein-domain patterns are clinical
  associations, not separate disease subtypes. Null-model findings and generic hearing-loss guidance are
  explicitly indirect. Congenital onset differs from prelingual onset, and neither is universal.

  The matching research narrative and bibliography were reviewed. PMID:37927186 is a TECTA family study
  and is now used for segregation and hearing-aid use. PMID:33559882 adds a distinct calcium/adaptation
  hypothesis rather than duplicating mechanical uncoupling. PMID:25564867 concerns striated-sheet mechanical
  properties; PMID:21368133 concerns CEACAM16 interaction in DFNA4 and remains contextual rather than
  a new DFNA8/12 causal branch. General hearing-loss papers are used only for appropriate context. The
  report's unresolved HP:0008565 and obsolete HP:0410007 bindings are not imported.

  The tagged GeneReviews overview was mined for clinical presentation, testing, care, surveillance, noise
  protection and counseling. Its TECTA table lists prelingual onset, while primary reports document exceptions;
  pooled hearing-loss frequencies and non-TECTA surveillance intervals are not assigned to this disease.
  No clinical efficacy trial specific to DFNA8/12 was identified in the matching report.
📚

References & Deep Research

References

4
PMID:20301607
Genetic Hearing Loss Overview.
No top-level findings curated for this source.
PMID:9590290
Mutations in the human alpha-tectorin gene cause autosomal dominant non-syndromic hearing impairment.
No top-level findings curated for this source.
PMID:24363064
Three deaf mice: mouse models for TECTA-based human hereditary deafness reveal domain-specific structural phenotypes in the tectorial membrane.
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.

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 (2)

Review TECTA hearing-loss mechanisms, phenotype limits and treatment evidence · 2026-09-23T06:50:32Z · View source

Substantive review of the whole existing entry. Confirmed no prior REVIEW event and no overlapping open PR when this worktree was created. This genetic hearing-loss disorder is eligible under the campaign excluding infectious and environmental diseases/poisonings; noise is a modifier, not its etiology. Read the matching OpenScientist scientific narrative, bibliography and validation appendix and all cited abstracts. Used the cached full scientific narratives of PMID:40583560, PMID:21520338 and PMID:26806019; the full methods/results/discussion of PMID:21567249; the relevant TECTA case and discussion of PMID:24130743; the full PMID:24363064 paper retrieved through EuropePMC XML; and newly regenerated full texts of PMID:37927186 and PMID:33559882 (results/discussion and relevant methods). Also retrieved and read PMID:18665028 to check an indirect histopathology attribution: its kindreds were ungenotyped, so they cannot establish human TECTA pathology. PMID:10196713 has abstract/paywall material rather than a usable full body; supplementary files were not independently retrieved. All cache changes were generated with just fetch-reference. The EuropePMC XML cache has an automatically extracted title of INTRODUCTION, but its article metadata identifies PMID:24363064; the entry cites the published PMID, not that extraction label. The failed direct PMC CAPTCHA cache is excluded. Corrected the major source-to-claim mismatches. The 2013 implanted TECTA patient was compound heterozygous for DFNB21 and did not receive EAS, so the case cannot establish dominant DFNA8/12 implant efficacy. The fourfold vital-dye result followed electrical stimulation of excised cochleae, not noise exposure in living mice; after noise, total hair-cell loss was not significantly greater, although its spatial distribution and emission-threshold recovery differed. Unchanged total RNA in the 2025 splice study does not prove normal mutant secretion or protein abundance. Congenital and prelingual onset are distinct; a child passed newborn screening before diagnosis. Stable Cys1036Tyr, progressive Asn465Lys and normal emissions in a young Cys1837Gly carrier limit blanket genotype and phenotype rules. Historical variant counts and cohort ascertainment are explicit. Added the omitted C1837G mouse and fixed the dangling generic Mouse discussion target. The L1820F/G1824D human family is stable, so lack of mouse progression is concordant for that allele. The audiogenic-seizure experiment involved C1619S, C1837G and L1820F/G1824D, not C1509G; susceptibility prevented the planned high-noise experiment. Added supported phenotype and vulnerability edges without extrapolating experimental injury to a proven human progression mechanism. PMID:33559882 is not merely duplicative: it supports a separate provisional calcium/adaptation hypothesis in a double-knockout model. PMID:37927186 was wrongly described as general hearing-loss literature; its family segregation and hearing-aid use now inform the entry. Eight-dimension deep-research assessment: (1) phenotypes adequate after correcting onset, severity/course and emission generalizations; no report-derived frequency is generalized to all patients; (2) subtypes adequate, with DFNA8/12 aliases and domain patterns retained within one disease and recessive DFNB21 differentiated; (3) pathophysiology adequate, preserving the matrix/coupling/amplification chain, linking experimental vulnerability and distinguishing the calcium hypothesis; (4) treatments adequate after replacing dominant implant overclaims with general candidacy and indirect recessive-case evidence, adding surveillance/noise protection and communication preferences; no disease-specific phase-II-or-later efficacy trial was surfaced by the report; (5) genetics adequate with segregation, splice effects, variant interpretation and historical-count limits; (6) diagnostics/biomarkers adequate with panels/genomic testing, VUS limits, audiology and family evaluation, without importing nonspecific diagnostic-yield figures; (7) references adequate with relevant full texts, explicit indirect evidence and real titles on all additions; (8) consumption adequate with resolved model/graph links and explicit human-versus-model boundaries. CEACAM16 interaction and striated-sheet biophysics remain supporting context rather than new disease subtypes or established human causal branches. No schema change was required. GeneReviews overview is tagged and its full current text was mined across clinical presentation, molecular diagnosis, management/surveillance and genetic counseling. TECTA-table prelingual onset is qualified by primary exceptions; generic hearing-loss frequencies and non-TECTA follow-up intervals are not assigned to DFNA8/12. Full text supports family evaluation despite a passed screen, individualized hearing support, general implant candidacy, noise avoidance, 50% variant transmission and personal reproductive choices. Local schema/ontology checks and all 78 quotation matches passed before recording this history, as did causal-target, entity-reference and GeneReviews checks. Formal author COMMENT, independent review and CI are separate completion gates for the PR. Independent review follow-up: moved the passed-newborn-screen case to at-risk-relative diagnosis; restored HUMAN_CLINICAL plus BACKGROUND for the C1509G human introduction quote; marked overview excerpts REVIEW_SYNTHESIS; added the directly quoted Asn465Lys progression result; and bound absent emissions to HP:6000182 after live OAK lookup. Replaced the three-word GeneReviews table excerpt rejected by CI with a full clinical-definition sentence; TECTA-specific prelingual onset remains qualified prose. Removed the uncited EuropePMC wrapper cache from the PR while retaining its local full text and recorded reading provenance. All changes are batched after independent review completion.

