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Inheritance

1

Autosomal dominant HP:0000006

Autosomal dominant transmission with age-dependent penetrance. Each child of a heterozygous affected individual has a 50% chance of inheriting the variant; this is not a 50% probability of hearing loss at a specified age. Earlier reported onset in males and a maternal-versus-paternal haplotype pattern arose in one pre-gene-mapping kindred and remain unreplicated modifier hypotheses. Normal hearing at one assessment does not exclude carrier status. Four tested mitochondrial variants were absent, which does not exclude all mitochondrial effects.

Autosomal dominant inheritance

Show evidence (4 references)

PMID:12925340 SUPPORT Human clinical

"The mode of inheritance is autosomal dominant with age-dependent penetrance."

Inheritance mode and the penetrance qualifier together.

PMID:12925340 SUPPORT Human clinical

"In those inheriting the DFNA25-associated haplotype from an affected mother, hearing loss invariably developed by the second decade of life, whereas those inheriting the DFNA25 haplotype from an affected father often maintained hearing levels comparable to those of age-matched control subjects,..."

The parent-of-origin observation, quoted in full so the size and source of the claim travel with it.

PMID:12925340 SUPPORT Human clinical

"None of 4 deafness-associated mitochondrial mutations screened (1555A>G, 7445A>G, Cins7472, and 7511T>C) were found to segregate in the family."

Only the four tested mitochondrial variants were excluded; the study did not sequence the mitochondrial genome or establish the cause of the parent-of-origin pattern.

+ 1 more reference

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Mechanistic Hypotheses

2

Presynaptic vesicular glutamate loading failure

presynaptic_glutamate_loading_failure CANONICAL

VGLUT3 deficiency prevents vesicular glutamate loading and auditory afferent activation in homozygous null mice despite preserved vesicle fusion and cochlear amplification. This is an established null-model mechanism and a candidate contributor to human SLC17A8 disease. It does not establish haploinsufficiency or uniform transport loss for dominant variants: A211V retains transport in tested heterologous systems, and human onset and severity vary.

Pathograph links

Altered VGLUT3 Function in the Inner Hair Cell -> Impaired Glutamate Release at the Inner Hair Cell Ribbon Synapse DIRECT The direct consequence of an unfilled vesicle, and the route the null mouse takes.

Impaired Glutamate Release at the Inner Hair Cell Ribbon Synapse -> Failure of Auditory Nerve Activation with Preserved Cochlear Amplification DIRECT An afferent terminal that receives no transmitter does not fire, however well the cochlea in front of it is working.

Stereociliary mechanotransduction failure preceding synaptic change

a211v_mechanotransduction_first EMERGING

Homozygous A224V mice develop inner hair cell stereocilia disruption and reduced summating potentials before marked ribbon enlargement and increased sustained exocytosis. This supports a mechanotransduction-first hypothesis in that model. Temporal order does not establish that the bundle lesion causes the synaptic changes, and the dominant human mechanism remains unconfirmed.

Pathograph links

Altered VGLUT3 Function in the Inner Hair Cell -> Inner Hair Cell Stereocilia Bundle Disruption INDIRECT UNKNOWN INTERMEDIATES The route the allele-matched knock-in mouse takes. It is marked INDIRECT because no mechanism connecting an altered vesicular transporter to hair-bundle architecture has been demonstrated; the knock-in shows the bundles collapse, not why.

Altered VGLUT3 Function in the Inner Hair Cell -> Synaptic Ribbon Enlargement INDIRECT UNKNOWN INTERMEDIATES The A224V genotype is associated with this later synaptic alteration; the intermediates and relationship to the early bundle defect remain unresolved.

Altered VGLUT3 Function in the Inner Hair Cell -> Increased Sustained Inner Hair Cell Exocytosis INDIRECT UNKNOWN INTERMEDIATES The A224V genotype is associated with this later synaptic alteration; the intermediates and relationship to the early bundle defect remain unresolved.

Inner Hair Cell Stereocilia Bundle Disruption -> Reduced Inner Hair Cell Receptor Potential DIRECT Bundle disruption and reduced summating potential support a mechanotransduction defect in the same homozygous model; direct mechanotransducer-current impairment was not measured.

Reduced Inner Hair Cell Receptor Potential -> Failure of Auditory Nerve Activation with Preserved Cochlear Amplification DIRECT Reduced inner hair cell receptor potential is proposed to reduce afferent drive. The model shows reduced summating and compound action potentials, but does not directly quantify sound-evoked glutamate release.

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Discussions and Knowledge Gaps

4

Does either mouse model DFNA25, when both are homozygous and the heterozygote - the genotype a patient actually has - is only mildly affected?

HUMAN MODEL MISMATCH OPEN mismatch_zygosity_of_the_dfna25_mouse_models

Attached to

pathophysiology#Heterozygous SLC17A8 Variant animal_models#VGLUT3 A224V knock-in mouse

Homozygous knock-in mice have progressive impairment but heterozygotes have only mild changes over six months. Lifespan, allele dose, genetic background and species-specific biology may contribute. Null rescue does not select the optimal strategy for dominant human alleles.

Proposed experiments

Lifespan-long auditory phenotyping of heterozygous VGLUT3 A224V mice

dfna25_aged_heterozygous_knockin

Follow heterozygous A224V and wild-type littermates across age with serial ABR, emissions and bundle morphology, accounting for background-related hearing loss.

Would support

pathophysiology#Heterozygous SLC17A8 Variant

Supporting outcome

A widening deficit would support age-dependent expression in this mouse model, without proving that homozygous pathology transfers to humans.

Refuting outcome

A plateau would argue against continued progression under the tested conditions; it would not establish universal tolerance of one allele.

How representative is the absent-emission finding in the original DFNA25 proband?

KNOWLEDGE GAP OPEN gap_why_patient_emissions_are_absent

Attached to

phenotypes#Absent Otoacoustic Emissions mechanistic_hypotheses#presynaptic_glutamate_loading_failure

The detailed primary human observation concerns one proband, while both main mouse models retain emissions. Broader human OAE, cochlear microphonic, ABR, age and exposure data are needed to separate cochlear and neural contributions. Controlled mouse noise experiments can test model susceptibility but cannot establish the cause of human findings.

Proposed experiments

Noise vulnerability in mice carrying one or two VGLUT3-p.A224V alleles

dfna25_noise_vulnerability_by_allele_dose

Expose wild-type, heterozygous and homozygous A224V mice to a controlled acoustic overexposure and compare distortion-product emission loss and threshold shift against unexposed littermates. This is the experiment the knock-in authors name as necessary to determine whether acoustic injury accounts for the discrepancy between mouse and patient emissions.

Would support

phenotypes#Absent Otoacoustic Emissions

Supporting outcome

Greater emission loss after controlled noise would support genotype-dependent susceptibility in mice and motivate human exposure studies.

Refuting outcome

No genotype difference would weaken this model-specific noise hypothesis under the tested exposure; it would not resolve human auditory-neuropathy classification.

How does a vesicular glutamate transporter variant collapse the inner hair cell stereocilia bundle?

KNOWLEDGE GAP OPEN gap_where_the_dfna25_lesion_starts

Attached to

mechanistic_hypotheses#presynaptic_glutamate_loading_failure mechanistic_hypotheses#a211v_mechanotransduction_first

A224V mice show bundle collapse despite retained transport in heterologous systems and comparable cochlear VGLUT3 immunofluorescence. Proteostasis, trafficking and the Cdh23 background remain candidate contributors. Identifying the mechanism could guide therapy, but a gene-directed intervention might affect both bundle and synaptic consequences.

Proposed experiments

Subcellular localisation and turnover of VGLUT3-p.A224V in inner hair cells

dfna25_vglut3_localisation_in_knockin_hair_cells

Track variant VGLUT3 in knock-in inner hair cells by immunogold electron microscopy and pulse-chase, testing directly whether it accumulates in the soma or apical compartment, whether proteostasis markers are engaged, and whether the cuticular plate cytoskeleton is disturbed before the bundles collapse.

Would support

mechanistic_hypotheses#a211v_mechanotransduction_first

Supporting outcome

Accumulation and proteostasis changes preceding bundle collapse would support this candidate mechanism; perturbation and rescue would be needed to test causation.

Refuting outcome

Normal localization and turnover would weaken this mechanism without excluding other allele-dependent or background effects.

Do the truncating and splice SLC17A8 alleles cause the same disease as the missense founder allele?

KNOWLEDGE GAP OPEN gap_dfna25_allele_class_heterogeneity

Attached to

genetic#SLC17A8

Missense, frameshift and splice alleles have unequal human and functional evidence. The frameshift and c.824C>A expression study retested reported alleles. Allelic heterogeneity does not by itself justify splitting a disease, and a normal heterozygous-null mouse does not resolve the human dominant mechanism.

Proposed experiments

Audiometric comparison of missense against truncating SLC17A8 carriers

dfna25_allele_class_audiogram_comparison

Collect audiograms and ages at onset across all published SLC17A8 heterozygotes and compare the founder missense families against the frameshift and splice-donor families, testing whether onset, progression rate and audiometric shape differ by allele class.

Would support

genetic#SLC17A8

Supporting outcome

Overlapping profiles would support shared clinical features without proving a shared molecular mechanism.

Refuting outcome

Reproducible differences would support allele-specific prognosis and further mechanistic work, without by themselves requiring separate disease entities.

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Pathophysiology

9

Heterozygous SLC17A8 Variant

The founding c.632C>T (p.A211V) variant segregated in two families with evidence of distant shared ancestry and was absent from 267 controls. Later reports include c.616dupA (p.M206Nfs*4) and c.763+1G>T. The 2016 frameshift report sequenced one proband from an affected pedigree; it did not demonstrate segregation across all eight affected relatives. Predicted truncation and splice disruption do not establish a shared dominant mechanism.

Genetic context SLC17A8 hgnc:20151 variant_origin: GERMLINE zygosity: HETEROZYGOUS

Reported disease-associated alleles are heterozygous. The entry does not assign one functional-impact category across missense, frameshift and splice variants: human dominance and normal heterozygous-null mouse hearing do not by themselves distinguish dosage loss, dominant-negative effects or other mechanisms.

Downstream

Altered VGLUT3 Function in the Inner Hair Cell Every proposed mechanism for this disease runs through the transporter that the variant sits in.

Show evidence (4 references)

PMID:18674745 SUPPORT Human clinical

"In two unrelated families, a heterozygous missense mutation, c.632C-->T (p.A211V), was found to segregate with DFNA25 deafness and was not present in 267 controls."

The founding allele, its zygosity, its segregation and its control screening.

PMID:18674745 SUPPORT Human clinical

"The A211 residue is conserved in VGLUT3 across species and in all human VGLUT subtypes (VGLUT1-3), suggesting an important functional role."

The conservation argument the founding paper rests the missense call on.

PMID:26797701 SUPPORT Human clinical

"The novel frameshift mutation, p.M206Nfs*4, in which methionine is changed to asparagine at amino acid position 206, resulted in a termination codon at amino acid position 209."

The 2016 report identified a frameshift in one sequenced proband and predicted truncation; it did not show cosegregation in all affected relatives.

+ 1 more reference

Altered VGLUT3 Function in the Inner Hair Cell

VGLUT3 supports glutamate loading into inner hair cell synaptic vesicles. Null mice lack functional auditory afferent transmission, but human A211V does not abolish uptake or quantal signaling in tested heterologous/autaptic preparations. Central-terminal protein reduction in the knock-in cannot be assumed in cochlear cells: the 2021 study found comparable inner hair cell VGLUT3 immunofluorescence and distribution between genotypes. Variant-specific effects therefore remain important.

Presynaptic vesicular glutamate loading failure Stereociliary mechanotransduction failure preceding synaptic change

cochlear inner hair cell CL:0000589

glutamate loading into inner hair cell synaptic vesicles GO:0098700

vesicular L-glutamate transport by VGLUT3 GO:0005313

inner hair cell synaptic vesicle GO:0008021

Downstream

Impaired Glutamate Release at the Inner Hair Cell Ribbon Synapse The direct consequence of an unfilled vesicle, and the route the null mouse takes.

Inner Hair Cell Stereocilia Bundle Disruption The route the allele-matched knock-in mouse takes. It is marked INDIRECT because no mechanism connecting an altered vesicular transporter to hair-bundle architecture has been demonstrated; the knock-in shows the bundles collapse, not why.

Synaptic Ribbon Enlargement The A224V genotype is associated with this later synaptic alteration; the intermediates and relationship to the early bundle defect remain unresolved.

Increased Sustained Inner Hair Cell Exocytosis The A224V genotype is associated with this later synaptic alteration; the intermediates and relationship to the early bundle defect remain unresolved.

Show evidence (4 references)

PMID:18674745 SUPPORT Model organism

"In the cochlea, VGLUT3 accumulates glutamate in the synaptic vesicles of the sensory inner hair cells (IHCs) before releasing it onto receptors of auditory-nerve terminals."

The normal function of the protein, which is what the disease removes or alters.

PMID:26797701 SUPPORT BACKGROUND Other

"among its isoforms (VGLUT1-3), only VGLUT3 is expressed selectively in the inner hair cells (IHCs)"

Inner hair cell expression provides a basis for nonredundant cochlear function. It does not explain the absence of extra-auditory findings in every carrier.

PMID:34783032 SUPPORT INDIRECT BACKGROUND In vitro / ex vivo

"This variation does not impair the glutamate vesicular accumulation, neither the quantal release nor the quantal content in hippocampal autaptic neurons"

A negative result at the level of transport itself, which is why this entry does not assert that the human missense allele simply stops glutamate loading. Graded IN_VITRO because the measurement is in cultured autaptic neurons.

+ 1 more reference

Impaired Glutamate Release at the Inner Hair Cell Ribbon Synapse

In the Ruel Slc17a8-null line, calcium-triggered vesicle turnover was preserved at two weeks and surviving ribbons had a normal ultrastructural appearance at three months, while auditory afferent signaling failed. Other null-model studies reported thin or elongated ribbons. The findings differ by study and preparation; they do not establish universally normal ribbon morphology or uniform transport loss in dominant human variants.

Presynaptic vesicular glutamate loading failure

cochlear inner hair cell CL:0000589

glutamate secretion at the inner hair cell afferent synapse GO:0014047 ↓ DECREASED

Animal models

Slc17a8 null mouse Mouse recapitulates The release failure and its localisation to vesicle content rather than fusion, both measured directly in the correct cell type.

Downstream

Failure of Auditory Nerve Activation with Preserved Cochlear Amplification An afferent terminal that receives no transmitter does not fire, however well the cochlea in front of it is working.

Show evidence (3 references)

PMID:18215623 SUPPORT Model organism

"We now report that mice lacking VGLUT3 are profoundly deaf due to the absence of glutamate release from hair cells at the first synapse in the auditory pathway."

The release failure stated directly, and its location at the first auditory synapse.

PMID:18674745 SUPPORT In vitro / ex vivo

"Ca(2+)-triggered synaptic-vesicle turnover was normal in IHCs of Slc17a8 null mice when probed by membrane capacitance measurements at 2 weeks of age."

The deliberate negative result that localises the defect to vesicle content rather than to exocytosis. Without it the node would be indistinguishable from a fusion defect.

PMID:18674745 SUPPORT Model organism

"We conclude that deafness in Slc17a8-deficient mice is due to a specific defect of vesicular glutamate uptake and release and that VGLUT3 is essential for auditory coding at the IHC synapse."

The founding paper's own conclusion about the null animal.

Inner Hair Cell Stereocilia Bundle Disruption

Homozygous A224V mice show progressive inner hair cell bundle fusion and collapse with relative preservation of outer hair cell bundles. VGLUT3 is not localized to stereocilia, and the molecular connection is unresolved. Protein misfolding/trafficking effects and interaction with the C57BL/6J Cdh23 background are hypotheses. Comparable inner hair cell immunofluorescence argues against gross protein accumulation but cannot exclude altered turnover or proteostasis.

Stereociliary mechanotransduction failure preceding synaptic change

cochlear inner hair cell CL:0000589

inner hair cell stereocilium bundle organization GO:0060122 ↓ DECREASED

Animal models

VGLUT3 A224V knock-in mouse Mouse recapitulates Collapse and fusion of the inner hair cell stereocilia bundles, with outer hair cell bundles spared - the model's primary structural finding.

Downstream

Reduced Inner Hair Cell Receptor Potential Bundle disruption and reduced summating potential support a mechanotransduction defect in the same homozygous model; direct mechanotransducer-current impairment was not measured.

Show evidence (1 reference)

PMID:34783032 SUPPORT Model organism

"Scanning electron microscopy examinations demonstrated the collapse of stereocilia bundles in IHCs, leaving those from outer hair cells unaffected."

The bundle finding and its restriction to inner hair cells.

Reduced Inner Hair Cell Receptor Potential

The summating potential is the gross cochlear correlate of the inner hair cell receptor potential, and it is reduced in the knock-in mouse. Because cochlear amplification is intact in the same animals, a smaller receptor potential is being generated from a normal mechanical input - which is what a transduction defect in the inner hair cell looks like from outside.

Stereociliary mechanotransduction failure preceding synaptic change

cochlear inner hair cell CL:0000589

mechanotransduction in the inner hair cell hair bundle GO:0050910 ↓ DECREASED

Animal models

VGLUT3 A224V knock-in mouse Mouse recapitulates The functional counterpart of the bundle collapse, measured as a reduced summating potential in an animal whose cochlear amplifier is intact.

Downstream

Failure of Auditory Nerve Activation with Preserved Cochlear Amplification Reduced inner hair cell receptor potential is proposed to reduce afferent drive. The model shows reduced summating and compound action potentials, but does not directly quantify sound-evoked glutamate release.

Show evidence (2 references)

PMID:34783032 SUPPORT Model organism

"The summating potential was reduced, indicating the alteration of inner hair cell (IHC) receptor potential."

The measurement and the authors' own interpretation of it.