Create: Autosomal Dominant Nonsyndromic Hearing Loss 12 (DFNA8/12, TECTA) · 2026-08-31T17:28:12Z · View source

De novo curation of DFNA12 (MONDO:0011102), the TECTA/alpha-tectorin dominant nonsyndromic hearing loss also written DFNA8/12. One openscientist deep-research report was generated and preflighted with "just preflight-dr ... MONDO:0011102", which PASSed with TECTA as the dominant gene mention and matching OMIM 601543. The report's own Term Validation section flagged HP:0008565 as not existing in HPO; that identifier is not bound anywhere here, and the exclusion is recorded in the entry notes so a later curator does not rediscover it from the report. Pathograph is a six-node mechanical chain: heterozygous TECTA missense variant, defective tectorial membrane matrix assembly, impaired mechanical coupling to outer hair cell stereocilia, cochlear amplifier failure, bilateral sensorineural hearing loss, plus a separate secondary outer hair cell vulnerability node covering the progressive genotypes. The dominant-negative mechanism is grounded on the DFNB21 comparison in PMID:9949200: heterozygous carriers of a truncating TECTA allele hear normally, which excludes haploinsufficiency as the mechanism of the dominant alleles. Three allele-matched mouse models are curated with modeled_mechanisms. Two carry UNCHANGED readouts recording real negative results. The C1619S line does not progress although the human family carrying the same substitution does, and the C1509G line has stable emission thresholds in quiet to six months. These ground a HUMAN_MODEL_MISMATCH discussion asking whether mouse lifespan or absent cumulative acoustic exposure explains the difference. A second discussion records the audiogenic seizure phenotype seen in all three models and never looked for in patients. A third records that the domain-to-audiogram correlation is many-to-one, since entactin and vWFD variants were later found to give mid-frequency loss that had been attributed to the ZP domain alone. Validated with just validate for schema and references, 46 of 46 snippets verified against cached references, plus just validate-terms, just check-entity-refs and just check-duplicate-keys, all passing. Term validation initially failed on an EBI OLS read timeout, which is a service error rather than a data error, and passed on retry.

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Autosomal Dominant Nonsyndromic Hearing Loss 12 (DFNA12 / DFNA8/12) — Comprehensive Disease Report
openscientist-autonomous 2026-08-31T17:16:08.382085

Autosomal Dominant Nonsyndromic Hearing Loss 12 (DFNA12 / DFNA8/12) — Comprehensive Disease Report

Evidence base: synthesized from primary literature (human clinical, mouse model, in vitro, and computational studies). Evidence source type is annotated per claim. PMIDs are given for all key statements.