PMID:34783032 SUPPORT Model organism

"These results suggest that DFNA25 stems from a failure in the mechano-transduction followed by a change in synaptic transfer."

The ordering claim that this hypothesis group is built on, stated by the authors as a suggestion rather than a demonstration - which is why the group is EMERGING.

Synaptic Ribbon Enlargement

Homozygous A224V inner hair cell ribbons enlarge markedly at four to six months, with preserved ribbon and synapse counts in the sampled region. This structural change follows early bundle abnormalities. Its causal contribution to hearing loss, including whether it is compensatory, remains unresolved.

cochlear inner hair cell CL:0000589

Animal models

VGLUT3 A224V knock-in mouse Mouse recapitulates Ribbon enlargement at four to six months in the homozygous knock-in.

Show evidence (1 reference)

PMID:34783032 SUPPORT DIRECT PRIMARY RESULT Model organism

"However, synaptic ribbons became abnormally elongated in knock‐in mice"

Mouse cochlear imaging supports ribbon enlargement, not a measured increase in glutamate secretion.

Increased Sustained Inner Hair Cell Exocytosis

At six months, freshly dissected homozygous A224V inner hair cells show increased sustained exocytic capacitance responses to long depolarizations, with preserved calcium currents and readily releasable pool responses. Capacitance measures membrane fusion rather than vesicular glutamate content or afferent neurotransmission. The change may reflect compensation or extrasynaptic release; it is not established as a cause of hearing loss.

cochlear inner hair cell CL:0000589

Animal models

VGLUT3 A224V knock-in mouse Mouse recapitulates Increased sustained exocytic capacitance response at six months.

Show evidence (1 reference)

PMID:34783032 SUPPORT DIRECT PRIMARY RESULT In vitro / ex vivo

"patch-clamp membrane capacitance measurements showed an increase in the rate of the sustained releasable pool exocytosis"

Ex-vivo patch-clamp measurements in isolated mouse organs of Corti; membrane fusion does not determine glutamate quantal content.

Failure of Auditory Nerve Activation with Preserved Cochlear Amplification

Slc17a8-null mice lack sound-evoked auditory responses while retaining otoacoustic emissions and electrically evoked brainstem responses. Homozygous A224V mice show progressive auditory threshold elevation with preserved emissions. Human otoacoustic-emission data are sparse and differ from these model findings; this node records experimental physiology rather than a universal human diagnostic signature.

type 1 spiral ganglion neuron CL:4023115 cochlear outer hair cell CL:0000601

sensory perception of sound GO:0007605 ↓ DECREASED

organ of Corti UBERON:0002227

Animal models

Slc17a8 null mouse Mouse recapitulates The three-way dissociation - no acoustic neural response, intact emissions, intact electrically evoked brainstem response - measured in one animal.

Downstream

Secondary Deafferentation of the Inner Hair Cell Loss of afferent signaling and later deafferentation occur in null mice; glutamate also has developmental effects, so this is not established as a direct use-dependent degeneration mechanism in humans.

Progressive High-Frequency Sensorineural Hearing Loss Impaired afferent sound encoding provides a model-based explanation for hearing loss. The progressive human course is not reproduced by the congenitally deaf null model.

Show evidence (2 references)

PMID:18674745 SUPPORT Model organism

"Null mice with a targeted deletion of Slc17a8 exon 2 lacked auditory-nerve responses to acoustic stimuli, although auditory brainstem responses could be elicited by electrical stimuli, and robust otoacoustic emissions were recorded."

All three halves of the dissociation in one sentence: no acoustic neural response, preserved electrical response, preserved emissions.

PMID:34783032 SUPPORT Model organism

"Using auditory brainstem response and distortion product otoacoustic emissions, we showed progressive hearing loss with intact cochlear amplification in the VGLUT3A224V/A224V mouse."

The same dissociation in the allele-matched model, and in progressive rather than congenital form.

Secondary Deafferentation of the Inner Hair Cell

Null mice show loss of afferent synapses, spiral ganglion neurons and lateral efferent endings; some neuronal loss precedes hearing onset. Older null cochleae also show inner hair cell and stereocilia degeneration. These observations raise questions about treatment timing, but do not define a human therapeutic window. Rescue studies in post-neonatal null mice remain distinct from dominant human disease.

spiral ganglion neuron CL:0011113

Animal models

Slc17a8 null mouse Mouse recapitulates The afferent synapses, spiral ganglion neurons and lateral efferent endings decline after the functional deficit is established.

Downstream

Progressive High-Frequency Sensorineural Hearing Loss Reduced afferent innervation may contribute to sustained hearing impairment in null models; its contribution and reversibility in human DFNA25 are unknown.

Show evidence (3 references)

PMID:18674745 SUPPORT Model organism

"Later, the number of afferent synapses, spiral ganglion neurons, and lateral efferent endings below sensory IHCs declined."

The deafferentation itself, and its late timing relative to the functional deficit.

PMID:18215623 SUPPORT Model organism

"The early degeneration of some cochlear ganglion neurons in knockout mice also indicates an important developmental role for the glutamate released by hair cells before the onset of hearing."

The developmental component, which is a different claim from use-dependent loss and is the reason a congenital null and an adult-onset human disease may diverge here.

PMID:40841774 SUPPORT Model organism

"In this study, we analyzed the cochlear structure of aged Vglut3KO mice, revealing significant degeneration of inner hair cells, synapses, and stereocilia."

The structural endpoint in the aged null animal.

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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

4

Ear 3

Progressive High-Frequency Sensorineural Hearing Loss High-frequency sensorineural hearing impairment HP:0001757

Course: PROGRESSIVE

Show evidence (2 references)

PMID:11115382 SUPPORT Human clinical

"we identified a novel dominant locus, DFNA25, for delayed-onset, progressive, high-frequency, nonsyndromic sensorineural hearing loss in a large, multigenerational United States family of Czech descent."

The phenotype as defined at the locus, in the founding kindred.

PMID:18674745 SUPPORT Human clinical

"We have identified SLC17A8, which encodes the vesicular glutamate transporter-3 (VGLUT3), as the gene responsible for DFNA25, an autosomal-dominant form of progressive, high-frequency nonsyndromic deafness."

The same phenotype restated once the gene was in hand.

Postlingual Delayed Onset Postlingual sensorineural hearing impairment HP:0008596

Show evidence (2 references)

PMID:12925340 SUPPORT Human clinical

"Affected individuals typically manifest a high-frequency, slowly progressive sensorineural hearing loss in the postlingual period."

The abstract explicitly says typically. The primary full text documents an early-onset exception; normal hearing through speech acquisition is not universal.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT INDIRECT REVIEW SYNTHESIS Other

"In general, autosomal dominant nonsyndromic hearing loss is postlingual, progressive, and high frequency."

General clinical baseline, not a SLC17A8-specific age distribution or exclusion of congenital presentations.

Absent Otoacoustic Emissions HP:6000182

Show evidence (1 reference)

PMID:34783032 SUPPORT INDIRECT BACKGROUND Human clinical

"In contrast, otoacoustic emissions were absent in patients harbouring the p.A211V allele"

Secondary discussion of the 2003 human study. Inspection of that primary full text limits the detailed OAE/ABR observation to the proband; the plural wording is not evidence for prevalence or a universal classification.

Other 1

Absence of Syndromic Features

Show evidence (1 reference)

PMID:28647561 SUPPORT Human clinical

"the clinical information about this family revealed that there are no other symptoms accompanied with HL"

The nonsyndromic statement in a reported dominant family.

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Genetic Associations

1

SLC17A8

Gene: SLC17A8 hgnc:20151 relationship_type: CAUSATIVE

Show evidence (2 references)

CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z SUPPORT Other

"Variants in this gene segregated with disease in 28 additional members in two families"

The segregation evidence behind the Definitive classification.

CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z SUPPORT Other

"In summary, SCL17A8 is definitively associated with autosomal dominant nonsyndromic hearing loss."

The panel's summary sentence. The gene symbol is transposed in the source record and is quoted as written.

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External Assertions

1

ClinGen SLC17A8-nonsyndromic hearing loss gene-disease validity assertion

ClinGen gene disease validity CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z

The ClinGen Hearing Loss Gene Curation Expert Panel raised the SLC17A8-autosomal dominant nonsyndromic hearing loss relationship from Strong in 2018 to Definitive in June 2023. Its assessment included at least eight variants in nine probands and segregation in 28 additional relatives. These are counts in that dated evidence assessment, not worldwide case totals or prevalence estimates.

Show evidence (3 references)

CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z SUPPORT Other

The expert-panel classification row itself, with gene, disease, inheritance mode and verdict.

CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z SUPPORT Other

"At least 8 unique variants (missense, frameshift, splice site) have been reported in humans in 9 probands"

Counts in the June 2023 ClinGen assessment, not current worldwide totals or a prevalence denominator.

CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z SUPPORT Other

"As a result of this reevaluation, the classification increased from Strong to Definitive due to additional case level evidence"

The expert panel upgraded the relationship from Strong to Definitive in 2023.