Summary (Answer to the Research Question)

Autosomal Dominant Nonsyndromic Hearing Loss 12 (DFNA12), now unified with DFNA8 as DFNA8/12, is a Mendelian, autosomal-dominant, nonsyndromic sensorineural hearing loss caused by heterozygous, predominantly missense mutations in TECTA (gene for α‑tectorin, a major non‑collagenous glycoprotein of the cochlear tectorial membrane). Mutant α‑tectorin is incorporated into and structurally poisons the tectorial membrane (a dominant‑negative mechanism), degrading the mechanical coupling between the tectorial membrane and the outer‑hair‑cell stereocilia that drives cochlear amplification and frequency tuning, producing bilateral, usually mid‑ or high‑frequency, prelingual‑to‑childhood‑onset sensorineural hearing loss. The affected α‑tectorin protein domain predicts the phenotype (ZP domain → mid‑frequency, often stable; zonadhesin/ZA domain and cysteine‑substituting variants → high‑frequency, progressive). DFNA8/12 is one of the most commonly identified single‑gene causes of autosomal dominant nonsyndromic hearing loss; management is auditory rehabilitation (hearing aids, and cochlear implantation/electric‑acoustic stimulation with favorable outcomes), with no disease‑modifying drug.

1. Disease Information

Overview. DFNA12 is a hereditary, nonsyndromic (isolated) sensorineural hearing impairment inherited in an autosomal dominant pattern. The DFNA8 and DFNA12 loci were both mapped to chromosome 11q and shown to result from mutations in the same gene, TECTA; the entity is therefore designated DFNA8/12 (human clinical/linkage: PMID 9763681, 9503015, 9590290). α‑Tectorin is "one of the major non-collagenous components of the tectorial membrane" of the inner ear (PMID 9590290).

Key identifiers. - OMIM (phenotype): 601543 (Deafness, autosomal dominant 12; encompassing DFNA8/12) - OMIM (gene TECTA): 602574 - Gene: TECTA — HGNC:11720; NCBI Gene 7007; Ensembl ENSG00000109927; UniProt O75443 (α‑tectorin, 2155 aa) - MONDO: DFNA12 corresponds to MONDO "autosomal dominant nonsyndromic hearing loss 12" (also captured under the DFNA8/12 concept); TECTA‑related dominant deafness - Orphanet: included within "Rare genetic deafness"/autosomal dominant nonsyndromic sensorineural deafness type DFNA - ICD‑10: H90.5 (sensorineural hearing loss, unspecified) / H90.3 (bilateral). ICD‑11: AB52 (sensorineural hearing loss) - MeSH: related terms "Hearing Loss, Sensorineural"; "Deafness"; gene "TECTA / tectorin alpha"

Synonyms / alternative names: DFNA8; DFNA12; DFNA8/12; TECTA‑related autosomal dominant nonsyndromic hearing loss; deafness, autosomal dominant 8/12; α‑tectorin–related dominant deafness.

Information source: aggregated disease-level resources (OMIM, published pedigrees/cohorts) and individual multigenerational family studies; not derived from population EHR.

2. Etiology

Causal factors — genetic. DFNA12 is a monogenic disorder. The sole established cause is a heterozygous pathogenic variant in TECTA. The initiating lesion is almost always a missense substitution (occasionally an in‑frame splice variant) affecting conserved residues of α‑tectorin (PMID 9590290, 40583560). "In both families, mutation analysis revealed missense mutations which replace conserved amino-acid residues within the zona pellucida domain of TECTA" (PMID 9590290).

Genetic risk factors. The causal variant itself is the risk factor; there are no separate susceptibility loci for the Mendelian form. The specific domain affected is the principal modifier of expression (see §4). No environmental modifiers are established.

Environmental risk factors. None established as causing DFNA12. As with any sensorineural hearing loss, generic aggravators (noise exposure, ototoxic drugs, aging) could additively worsen hearing; notably, in the Tecta^C1509G/+ mouse, noise exposure caused incomplete recovery and increased outer‑hair‑cell loss versus wild type (model organism: PMID 21567249), suggesting gene–environment interaction whereby a defective tectorial membrane increases vulnerability to noise. TECTA is also among genes implicated in age‑related (multifactorial) hearing loss (PMID 42379497).

Protective factors. None specifically identified. A single functional TECTA allele is sufficient for near‑normal hearing (DFNB21 heterozygous carriers are unaffected), which is why complete loss‑of‑function is only pathogenic when biallelic (PMID 9949200).

Gene–environment interaction. Inferred increased susceptibility to noise‑induced damage on a mutant‑TECTA background (model organism evidence: PMID 21567249); direct human data limited.

Infectious agents: not applicable.

3. Phenotypes

Core phenotype: bilateral, symmetric, nonsyndromic sensorineural hearing loss with no vestibular, visual, renal, or other systemic involvement.

Phenotype Type HPO term Characteristics / frequency
Sensorineural hearing impairment clinical sign HP:0000407 Defining feature, ~100% of affected
Bilateral sensorineural hearing impairment clinical sign HP:0008619 Bilateral, usually symmetric
Mid-frequency sensorineural hearing impairment ("cookie-bite"/U‑shaped audiogram) clinical sign HP:0410007 / HP:0008542 Typical of ZP‑domain variants (PMID 21520338, 37927186, 9763681)
High-frequency hearing impairment clinical sign HP:0000399 / HP:0008565 Typical of ZA‑domain variants (PMID 21520338, 24363064)
Congenital / prelingual sensorineural hearing impairment clinical sign HP:0008527 Many families prelingual/congenital (PMID 9763681)
Progressive sensorineural hearing impairment clinical sign HP:0000408 With cysteine‑substituting / ZA variants (PMID 21520338, 24363064)

Age of onset: congenital/prelingual to childhood; some late‑onset/progressive forms present in adulthood (PMID 9763681, 42379497). Severity: mild to severe (moderate‑to‑severe common); "moderate to severe... U-shaped form with maximum loss at 2,000 Hz" in the original DFNA8 family (PMID 9763681). Progression: frequently stable/nonprogressive for ZP non‑cysteine variants; progressive for cysteine‑substituting and ZA‑domain variants (PMID 21520338, 24363064). Frequency among affected: hearing loss is fully penetrant in most reported families; configuration/severity vary by genotype.

Quality-of-life impact: hearing loss impairs speech perception, communication, and (for prelingual cases) spoken‑language acquisition and education; early amplification mitigates these effects. No disease‑specific QoL instrument data (EQ‑5D/SF‑36) are available specifically for DFNA12; general SNHL QoL literature applies.

4. Genetic / Molecular Information

Causal gene: TECTA (α‑tectorin), 11q23.3; OMIM 602574; HGNC:11720; NCBI Gene 7007; UniProt O75443. Encodes a large secreted, GPI‑anchored (during trafficking) modular glycoprotein of 2155 aa with an entactin/nidogen‑G1‑like (NIDO) domain, three von Willebrand factor type D (vWFD1–3) repeats within a zonadhesin‑like (ZA) region, and a C‑terminal zona pellucida (ZP) domain (PMID 9590290, 21520338).

Pathogenic variants. - Variant type/class: predominantly missense in DFNA8/12; occasionally in‑frame/aberrant splice variants (e.g., c.5999G>A p.Gly2000Glu causing exon‑20 mis‑splicing; c.5383+6T>A causing exon‑16 skipping) (PMID 40583560). Truncating variants (nonsense/frameshift/splice/large deletions) instead cause recessive DFNB21 (PMID 17431902, 18022253, 9949200). - Distribution across domains: mutations occur in all domains — entactin/NIDO, vWFD1–3, D1–D2 and TIL2 connectors, and ZP (PMID 21520338). - Representative variants: p.Cys1509Gly (C1509G), p.Cys1619Ser (ZA), p.Leu1820Phe+Gly1824Asp and p.Cys1837Gly (ZP), p.Thr1866Met, p.Arg1890Cys, p.Cys1036Tyr, p.Val317Glu, near‑ZP c.6183G>T (PMID 20947814, 21520338, 24363064, 37927186). - Classification (ACMG/AMP): pathogenic/likely pathogenic when segregating and absent from controls; segregation analysis is often decisive for reclassifying VUS (e.g., c.6183G>T upgraded to likely pathogenic; PMID 37927186). - Allele frequency: pathogenic DFNA8/12 missense alleles are rare/absent in gnomAD and matched controls (PMID 20947814, 21520338). - Origin: germline; de novo cases possible but most are familial. Not somatic. - Functional consequence: dominant‑negative for DFNA8/12 missense alleles (mutant α‑tectorin incorporated into TM disrupts its assembly); loss‑of‑function for recessive DFNB21 alleles (PMID 9949200).

Modifier genes: the affected α‑tectorin domain is the dominant determinant of expressivity (PMID 21520338). Interacting TM proteins (β‑tectorin/TECTB, CEACAM16, OTOG/OTOGL, collagen II) could theoretically modify phenotype; CEACAM16 co‑immunoprecipitates with α‑tectorin and its mutation causes DFNA4 (PMID 21368133). No formal human modifier‑gene study for DFNA12.

Epigenetic information: none established for DFNA12.

Chromosomal abnormalities: point mutations, not aneuploidy/translocations. Large intragenic deletions (e.g., exon‑10 deletion) occur in the recessive form and require CNV‑aware analysis (PMID 17431902). Historically, TECTA haploinsufficiency was proposed to contribute to hearing loss in some Jacobsen‑syndrome (11q deletion) cases (PMID 9503015).