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Medical Actions

5

Hearing Aids

Action: hearing aid fitting Ontology label: Rehabilitation NCIT:C15315

Platform: Device

Offer audiologist-fitted amplification and communication support according to hearing thresholds, speech testing and individual preferences. This follows general genetic hearing-loss care; genotype-specific benefit cannot be predicted from the null mouse or an isolated OAE finding.

Show evidence (1 reference)

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-aid guidance, not a DFNA25 outcome estimate.

Cochlear Implantation

Action: cochlear device implantation Ontology label: Surgical Procedure NCIT:C15329

Platform: Device

Consider cochlear implantation under standard audiologic candidacy assessment when amplification provides insufficient benefit. Preserved electrically evoked responses in null mice provide mechanistic plausibility, but do not establish human DFNA25 implant efficacy or guarantee preservation of the neural target.

Mechanism Target:

BYPASSES Failure of Auditory Nerve Activation with Preserved Cochlear Amplification — Direct electrical stimulation of the spiral ganglion substitutes for the defective inner hair cell synapse.

Show evidence (1 reference)

PMID:18674745 SUPPORT Model organism

"although auditory brainstem responses could be elicited by electrical stimuli"

The preserved electrical responsiveness that an implant would exploit. Model evidence for a human intervention, so the claim in the description is plausibility rather than efficacy.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Habilitation for hearing loss includes improved access to sound through hearing aids or cochlear implants"

General habilitation options; no SLC17A8-specific outcome is asserted.

AAV-mediated VGLUT3 Gene Replacement

Action: gene therapy Ontology label: Gene Therapy NCIT:C15238

Platform: Gene therapy

Preclinical gene replacement has restored auditory responses in homozygous null mice after neonatal cochlear AAV1 delivery, adult intracisternal delivery through the cochlear aqueduct, and AAV8 injection at five weeks with assessment 27 weeks later. The latter does not demonstrate reversal after treatment of already aged animals. These interventions have not established efficacy in dominant A211V disease; augmentation, suppression or combined strategies require variant-specific testing. No human SLC17A8 interventional study was identified in the reviewed research; the registered NCT01802190 study is observational.

Mechanism Target:

RESTORES Altered VGLUT3 Function in the Inner Hair Cell — Restoring VGLUT3 protein to the inner hair cell addresses the molecular lesion rather than its consequences - in an animal that has none of the protein to begin with.

Show evidence (2 references)

PMID:22841313 SUPPORT Model organism

"Within 2 weeks of AAV1-VGLUT3 delivery, auditory brainstem response (ABR) thresholds normalize, along with partial rescue of the startle response."

The functional rescue, in the null mouse.

PMID:40841774 SUPPORT Model organism

"Auditory brainstem response (ABR) testing demonstrated restoration of auditory function following gene therapy."

Mice were injected at five weeks and evaluated 27 weeks later, so the aged endpoint does not establish efficacy when treatment starts in aged animals.

Show evidence (2 references)

PMID:22841313 SUPPORT Model organism

"These findings represent a successful restoration of hearing by gene replacement in mice, which is a significant advance toward gene therapy of human deafness."

The authors' own framing of how far the result reaches - toward human therapy, not to it.

DOI:10.1126/scitranslmed.abq3916 SUPPORT DIRECT PRIMARY RESULT Model organism

"rescued hearing in adult deaf Slc17A8 −/− mice by restoring VGLUT3 protein expression in inner hair cells"

Primary 2023 adult-null-mouse rescue supporting the CSF-delivery theme in the research report.

Audiologic surveillance and noise protection

Follow hearing serially and adjust rehabilitation as needed. Avoid repeated loud-noise overexposure using general hearing-loss guidance. No SLC17A8-specific surveillance interval or proven genotype-specific noise susceptibility is inferred.

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 baseline.

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 precaution; no demonstrated DFNA25-specific disease-modifying effect.

Genetic counseling

Action: Genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Discuss 50% variant transmission per pregnancy, variable onset and penetrance, familial testing and reproductive options. Counseling should respect individual communication and reproductive preferences.

Show evidence (2 references)

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."

General autosomal dominant transmission probability, distinct from penetrance.

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 identification of the familial variant.

🔬

Diagnosis

3

Pure-Tone Audiometry

Audiometric assessment documents and tracks the delayed-onset, progressive, high-frequency-predominant sensorineural hearing loss that defines DFNA25, as a step separate from the molecular testing described in the row below.

audiometric test NCIT:C38036

pure-tone threshold audiometry LOINC:89015-2 hearing threshold, left ear, 500 Hz LOINC:89024-4 hearing threshold, right ear, 500 Hz LOINC:89025-1 hearing threshold, left ear, 1000 Hz LOINC:89016-0 hearing threshold, right ear, 1000 Hz LOINC:89017-8 hearing threshold, left ear, 2000 Hz LOINC:89018-6 hearing threshold, right ear, 2000 Hz LOINC:89019-4 hearing threshold, left ear, 4000 Hz LOINC:89022-8 hearing threshold, right ear, 4000 Hz LOINC:89023-6

No reference range is recorded: the cited founding-locus report states the loss is progressive and high-frequency-predominant but gives no severity grade or dB cut-off specific to DFNA25.

Show evidence (1 reference)

PMID:11115382 SUPPORT Human clinical

"we identified a novel dominant locus, DFNA25, for delayed-onset, progressive, high-frequency, nonsyndromic sensorineural hearing loss in a large, multigenerational United States family of Czech descent."

States the progressive, high-frequency-predominant audiometric pattern that these measurements document and track over serial audiograms.

Molecular testing of SLC17A8

Combine audiologic assessment, examination for syndromic findings, family history and molecular testing. A hearing-loss multigene panel or genomic testing can identify SLC17A8 alongside overlapping causes. Testing a known familial pathogenic variant clarifies carrier status; audiometry independently measures current hearing and progression.

Show evidence (3 references)

PMID:28647561 SUPPORT Human clinical

"To identify a causative mutation of HL in this family, we performed whole-exome sequencing of 4 family members, 3 affected and an unaffected."

Family exome sequencing identified the splice-site variant; the paper does not state that linkage was unavailable.

PMID:26797701 SUPPORT Human clinical

"In this study, we performed a genetic analysis of 87 unrelated Korean patients with ADNSHL to determine whether the SLC17A8 gene affects hearing ability in the Korean population."

The screened cohort comprised 87 unrelated dominant-hearing-loss probands; the single candidate frameshift does not provide a general diagnostic yield.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Single-gene testing (sequence analysis of a given gene, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended."

General initial diagnostic strategy; targeted testing for a known familial variant is a separate indication.

Variant interpretation as a distinct problem in this gene

Evaluate each variant using segregation, population data, phenotype and functional evidence. A VUS does not confirm or exclude DFNA25. The 2016 full text found I78V did not cosegregate and A374S also occurred in normal-hearing controls, illustrating why conservation and predictions alone are insufficient. Cell-culture effects of c.616dupA and c.824C>A are functional support, not proof of a shared mechanism or clinical pathogenicity.

Show evidence (3 references)

PMID:34145196 SUPPORT Other

"Although several suspected pathogenic mutations of the SLC17a8 gene have been identified in humans, few studies have confirmed their pathogenicity."

The interpretation problem stated by the authors as their motivation.

PMID:34145196 SUPPORT In vitro / ex vivo

"The c.616dupA mutation in the SLC17a8 gene resulted in a significant decrease in transcriptional activity of mRNA, and the expression of VGluT3 was also reduced. The c.824C>A mutation in the SLC17a8 gene resulted in abnormal VGluT3, although this mutation did not affect the transcriptional..."

Two alleles in one gene with two different molecular consequences, measured in cell culture.

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 variant-interpretation guidance.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Autosomal Dominant Nonsyndromic Hearing Loss 25:

Presbycusis and noise-induced hearing loss

Overlapping Features Age-related and noise-related hearing loss can resemble DFNA25. Pedigree information and molecular testing help distinguish causes, while acquired exposures and genetic disease may coexist. Audiogram shape alone is insufficient.

Show evidence (2 references)

PMID:12925340 SUPPORT Human clinical

"It is difficult to differentiate delayed-onset high-frequency sensorineural hearing loss inherited as a simple mendelian trait like DFNA25-associated hearing loss from that due to noise exposure or presbycusis, disorders that may also have a genetic component."

The difficulty stated as the study's own conclusion.

PMID:18674745 SUPPORT BACKGROUND Human clinical

"Autosomal-dominant sensorineural hearing loss is genetically heterogeneous, with a phenotype closely resembling presbycusis, the most common sensory defect associated with aging in humans."

The same resemblance stated for the dominant class DFNA25 belongs to.

🔬

Clinical Trials

1

NCT01802190 NOT_APPLICABLE TERMINATED

Observational genetic screening and phenotypic characterization of SLC17A8/DFNA25 and POU4F3/DFNA15 in dominant hearing loss. This registration does not test a therapy or establish clinical efficacy.

Show evidence (1 reference)

clinicaltrials:NCT01802190 SUPPORT Other

"The study will allow to identify the prevalence of the SLC17A8 gene mutations in patients suffering from deafness."