5. Environmental Information

DFNA12 is a purely genetic disorder; no environmental, lifestyle, or infectious agent causes it. Generic exacerbating exposures (loud noise, ototoxic aminoglycosides/cisplatin, aging) may additively worsen hearing, and mouse data indicate a defective tectorial membrane increases susceptibility to noise‑induced outer‑hair‑cell loss (model organism: PMID 21567249). No dietary/occupational protective or causal factors are established.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

  1. A heterozygous TECTA missense (or in‑frame splice) mutation alters a conserved residue in a specific α‑tectorin domain (entactin/NIDO, vWFD/ZA, or ZP) — results in a structurally abnormal α‑tectorin monomer (human genetics: PMID 9590290; splicing: PMID 40583560).
  2. The mutant α‑tectorin is secreted by cochlear supporting/interdental cells and incorporated into the assembling tectorial membrane, where it acts dominant‑negatively on α‑tectorin self‑assembly and its interactions with β‑tectorin and type II collagen (inferred from unaffected DFNB21 heterozygotes vs affected DFNA8/12 heterozygotes: PMID 9949200; TM assembly: PMID 26806019).
  3. This leads to a domain‑specific structural defect of the tectorial membrane — e.g., ZP‑domain mutations vs ZA‑domain mutations "generate distinctly different changes in the structure of the TM" (loss/disorganization of the striated‑sheet matrix, altered collagen crosslinking, shortening, or detachment) (model organism: PMID 24363064; PMID 25564867; PMID 26806019).
  4. Branch A (ZP domain): predominantly disrupts the mid/apical TM → mid‑frequency loss, often stable (PMID 21520338, 24363064).
  5. Branch B (ZA/zonadhesin domain or cysteine substitution): disrupts basal TM/covalent crosslinking → high‑frequency and/or progressive loss (PMID 21520338, 24363064).
  6. The abnormal TM results in defective mechanical coupling to the outer‑hair‑cell (OHC) stereocilia — e.g., a shortened TM contacts only the first OHC row and increases shear force on those stereocilia by ~50% (computational + model organism: PMID 21567249).
  7. This impairs the cochlear amplifier: the TM normally "ensures that outer hair cells can effectively respond to basilar membrane motion and that feedback is delivered with the appropriate gain and timing required for amplification"; when α‑tectorin is defective the cochlea is ~35 dB less sensitive (model organism: PMID 11087000).
  8. Loss of active amplification and frequency selectivity results in elevated auditory thresholds in the affected frequency band — clinically, bilateral sensorineural hearing loss (human: PMID 9763681, 37927186).
  9. Downstream/secondary (inferred): increased OHC vulnerability to noise and altered prestin expression may add a slowly progressive component in some genotypes (model organism: PMID 21567249).

Upstream vs downstream: upstream = mutant protein + TM matrix defect (primary lesion in an acellular extracellular matrix); downstream = OHC mechanotransduction/amplification failure and threshold elevation. The spiral ganglion/auditory nerve and hair‑cell bodies are largely preserved, which is therapeutically important (basis for good cochlear‑implant outcomes).

Molecular pathways / processes. This is primarily an extracellular‑matrix (ECM) assembly disorder rather than a classical signaling‑cascade disease. Relevant GO biological processes: sensory perception of sound (GO:0007605), detection of mechanical stimulus involved in sensory perception of sound (GO:0050910), inner ear morphogenesis (GO:0042472), extracellular matrix organization (GO:0030198), tectorial membrane development. Cellular component: extracellular matrix (GO:0031012) / tectorial membrane. No apoptosis/inflammation/immune or metabolic pathway is centrally implicated; late OHC loss (model) would proceed via mechanical stress rather than a defined death pathway.

Protein dysfunction. Structural (dominant‑negative) rather than enzymatic; α‑tectorin has no catalytic activity — it is a structural ECM glycoprotein. Cysteine substitutions disrupt disulfide‑mediated crosslinking, correlating with progressive phenotypes (PMID 21520338).

Immune involvement / metabolic / epigenetic: not implicated.

Cell types (CL): outer hair cell (CL:0000601), inner hair cell (CL:0000589), cochlear supporting/interdental cells (tectorin‑secreting).

Molecular profiling: no human transcriptomic/proteomic/metabolomic disease signatures reported; mechanistic data derive from mouse cochlear physiology, immunogold/freeze‑etch ultrastructure (PMID 26806019), and atomic‑force microscopy of TM mechanics (PMID 25564867).

7. Anatomical Structures Affected

  • Organ level: the inner ear (UBERON:0001846), specifically the cochlea (UBERON:0001844) — the auditory (nervous/special‑sense) system. No secondary organ involvement; vestibular function is spared (nonsyndromic).
  • Primary structure: the tectorial membrane (UBERON:0002233), an acellular ECM within the organ of Corti (UBERON:0002227), and its attachment to the spiral limbus (PMID 26806019).
  • Tissue/cell level: sensory epithelium of the organ of Corti; outer hair cells (CL:0000601) and inner hair cells (CL:0000589) are functionally affected via the abnormal overlying TM; tectorin‑secreting supporting/interdental cells produce the defective matrix.
  • Subcellular (GO‑CC): extracellular matrix (GO:0031012) / tectorial membrane; α‑tectorin is a secreted glycoprotein.
  • Localization / lateralization: bilateral, usually symmetric (HP:0008619).

8. Temporal Development

  • Onset: typically congenital/prelingual to early childhood; described as "congenital, nonprogressive" in the founder DFNA8 family (PMID 9763681). Some genotypes present later (adult/late‑onset), overlapping age‑related hearing loss (PMID 42379497).
  • Onset pattern: insidious/chronic (not acute).
  • Progression: stable/nonprogressive for many ZP non‑cysteine variants; slowly progressive for cysteine‑substituting and ZA‑domain variants (PMID 21520338, 24363064). Progression rate is slow when present.
  • Disease course: chronic, lifelong; not episodic/relapsing.
  • Remission: none spontaneously; only functional improvement with amplification/implantation.
  • Critical period: the window for spoken‑language acquisition in prelingual cases makes early identification (newborn screening) and early amplification essential.

9. Inheritance and Population

  • Inheritance: autosomal dominant (MONDO/OMIM 601543); recessive DFNB21 (OMIM 603629) at the same locus from biallelic LOF alleles (PMID 9949200).
  • Penetrance: generally high/complete in reported families (clear multigenerational segregation; e.g., 5‑generation pedigree, PMID 40583560).
  • Expressivity: variable and domain‑dependent (frequency band, severity, progression) (PMID 21520338, 24363064).
  • Genetic anticipation: none (not a repeat‑expansion disorder).
  • Germline mosaicism: not specifically documented; de novo variants possible.
  • Founder effects: confirmed for recurrent alleles — "four of them—p.Cys1036Tyr, p.Cys1837Gly, p.Thr1866Met, and p.Arg1890Cys—were observed in more than one unrelated family. For two of these mutations founder effects were also confirmed" (PMID 21520338).
  • Consanguinity: relevant to recessive DFNB21, not to dominant DFNA12.
  • Carrier frequency: pathogenic dominant alleles are rare; not a routine carrier‑screening target.
  • Epidemiology: no precise prevalence figure exists for DFNA12 specifically. Background: hearing impairment affects ~1 in 500 newborns, and ~80% of genetic hearing loss is nonsyndromic (PMID 25281338). DFNA8/12 is "the most identified subtype of nonsyndromic autosomal dominant hearing loss" (PMID 21520338) and a leading cause among molecularly solved adult‑onset dominant SNHL (top gene, 4/15 solved cases, PMID 36190904).
  • Population/geography: reported worldwide (Spanish, Belgian, English, Austrian, French, Korean, Chinese, Iranian, Croatian, etc.); no strong ethnic predilection; specific founder alleles are population‑enriched.
  • Sex ratio: ~1:1 (autosomal). Age distribution: all ages (onset childhood; diagnosis across the lifespan).

10. Diagnostics

  • Audiologic testing (clinical signs): pure‑tone audiometry (mid‑frequency "cookie‑bite"/U‑shaped or high‑frequency SNHL), tympanometry (normal middle ear), otoacoustic emissions and auditory brainstem response (ABR) — abnormal, consistent with cochlear/OHC dysfunction; newborn OAE/ABR screening detects congenital cases.
  • Laboratory/biomarkers: none; no blood/urine biomarker. Diagnosis is audiologic + genetic.
  • Imaging: temporal‑bone CT/MRI is typically normal (no malformation) — used to exclude structural/other causes.
  • Genetic testing (definitive): recommended approach is NGS. Comprehensive hearing‑loss gene panels or whole‑exome/whole‑genome sequencing including TECTA; single‑gene TECTA testing when the audiogram (mid‑frequency, dominant family history) is suggestive. CNV/deletion analysis needed to detect large intragenic deletions. Diagnostic yield of NGS panels/WES in bilateral SNHL is ~20–48% (PMID 38224868: "48% (50/105) of patients were genetically diagnosed"; PMID 36804529: 39.5%; adult SNHL 23% with TECTA the top gene, PMID 36190904). Karyotype/CMA/FISH/mtDNA/repeat‑expansion testing are not indicated for isolated DFNA12.
  • Clinical criteria: diagnosis = bilateral nonsyndromic SNHL + AD family history + a pathogenic/likely‑pathogenic heterozygous TECTA variant with segregation (ACMG/AMP).
  • Differential diagnosis: other mid‑frequency dominant SNHL genes (EYA4/DFNA10, COL11A2/DFNA13, CEACAM16/DFNA4, WFS1/DFNA6/14/38 [low‑frequency], DIAPH1, P2RX2/DFNA41, KCNQ4/DFNA2) (PMID 25809937, 36190904, 37041640); exclude GJB2/GJB6, syndromic causes, noise/ototoxic/age‑related loss.
  • Screening/cascade: newborn hearing screening; cascade genetic testing of at‑risk relatives once the familial variant is known.