Registry summary describes an observational research aim, not a reported prevalence or treatment result.

🐁

Animal Models

2

Slc17a8 null mouse

Homozygous Slc17a8 null mice model complete loss of vesicular glutamate transmission with profound hearing loss and extra-cochlear effects including seizures. The published vestibular study found strongly reduced quantal transmission but relatively preserved spontaneous vestibular nerve activity and most balance tests, with some assay differences. Nonquantal compensation is proposed; this is not proof of normal human vestibular function.

Species

Mouse

Genotype

Slc17a8 (Vglut3) exon 2 targeted deletion, homozygous null

Publication

PMID:18674745

Pathograph links

Impaired Glutamate Release at the Inner Hair Cell Ribbon Synapse recapitulates fidelity: moderate The release failure and its localisation to vesicle content rather than fusion, both measured directly in the correct cell type.

Limitations: Homozygous null mice model complete VGLUT3 loss, not the heterozygous human genotypes. Congenital profound deafness and mouse epilepsy do not reproduce the typical progressive nonsyndromic presentation.

Readouts

Calcium-triggered synaptic vesicle turnover in inner hair cells

Direction: UNCHANGED

Interpretation: Exocytosis itself is normal. A deliberate negative result, and the one that makes the defect a cargo defect rather than a release-machinery defect.

Show evidence (1 reference)

PMID:18674745 SUPPORT In vitro / ex vivo

"Ca(2+)-triggered synaptic-vesicle turnover was normal in IHCs of Slc17a8 null mice when probed by membrane capacitance measurements at 2 weeks of age."

The capacitance measurement behind this readout.

Ribbon synapse ultrastructure at three months

Direction: UNCHANGED

Interpretation: Surviving ribbons appeared normal in this line at three months despite reduced synapse numbers. Other null-model studies reported altered ribbon shape; this result is specific to this study.

Show evidence (1 reference)

PMID:18674745 SUPPORT Model organism

"Ribbon synapses remaining by 3 months of age had a normal ultrastructural appearance."

The electron-microscopy observation behind this readout.

Show evidence (1 reference)

PMID:18215623 SUPPORT Model organism

"We now report that mice lacking VGLUT3 are profoundly deaf due to the absence of glutamate release from hair cells at the first synapse in the auditory pathway."

Supports treating this model as informative for the release node.

Failure of Auditory Nerve Activation with Preserved Cochlear Amplification recapitulates fidelity: moderate The three-way dissociation - no acoustic neural response, intact emissions, intact electrically evoked brainstem response - measured in one animal.

Limitations: Detailed human OAE/ABR testing in the 2003 report concerns one proband. The mouse dissociation cannot establish the physiology of all carriers or clinical implant outcomes.

Readouts

Otoacoustic emissions

Direction: UNCHANGED

Interpretation: Outer hair cell amplification is preserved, placing the lesion downstream of the cochlear amplifier. A negative result, and the load-bearing one.

Show evidence (1 reference)

PMID:18674745 SUPPORT Model organism

"robust otoacoustic emissions were recorded"

The emissions measurement behind this readout.

Electrically evoked auditory brainstem response

Direction: UNCHANGED

Interpretation: The ascending auditory pathway can still be driven when the defective synapse is bypassed, which is the observation that makes cochlear implantation biologically plausible in this disease.

Show evidence (1 reference)

PMID:18674745 SUPPORT Model organism

"although auditory brainstem responses could be elicited by electrical stimuli"

The electrical-stimulation measurement behind this readout.

Show evidence (1 reference)

PMID:18674745 SUPPORT Model organism

"Null mice with a targeted deletion of Slc17a8 exon 2 lacked auditory-nerve responses to acoustic stimuli, although auditory brainstem responses could be elicited by electrical stimuli, and robust otoacoustic emissions were recorded."

Supports treating this model as informative for the dissociation node.

Secondary Deafferentation of the Inner Hair Cell recapitulates fidelity: low The afferent synapses, spiral ganglion neurons and lateral efferent endings decline after the functional deficit is established.

Limitations: The null model has complete congenital loss of signaling and developmental neuronal effects. Human onset is variable and usually later; human synapse-count evidence is lacking in the reviewed sources.

Readouts

Afferent synapse and spiral ganglion neuron counts

Direction: DECREASED

Interpretation: The afferent population beneath the inner hair cell falls over time in the null animal.

Show evidence (1 reference)

PMID:18674745 SUPPORT Model organism

"Later, the number of afferent synapses, spiral ganglion neurons, and lateral efferent endings below sensory IHCs declined."

The counting result behind this readout.

Show evidence (1 reference)

PMID:18215623 SUPPORT Model organism

"The early degeneration of some cochlear ganglion neurons in knockout mice also indicates an important developmental role for the glutamate released by hair cells before the onset of hearing."

Supports the model for this node while naming the developmental confound that limits its fidelity.

Show evidence (1 reference)

DOI:10.1038/s41598-026-43836-7 SUPPORT INDIRECT PRIMARY RESULT Model organism

"We propose that non-quantal transmission is sufficient to support vestibular nerve physiology and behavioral function in Vglut3 −/− mice."

The published study proposes a compensatory explanation from mouse physiology and behavioral tests; some assay differences and limited sampling preclude universal normality.

VGLUT3 A224V knock-in mouse

The allele-matched model, and the reason this entry carries two hypothesis groups. A single point mutation was introduced into exon 5 of mouse Slc17a8, exchanging the codon for the alanine that corresponds to human A211. It reproduces the progressive course the null mouse does not, and it reaches a different conclusion about where the disease starts.

Species

Mouse

Genotype

Slc17a8 p.A224V knock-in (mouse equivalent of human p.A211V), homozygous

Publication

PMID:34783032

Pathograph links

Inner Hair Cell Stereocilia Bundle Disruption recapitulates fidelity: moderate Collapse and fusion of the inner hair cell stereocilia bundles, with outer hair cell bundles spared - the model's primary structural finding.

Limitations: Homozygosity differs from human dominant inheritance. The C57BL/6J Cdh23 background may modify the bundle phenotype; this has not been separated experimentally. No corresponding human cochlear morphology was demonstrated.

Readouts

Inner hair cell stereocilia bundle morphology by scanning electron microscopy

Direction: ALTERED

Interpretation: Inner hair cell bundles collapse; outer hair cell bundles do not. The contrast within the same cochlea is what makes this a cell-type-specific lesion rather than general degeneration.

Show evidence (1 reference)

PMID:34783032 SUPPORT Model organism

"Scanning electron microscopy examinations demonstrated the collapse of stereocilia bundles in IHCs, leaving those from outer hair cells unaffected."

The microscopy result behind this readout.

Show evidence (1 reference)

PMID:34783032 SUPPORT Model organism

"These results suggest that DFNA25 stems from a failure in the mechano-transduction followed by a change in synaptic transfer."

The authors' claim that this model's structural finding is the disease's starting point, which is what makes the model informative for this node.

Reduced Inner Hair Cell Receptor Potential recapitulates fidelity: moderate The functional counterpart of the bundle collapse, measured as a reduced summating potential in an animal whose cochlear amplifier is intact.

Limitations: The summating potential is a gross cochlear potential and an indirect index of the inner hair cell receptor potential rather than a recording from the cell. It is not measured clinically in DFNA25 patients, so there is no human comparison.

Readouts

Summating potential

Direction: DECREASED

Interpretation: A smaller receptor-potential correlate from a mechanically normal input, consistent with a transduction rather than an amplification deficit.

Show evidence (1 reference)

PMID:34783032 SUPPORT Model organism

"The summating potential was reduced, indicating the alteration of inner hair cell (IHC) receptor potential."

The measurement behind this readout.

Show evidence (1 reference)

PMID:34783032 SUPPORT Model organism

"The summating potential was reduced, indicating the alteration of inner hair cell (IHC) receptor potential."

Measured cochlear potential supports the model-to-mechanism link, with the indirect nature of the receptor-potential readout stated in its limitations.

Synaptic Ribbon Enlargement recapitulates fidelity: moderate Ribbon enlargement at four to six months in the homozygous knock-in.

Limitations: Elongated and enlarged ribbons are not necessarily opposite findings. Morphology differs between studies and models; compensation, pathogenic contribution and relevance to human heterozygotes remain unresolved.

Readouts

Synaptic ribbon size by super-resolution microscopy

Direction: INCREASED

Interpretation: Ribbons are larger than wild type in the knock-in animal.

Show evidence (1 reference)

PMID:34783032 SUPPORT Model organism

"Using super-resolution microscopy, we observed oversized synaptic ribbons"

The imaging result behind this readout.

Show evidence (1 reference)

PMID:34783032 SUPPORT Model organism

"In addition, IHC ribbon synapses underwent structural and functional modifications at later stages."

Supports the model for this node and fixes its position late in the sequence.

Increased Sustained Inner Hair Cell Exocytosis recapitulates fidelity: moderate Increased sustained exocytic capacitance response at six months.

Limitations: An ex-vivo membrane-fusion readout, not a direct measure of glutamate release or evidence that increased secretion causes the hearing deficit.