11. Outcome / Prognosis

  • Survival/mortality: DFNA12 is not life‑limiting; normal life expectancy; no disease‑specific mortality.
  • Morbidity/disability: the burden is communication disability from bilateral SNHL; magnitude depends on severity/onset. For prelingual cases, untreated loss impairs language and educational attainment; early intervention markedly improves outcomes.
  • Disease course: chronic and lifelong; often stable (ZP) or slowly progressive (ZA/cysteine variants).
  • Recovery: no spontaneous recovery of hearing; functional recovery is achievable with hearing aids or cochlear implantation/EAS.
  • Prognostic factors: the affected α‑tectorin domain / variant type is the key prognostic marker for audiometric configuration and progression (PMID 21520338, 24363064); preserved neural elements predict good CI outcomes (PMID 24130743). Quality‑of‑life outcomes track with device benefit; no molecular prognostic biomarker beyond genotype.

12. Treatment

No pharmacological, gene, cell, RNA, or curative therapy exists for DFNA8/12. Management is auditory (re)habilitation, genotype‑informed.

  • Amplification (first‑line, mild–severe): hearing aids (NCIT: Hearing Aid) and assistive listening devices.
  • Cochlear implantation (severe–profound): effective; because the primary lesion is in the acellular TM with preserved spiral ganglion/auditory nerve, implantation restores useful hearing. TECTA patients "showed relatively good auditory performance with CI including EAS" (PMID 24130743). NCIT: Cochlear Implant (C50143).
  • Electric‑acoustic stimulation (EAS): appropriate where useful residual low‑frequency hearing remains (common with mid/high‑frequency‑predominant TECTA loss) (PMID 24130743).
  • Rehabilitation/supportive: speech‑language therapy, auditory training, educational support, sign‑language/communication options as chosen (NCIT: Speech Therapy; Auditory Rehabilitation).
  • Pharmacogenomics: not applicable.
  • Experimental/future: no DFNA12‑specific trials; general inner‑ear gene therapy / antisense (allele‑specific knockdown of a dominant‑negative allele) are conceptual future directions but not yet clinical for TECTA.
  • Treatment strategy: severity‑ and genotype‑guided algorithm — early amplification → CI/EAS if amplification insufficient → lifelong audiologic follow‑up. CHEBI drug entities: none applicable.

13. Prevention

  • Primary prevention: the disorder cannot be prevented in mutation carriers; genetic counseling (50% offspring risk per affected heterozygote) and reproductive options—preimplantation genetic testing (PGT‑M) or prenatal diagnosis when the familial variant is known—can prevent transmission.
  • Secondary prevention: universal newborn hearing screening (OAE/ABR) plus cascade genetic testing enables early diagnosis and early amplification during the critical language‑acquisition window.
  • Tertiary prevention: early/optimal amplification or implantation to prevent secondary language, educational, and psychosocial complications; avoid additive insults (noise protection, avoid ototoxic drugs), supported by mouse evidence of heightened noise vulnerability (PMID 21567249).
  • Counseling: genetic counseling per NSGC/ACMG; immunization/public‑health/environmental measures are not applicable to this genetic condition.

14. Other Species / Natural Disease

  • Taxonomy / orthologs: Mouse Mus musculus (NCBI Taxon 10090), gene Tecta (NCBI Gene 21683), on chromosome 9 (syntenic to human 11q; PMID 9503015). Orthologs exist in rat, zebrafish, and other vertebrates; α‑tectorin and the tectorial membrane are evolutionarily conserved across mammals.
  • Natural disease: no well‑characterized spontaneous companion‑animal or wildlife TECTA deafness is prominently reported in OMIA for DFNA12; the disease is studied via engineered mouse models rather than natural animal disease.
  • Comparative biology: the mouse faithfully models human TM biology; the genotype–phenotype correlation is conserved (ZP vs ZA domain → distinct TM defects and audiometric configurations; PMID 24363064). A species‑specific incidental finding is audiogenic seizure susceptibility in Tecta knock‑in mice, not seen in humans (PMID 24363064).
  • Transmission: not applicable (non‑infectious, non‑zoonotic).

15. Model Organisms

Primary model: mouse (mammalian). Faithful recapitulation of human DFNA8/12 mechanism and genotype–phenotype correlation.

  • Tecta knockout (targeted deletion): TMs detached from the cochlear epithelium, lacking all non‑collagenous matrix; basilar membrane still tuned but 35 dB less sensitive; abnormal cochlear microphonic phase/symmetry — established the TM's role in cochlear‑amplifier gain/timing (PMID 11087000). Models the recessive/LOF (DFNB21) situation and TM function.
  • Knock‑in point‑mutation lines (model dominant DFNA8/12): Tecta^L1820F,G1824D/+ and Tecta^C1837G/+ (ZP‑domain; stable and progressive mid‑frequency loss, respectively) and Tecta^C1619S/+ (ZA‑domain; progressive high‑frequency loss). "Mutations in the ZP and ZA domains generate distinctly different changes in the structure of the TM"; ABR thresholds elevated 30–40 dB (ZP) and 20–30 dB (ZA) over 8–40 kHz (PMID 24363064).
  • Tecta^C1509G/+: shortened TM contacting only the first OHC row, ~50% increased stereocilia shear force, increased noise vulnerability/OHC loss (PMID 21567249).
  • Tecta/Tectb double mutant: fully detached TM; used to show ECM regulation of OHC Ca²⁺, MET currents, and otoacoustic emissions (PMID 33559882).