Readouts

Sustained releasable pool exocytosis rate

Direction: INCREASED

Interpretation: Sustained vesicle fusion is increased under imposed depolarization; glutamate quantal content was not measured.

Show evidence (1 reference)

PMID:34783032 SUPPORT In vitro / ex vivo

"patch-clamp membrane capacitance measurements showed an increase in the rate of the sustained releasable pool exocytosis"

The capacitance measurement behind this readout.

Show evidence (1 reference)

PMID:34783032 SUPPORT DIRECT PRIMARY RESULT In vitro / ex vivo

"patch-clamp membrane capacitance measurements showed an increase in the rate of the sustained releasable pool exocytosis"

Ex-vivo patch-clamp measurements in isolated mouse organs of Corti; membrane fusion does not determine glutamate quantal content.

{ }

Source YAML

click to show

name: Autosomal Dominant Nonsyndromic Hearing Loss 25
creation_date: "2026-09-01T20:30:00Z"
category: Mendelian
disease_term:
  preferred_term: autosomal dominant nonsyndromic hearing loss 25
  term:
    id: MONDO:0011568
    label: autosomal dominant nonsyndromic hearing loss 25
synonyms:
- DFNA25
- deafness, autosomal dominant 25
- autosomal dominant nonsyndromic deafness 25
- SLC17A8 autosomal dominant nonsyndromic deafness
- autosomal dominant nonsyndromic deafness caused by mutation in SLC17A8
description: >-
  SLC17A8-related autosomal dominant nonsyndromic hearing loss is usually progressive and predominantly
  high-frequency, with variable onset and age-dependent penetrance. VGLUT3 loads glutamate into inner
  hair cell synaptic vesicles. Human segregation establishes the gene-disease relationship, but the dominant
  molecular mechanism remains unresolved. Homozygous null mice lack sound-evoked afferent signaling; homozygous
  A224V knock-in mice, modeling human A211V, develop inner hair cell bundle disruption followed by ribbon
  and exocytosis changes. Heterozygous knock-in mice have a much milder phenotype. These models establish
  complementary experimental findings rather than interchangeable accounts of human disease. The limited
  human otoacoustic-emission data do not settle whether DFNA25 belongs within the auditory neuropathy
  spectrum.
parents:
- Autosomal Dominant Nonsyndromic Hearing Loss
- Hereditary Hearing Loss

external_assertions:
- name: ClinGen SLC17A8-nonsyndromic hearing loss gene-disease validity assertion
  source: ClinGen
  assertion_type: gene_disease_validity
  external_id: CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z
  url: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z
  description: >-
    The ClinGen Hearing Loss Gene Curation Expert Panel raised the SLC17A8-autosomal dominant nonsyndromic
    hearing loss relationship from Strong in 2018 to Definitive in June 2023. Its assessment included
    at least eight variants in nine probands and segregation in 28 additional relatives. These are counts
    in that dated evidence assessment, not worldwide case totals or prevalence estimates.
  evidence:
  - reference: CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z
    reference_title: SLC17A8 / nonsyndromic genetic hearing loss (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SLC17A8 | HGNC:20151 | nonsyndromic genetic hearing loss | MONDO:0019497 | AD | Definitive"
    explanation: >-
      The expert-panel classification row itself, with gene, disease, inheritance mode and
      verdict.
  - reference: CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z
    reference_title: SLC17A8 / nonsyndromic genetic hearing loss (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      At least 8 unique variants (missense, frameshift, splice site) have been reported in
      humans in 9 probands
    explanation: >-
      Counts in the June 2023 ClinGen assessment, not current worldwide totals or a prevalence denominator.
  - reference: CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z
    reference_title: SLC17A8 / nonsyndromic genetic hearing loss (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      As a result of this reevaluation, the classification increased from Strong to
      Definitive due to additional case level evidence
    explanation: >-
      The expert panel upgraded the relationship from Strong to Definitive in 2023.

mechanistic_hypotheses:
- hypothesis_group_id: presynaptic_glutamate_loading_failure
  hypothesis_label: Presynaptic vesicular glutamate loading failure
  status: CANONICAL
  description: >-
    VGLUT3 deficiency prevents vesicular glutamate loading and auditory afferent activation in homozygous
    null mice despite preserved vesicle fusion and cochlear amplification. This is an established null-model
    mechanism and a candidate contributor to human SLC17A8 disease. It does not establish haploinsufficiency
    or uniform transport loss for dominant variants: A211V retains transport in tested heterologous systems,
    and human onset and severity vary.
- hypothesis_group_id: a211v_mechanotransduction_first
  hypothesis_label: Stereociliary mechanotransduction failure preceding synaptic change
  status: EMERGING
  description: >-
    Homozygous A224V mice develop inner hair cell stereocilia disruption and reduced summating potentials
    before marked ribbon enlargement and increased sustained exocytosis. This supports a mechanotransduction-first
    hypothesis in that model. Temporal order does not establish that the bundle lesion causes the synaptic
    changes, and the dominant human mechanism remains unconfirmed.

pathophysiology:
- name: Heterozygous SLC17A8 Variant
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    The founding c.632C>T (p.A211V) variant segregated in two families with evidence of distant shared
    ancestry and was absent from 267 controls. Later reports include c.616dupA (p.M206Nfs*4) and c.763+1G>T.
    The 2016 frameshift report sequenced one proband from an affected pedigree; it did not demonstrate
    segregation across all eight affected relatives. Predicted truncation and splice disruption do not
    establish a shared dominant mechanism.
  genetic_context:
    gene:
      preferred_term: SLC17A8
      term:
        id: hgnc:20151
        label: SLC17A8
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    description: >-
      Reported disease-associated alleles are heterozygous. The entry does not assign one functional-impact
      category across missense, frameshift and splice variants: human dominance and normal heterozygous-null
      mouse hearing do not by themselves distinguish dosage loss, dominant-negative effects or other mechanisms.
  downstream:
  - target: Altered VGLUT3 Function in the Inner Hair Cell
    causal_link_type: DIRECT
    description: >-
      Every proposed mechanism for this disease runs through the transporter that the
      variant sits in.
  evidence:
  - reference: PMID:18674745
    reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In two unrelated families, a heterozygous missense mutation, c.632C-->T (p.A211V), was
      found to segregate with DFNA25 deafness and was not present in 267 controls.
    explanation: >-
      The founding allele, its zygosity, its segregation and its control screening.
  - reference: PMID:18674745
    reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The A211 residue is conserved in VGLUT3 across species and in all human VGLUT subtypes
      (VGLUT1-3), suggesting an important functional role.
    explanation: >-
      The conservation argument the founding paper rests the missense call on.
  - reference: PMID:26797701
    reference_title: Screening of the SLC17A8 gene as a causative factor for autosomal dominant non-syndromic hearing loss in Koreans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The novel frameshift mutation, p.M206Nfs*4, in which methionine is changed to
      asparagine at amino acid position 206, resulted in a termination codon at amino acid
      position 209.
    explanation: >-
      The 2016 report identified a frameshift in one sequenced proband and predicted truncation; it did
      not show cosegregation in all affected relatives.
  - reference: PMID:28647561
    reference_title: Identification of a novel splicing mutation within SLC17A8 in a Korean family with hearing loss by whole-exome sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A novel splicing mutation, c.763+1G>T, in the solute carrier family 17, member 8
      (SLC17A8) gene was identified in the patients, and the genotypes of the mutation were
      co-segregated with the phenotype of HL.
    explanation: >-
      The splice-donor allele and its co-segregation in a three-generation dominant family.

- name: Altered VGLUT3 Function in the Inner Hair Cell
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    VGLUT3 supports glutamate loading into inner hair cell synaptic vesicles. Null mice lack functional
    auditory afferent transmission, but human A211V does not abolish uptake or quantal signaling in tested
    heterologous/autaptic preparations. Central-terminal protein reduction in the knock-in cannot be assumed
    in cochlear cells: the 2021 study found comparable inner hair cell VGLUT3 immunofluorescence and distribution
    between genotypes. Variant-specific effects therefore remain important.
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  molecular_functions:
  - preferred_term: vesicular L-glutamate transport by VGLUT3
    term:
      id: GO:0005313
      label: L-glutamate transmembrane transporter activity
  biological_processes:
  - preferred_term: glutamate loading into inner hair cell synaptic vesicles
    term:
      id: GO:0098700
      label: neurotransmitter loading into synaptic vesicle
  cellular_components:
  - preferred_term: inner hair cell synaptic vesicle
    term:
      id: GO:0008021
      label: synaptic vesicle
  downstream:
  - target: Impaired Glutamate Release at the Inner Hair Cell Ribbon Synapse
    causal_link_type: DIRECT
    hypothesis_groups:
    - presynaptic_glutamate_loading_failure
    description: >-
      The direct consequence of an unfilled vesicle, and the route the null mouse takes.
  - target: Inner Hair Cell Stereocilia Bundle Disruption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - a211v_mechanotransduction_first
    description: >-
      The route the allele-matched knock-in mouse takes. It is marked INDIRECT because no
      mechanism connecting an altered vesicular transporter to hair-bundle architecture has
      been demonstrated; the knock-in shows the bundles collapse, not why.
  - target: Synaptic Ribbon Enlargement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - a211v_mechanotransduction_first
    description: >-
      The A224V genotype is associated with this later synaptic alteration; the intermediates and relationship
      to the early bundle defect remain unresolved.
    evidence:
    - reference: PMID:34783032
      reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In addition, IHC ribbon synapses underwent structural and functional modifications at later stages.
      explanation: >-
        The genotype-associated synaptic findings do not prove that reduced receptor potential caused
        them.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  - target: Increased Sustained Inner Hair Cell Exocytosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - a211v_mechanotransduction_first
    description: >-
      The A224V genotype is associated with this later synaptic alteration; the intermediates and relationship
      to the early bundle defect remain unresolved.
    evidence:
    - reference: PMID:34783032
      reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        patch-clamp membrane capacitance measurements showed an increase in the rate of the sustained
        releasable pool exocytosis
      explanation: >-
        The genotype-associated synaptic findings do not prove that reduced receptor potential caused
        them.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  evidence:
  - reference: PMID:18674745
    reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In the cochlea, VGLUT3 accumulates glutamate in the synaptic vesicles of the sensory
      inner hair cells (IHCs) before releasing it onto receptors of auditory-nerve terminals.
    explanation: >-
      The normal function of the protein, which is what the disease removes or alters.
  - reference: PMID:26797701
    reference_title: Screening of the SLC17A8 gene as a causative factor for autosomal dominant non-syndromic hearing loss in Koreans.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      among its isoforms (VGLUT1-3), only VGLUT3 is expressed selectively in the inner hair
      cells (IHCs)
    explanation: >-
      Inner hair cell expression provides a basis for nonredundant cochlear function. It does not explain
      the absence of extra-auditory findings in every carrier.
    quote_role: BACKGROUND
  - reference: PMID:34783032
    reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This variation does not impair the glutamate vesicular accumulation, neither the
      quantal release nor the quantal content in hippocampal autaptic neurons
    explanation: >-
      A negative result at the level of transport itself, which is why this entry does not
      assert that the human missense allele simply stops glutamate loading. Graded IN_VITRO
      because the measurement is in cultured autaptic neurons.

    quote_role: BACKGROUND
    directness: INDIRECT
  - reference: PMID:34783032
    reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the p.A224V variant does not disturb the VGLUT3 targeting within the hair cell cytoplasm.
    explanation: >-
      Semi-quantitative mouse cochlear immunofluorescence; this limits extrapolation from reduced central-terminal
      expression.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Impaired Glutamate Release at the Inner Hair Cell Ribbon Synapse
  biological_scale: CELLULAR
  description: >-
    In the Ruel Slc17a8-null line, calcium-triggered vesicle turnover was preserved at two weeks and surviving
    ribbons had a normal ultrastructural appearance at three months, while auditory afferent signaling
    failed. Other null-model studies reported thin or elongated ribbons. The findings differ by study
    and preparation; they do not establish universally normal ribbon morphology or uniform transport loss
    in dominant human variants.
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  biological_processes:
  - preferred_term: glutamate secretion at the inner hair cell afferent synapse
    modifier: DECREASED
    term:
      id: GO:0014047
      label: glutamate secretion
  downstream:
  - target: Failure of Auditory Nerve Activation with Preserved Cochlear Amplification
    causal_link_type: DIRECT
    hypothesis_groups:
    - presynaptic_glutamate_loading_failure
    description: >-
      An afferent terminal that receives no transmitter does not fire, however well the
      cochlea in front of it is working.
  evidence:
  - reference: PMID:18215623
    reference_title: Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We now report that mice lacking VGLUT3 are profoundly deaf due to the absence of
      glutamate release from hair cells at the first synapse in the auditory pathway.
    explanation: >-
      The release failure stated directly, and its location at the first auditory synapse.
  - reference: PMID:18674745
    reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Ca(2+)-triggered synaptic-vesicle turnover was normal in IHCs of Slc17a8 null mice when
      probed by membrane capacitance measurements at 2 weeks of age.
    explanation: >-
      The deliberate negative result that localises the defect to vesicle content rather than
      to exocytosis. Without it the node would be indistinguishable from a fusion defect.
  - reference: PMID:18674745
    reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We conclude that deafness in Slc17a8-deficient mice is due to a specific defect of
      vesicular glutamate uptake and release and that VGLUT3 is essential for auditory coding
      at the IHC synapse.
    explanation: >-
      The founding paper's own conclusion about the null animal.

- name: Inner Hair Cell Stereocilia Bundle Disruption
  biological_scale: CELLULAR
  description: >-
    Homozygous A224V mice show progressive inner hair cell bundle fusion and collapse with relative preservation
    of outer hair cell bundles. VGLUT3 is not localized to stereocilia, and the molecular connection is
    unresolved. Protein misfolding/trafficking effects and interaction with the C57BL/6J Cdh23 background
    are hypotheses. Comparable inner hair cell immunofluorescence argues against gross protein accumulation
    but cannot exclude altered turnover or proteostasis.
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  biological_processes:
  - preferred_term: inner hair cell stereocilium bundle organization
    modifier: DECREASED
    term:
      id: GO:0060122
      label: inner ear receptor cell stereocilium organization
  downstream:
  - target: Reduced Inner Hair Cell Receptor Potential
    causal_link_type: DIRECT
    hypothesis_groups:
    - a211v_mechanotransduction_first
    description: >-
      Bundle disruption and reduced summating potential support a mechanotransduction defect in the same
      homozygous model; direct mechanotransducer-current impairment was not measured.
  evidence:
  - reference: PMID:34783032
    reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Scanning electron microscopy examinations demonstrated the collapse of stereocilia
      bundles in IHCs, leaving those from outer hair cells unaffected.
    explanation: >-
      The bundle finding and its restriction to inner hair cells.

- name: Reduced Inner Hair Cell Receptor Potential
  biological_scale: CELLULAR
  description: >-
    The summating potential is the gross cochlear correlate of the inner hair cell receptor
    potential, and it is reduced in the knock-in mouse. Because cochlear amplification is
    intact in the same animals, a smaller receptor potential is being generated from a normal
    mechanical input - which is what a transduction defect in the inner hair cell looks like
    from outside.
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  biological_processes:
  - preferred_term: mechanotransduction in the inner hair cell hair bundle
    modifier: DECREASED
    term:
      id: GO:0050910
      label: detection of mechanical stimulus involved in sensory perception of sound
  downstream:
  - target: Failure of Auditory Nerve Activation with Preserved Cochlear Amplification
    causal_link_type: DIRECT
    hypothesis_groups:
    - a211v_mechanotransduction_first
    description: >-
      Reduced inner hair cell receptor potential is proposed to reduce afferent drive. The model shows
      reduced summating and compound action potentials, but does not directly quantify sound-evoked glutamate
      release.
  evidence:
  - reference: PMID:34783032
    reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The summating potential was reduced, indicating the alteration of inner hair cell (IHC)
      receptor potential.
    explanation: >-
      The measurement and the authors' own interpretation of it.
  - reference: PMID:34783032
    reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These results suggest that DFNA25 stems from a failure in the mechano-transduction
      followed by a change in synaptic transfer.
    explanation: >-
      The ordering claim that this hypothesis group is built on, stated by the authors as a
      suggestion rather than a demonstration - which is why the group is EMERGING.