Model characteristics. Strengths: reproduce domain‑specific TM ultrastructural defects, threshold elevations, and stability/progression matching human genotypes; enable cochlear micromechanics, OAE/ABR, and AFM studies. Limitations: murine hearing frequency range differs from human; incidental audiogenic seizures; long‑term human progression not fully captured. Resources: MGI (Tecta), IMPC/IMSR for strain availability.

Supported and Refuted Hypotheses

Supported: - H1: DFNA12 is caused by heterozygous (mostly missense) TECTA mutations — supported (PMID 9590290, 21520338). - H2: The affected α‑tectorin domain predicts audiometric phenotype/progression — supported in humans and mice (PMID 21520338, 24363064). - H3: DFNA8/12 missense alleles act by a dominant‑negative mechanism (vs LOF recessive DFNB21) — supported (PMID 9949200). - H4: The tectorial‑membrane defect impairs cochlear amplification, elevating thresholds — supported (PMID 11087000, 21567249). - H5: Neural elements are preserved, enabling good CI/EAS outcomes — supported (PMID 24130743).

Refuted / not supported: - That TECTA haploinsufficiency alone causes dominant deafness — refuted for the classic form (heterozygous LOF carriers are unaffected; dominance requires a dominant‑negative missense allele) (PMID 9949200). - That DFNA12 involves vestibular, systemic, immune, or metabolic dysfunction — not supported (strictly nonsyndromic/cochlear).

Limitations and Future Directions

  • Epidemiology: no precise prevalence/incidence for DFNA12 specifically; figures are inferred from ADNSHL cohorts.
  • Omics: no human transcriptomic/proteomic/metabolomic disease signatures; mechanism rests on mouse physiology and ultrastructure.
  • Penetrance/modifiers: quantitative penetrance and formal modifier‑gene studies are lacking.
  • Therapeutics: no molecular therapy; allele‑specific silencing or gene‑editing of dominant‑negative alleles and inner‑ear gene therapy are logical but unproven future directions.
  • Human structural biology: no experimental α‑tectorin structure; AlphaFold models (UniProt O75443) could refine variant‑effect prediction.

Key References (PMID)

9590290 (gene discovery); 9763681, 9503015 (locus mapping); 21520338 (mutation spectrum & genotype–phenotype/founder effects); 24363064 (three knock‑in mouse models); 11087000 (Tecta KO – cochlear amplification); 21567249 (C1509G shortened TM mechanics); 26806019 (TM assembly/crosslinking); 33559882 (Tecta/Tectb detached TM); 25564867 (TM striated‑sheet mechanics); 9949200 (dominant‑negative vs DFNB21 LOF); 17431902, 18022253, 27368438, 28012541 (DFNB21 LOF alleles); 20947814, 37927186, 40583560 (human variants/segregation/splicing); 21368133 (CEACAM16–α‑tectorin/DFNA4); 36190904, 38224868, 36804529, 24130743 (diagnostics & CI/EAS); 25281338, 42379497 (epidemiology/ARHL context); 25809937 (mid‑frequency SNHL differential).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 23
Resolved 23
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 3
Quoted claims found in source 3
Quoted claims not found in source 0
References weighed for topical relevance 23
On topic 16
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 20
Resolved 17
Unresolved (possible confabulation) 1
Obsolete 1
Unverifiable 1
Terms whose name was checked 6
Terms named correctly 0
Terms named as a different term 4
Terms whose name is worth a second look 2

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:

  • HP:0000407 (1 mention) - the report calls it "clinical sign"; HP calls it Sensorineural hearing impairment
  • HP:0008619 (2 mentions) - the report calls it "clinical sign", "Localization / lateralization: bilateral, usually symmetric"; HP calls it Bilateral sensorineural hearing impairment**
  • HP:0008527 (1 mention) - the report calls it "clinical sign"; HP calls it Congenital sensorineural hearing impairment
  • HP:0000408 (1 mention) - the report calls it "clinical sign"; HP calls it Progressive sensorineural hearing impairment

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

  • HP:0008565 (1 mention) - HP does not contain this term

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • HP:0410007 (obsolete Abnormality of cartilage morphology) (1 mention) - replaced by HP:0002763

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:

  • UBERON:0001846 (1 mention) - the report calls it "Organ level: the inner ear"; UBERON calls it internal ear, and lists "inner ear" among its other names
  • UBERON:0002233 (1 mention) - the report calls it "Primary structure: the tectorial membrane"; UBERON calls it tectorial membrane of cochlea, and lists "tectorial membrane" among its other names

Terms named inconsistently

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

  • HP:0008619 - called "clinical sign", "Localization / lateralization: bilateral**, usually symmetric"