- name: Synaptic Ribbon Enlargement
  biological_scale: CELLULAR
  description: >-
    Homozygous A224V inner hair cell ribbons enlarge markedly at four to six months, with preserved ribbon
    and synapse counts in the sampled region. This structural change follows early bundle abnormalities.
    Its causal contribution to hearing loss, including whether it is compensatory, remains unresolved.
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  evidence:
  - reference: PMID:34783032
    reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      However, synaptic ribbons became abnormally elongated in knock‐in mice
    explanation: >-
      Mouse cochlear imaging supports ribbon enlargement, not a measured increase in glutamate secretion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Increased Sustained Inner Hair Cell Exocytosis
  biological_scale: CELLULAR
  description: >-
    At six months, freshly dissected homozygous A224V inner hair cells show increased sustained exocytic
    capacitance responses to long depolarizations, with preserved calcium currents and readily releasable
    pool responses. Capacitance measures membrane fusion rather than vesicular glutamate content or afferent
    neurotransmission. The change may reflect compensation or extrasynaptic release; it is not established
    as a cause of hearing loss.
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  evidence:
  - reference: PMID:34783032
    reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      patch-clamp membrane capacitance measurements showed an increase in the rate of the sustained releasable
      pool exocytosis
    explanation: >-
      Ex-vivo patch-clamp measurements in isolated mouse organs of Corti; membrane fusion does not determine
      glutamate quantal content.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Failure of Auditory Nerve Activation with Preserved Cochlear Amplification
  biological_scale: TISSUE
  description: >-
    Slc17a8-null mice lack sound-evoked auditory responses while retaining otoacoustic emissions and electrically
    evoked brainstem responses. Homozygous A224V mice show progressive auditory threshold elevation with
    preserved emissions. Human otoacoustic-emission data are sparse and differ from these model findings;
    this node records experimental physiology rather than a universal human diagnostic signature.
  cell_types:
  - preferred_term: type 1 spiral ganglion neuron
    term:
      id: CL:4023115
      label: type 1 spiral ganglion neuron
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  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
  downstream:
  - target: Secondary Deafferentation of the Inner Hair Cell
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Loss of afferent signaling and later deafferentation occur in null mice; glutamate also has developmental
      effects, so this is not established as a direct use-dependent degeneration mechanism in humans.
  - target: Progressive High-Frequency Sensorineural Hearing Loss
    causal_link_type: DIRECT
    description: >-
      Impaired afferent sound encoding provides a model-based explanation for hearing loss. The progressive
      human course is not reproduced by the congenitally deaf null model.
  evidence:
  - reference: PMID:18674745
    reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Null mice with a targeted deletion of Slc17a8 exon 2 lacked auditory-nerve responses to
      acoustic stimuli, although auditory brainstem responses could be elicited by electrical
      stimuli, and robust otoacoustic emissions were recorded.
    explanation: >-
      All three halves of the dissociation in one sentence: no acoustic neural response,
      preserved electrical response, preserved emissions.
  - reference: PMID:34783032
    reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Using auditory brainstem response and distortion product otoacoustic emissions, we
      showed progressive hearing loss with intact cochlear amplification in the
      VGLUT3A224V/A224V mouse.
    explanation: >-
      The same dissociation in the allele-matched model, and in progressive rather than
      congenital form.
- name: Secondary Deafferentation of the Inner Hair Cell
  biological_scale: TISSUE
  description: >-
    Null mice show loss of afferent synapses, spiral ganglion neurons and lateral efferent endings; some
    neuronal loss precedes hearing onset. Older null cochleae also show inner hair cell and stereocilia
    degeneration. These observations raise questions about treatment timing, but do not define a human
    therapeutic window. Rescue studies in post-neonatal null mice remain distinct from dominant human
    disease.
  cell_types:
  - preferred_term: spiral ganglion neuron
    term:
      id: CL:0011113
      label: spiral ganglion neuron
  downstream:
  - target: Progressive High-Frequency Sensorineural Hearing Loss
    causal_link_type: DIRECT
    description: >-
      Reduced afferent innervation may contribute to sustained hearing impairment in null models; its
      contribution and reversibility in human DFNA25 are unknown.
  evidence:
  - reference: PMID:18674745
    reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Later, the number of afferent synapses, spiral ganglion neurons, and lateral efferent
      endings below sensory IHCs declined.
    explanation: >-
      The deafferentation itself, and its late timing relative to the functional deficit.
  - reference: PMID:18215623
    reference_title: Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The early degeneration of some cochlear ganglion neurons in knockout mice also
      indicates an important developmental role for the glutamate released by hair cells
      before the onset of hearing.
    explanation: >-
      The developmental component, which is a different claim from use-dependent loss and is
      the reason a congenital null and an adult-onset human disease may diverge here.
  - reference: PMID:40841774
    reference_title: Gene therapy restores auditory function and rescues damaged inner hair cells in an aged Vglut3 knockout mouse model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In this study, we analyzed the cochlear structure of aged Vglut3KO mice, revealing
      significant degeneration of inner hair cells, synapses, and stereocilia.
    explanation: >-
      The structural endpoint in the aged null animal.

phenotypes:
- category: Otologic
  name: Progressive High-Frequency Sensorineural Hearing Loss
  description: >-
    Progressive, predominantly high-frequency sensorineural hearing loss is the characteristic presentation
    in the founding families. Audiogram shape and severity vary. Family-based ascertainment and a dated
    ClinGen proband count do not support a population-wide phenotype frequency.
  phenotype_term:
    preferred_term: High-frequency sensorineural hearing impairment
    term:
      id: HP:0001757
      label: High-frequency sensorineural hearing impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:11115382
    reference_title: "DFNA25, a novel locus for dominant nonsyndromic hereditary hearing impairment, maps to 12q21-24."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified a novel dominant locus, DFNA25, for delayed-onset, progressive,
      high-frequency, nonsyndromic sensorineural hearing loss in a large, multigenerational
      United States family of Czech descent.
    explanation: >-
      The phenotype as defined at the locus, in the founding kindred.
  - reference: PMID:18674745
    reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified SLC17A8, which encodes the vesicular glutamate transporter-3
      (VGLUT3), as the gene responsible for DFNA25, an autosomal-dominant form of
      progressive, high-frequency nonsyndromic deafness.
    explanation: >-
      The same phenotype restated once the gene was in hand.

- category: Otologic
  name: Postlingual Delayed Onset
  description: >-
    Postlingual onset is typical, not universal. The 2003 full clinical report includes a child whose
    loss was suspected at birth and confirmed by diagnostic ABR at three months. A normal newborn screen
    cannot exclude later-onset genetic hearing loss.
  phenotype_term:
    preferred_term: Postlingual sensorineural hearing impairment
    term:
      id: HP:0008596
      label: Postlingual sensorineural hearing impairment
  evidence:
  - reference: PMID:12925340
    reference_title: Phenotypic characterization of hereditary hearing impairment linked to DFNA25.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals typically manifest a high-frequency, slowly progressive
      sensorineural hearing loss in the postlingual period.
    explanation: >-
      The abstract explicitly says typically. The primary full text documents an early-onset exception;
      normal hearing through speech acquisition is not universal.

  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In general, autosomal dominant nonsyndromic hearing loss is postlingual, progressive, and high frequency.
    explanation: >-
      General clinical baseline, not a SLC17A8-specific age distribution or exclusion of congenital presentations.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
- category: Otologic
  name: Absent Otoacoustic Emissions
  description: >-
    The 2003 family report documents absent transient-evoked emissions and no repeatable ABR in the proband
    III:14. The later knock-in discussion generalizes this to patients, but the primary detailed test
    report is not a cohort-wide denominator. No frequency or universal exclusion of auditory neuropathy
    is inferred. Acquired cochlear injury and mixed mechanisms remain possible explanations.
  phenotype_term:
    preferred_term: Absent otoacoustic emissions
    term:
      id: HP:6000182
      label: Absent otoacoustic emissions
  evidence:
  - reference: PMID:34783032
    reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, otoacoustic emissions were absent in patients harbouring the p.A211V allele
    explanation: >-
      Secondary discussion of the 2003 human study. Inspection of that primary full text limits the detailed
      OAE/ABR observation to the proband; the plural wording is not evidence for prevalence or a universal
      classification.
    quote_role: BACKGROUND
    directness: INDIRECT
- category: Otologic
  name: Absence of Syndromic Features
  description: >-
    The reported Korean splice-variant family had hearing loss without accompanying symptoms. This supports
    a nonsyndromic human presentation. Vestibular sparing in null mice is a separate experimental observation
    and cannot establish normal vestibular function in every human carrier.
  evidence:
  - reference: PMID:28647561
    reference_title: Identification of a novel splicing mutation within SLC17A8 in a Korean family with hearing loss by whole-exome sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the clinical information about this family revealed that there are no other symptoms
      accompanied with HL
    explanation: >-
      The nonsyndromic statement in a reported dominant family.
genetic:
- name: SLC17A8
  gene_term:
    preferred_term: SLC17A8
    term:
      id: hgnc:20151
      label: SLC17A8
  relationship_type: CAUSATIVE
  notes: >-
    SLC17A8 encodes VGLUT3. ClinGen classified its dominant nonsyndromic hearing loss relationship as
    Definitive in 2023; the counted probands and variants describe that assessment. A211V, c.616dupA and
    c.763+1G>T differ in their supporting segregation and functional evidence. The 2016 frameshift was
    found in one sequenced proband with an affected pedigree; the splice report demonstrated cosegregation,
    but did not establish transcript consequences in its abstract. The 2021 cell study tested the already
    reported c.616dupA alongside c.824C>A, rather than discovering two additional alleles.
  evidence:
  - reference: CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z
    reference_title: SLC17A8 / nonsyndromic genetic hearing loss (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Variants in this gene segregated with disease in 28 additional members in two families
    explanation: >-
      The segregation evidence behind the Definitive classification.
  - reference: CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z
    reference_title: SLC17A8 / nonsyndromic genetic hearing loss (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In summary, SCL17A8 is definitively associated with autosomal dominant nonsyndromic
      hearing loss.
    explanation: >-
      The panel's summary sentence. The gene symbol is transposed in the source record and is
      quoted as written.

inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Autosomal dominant transmission with age-dependent penetrance. Each child of a heterozygous affected
    individual has a 50% chance of inheriting the variant; this is not a 50% probability of hearing loss
    at a specified age. Earlier reported onset in males and a maternal-versus-paternal haplotype pattern
    arose in one pre-gene-mapping kindred and remain unreplicated modifier hypotheses. Normal hearing
    at one assessment does not exclude carrier status. Four tested mitochondrial variants were absent,
    which does not exclude all mitochondrial effects.
  evidence:
  - reference: PMID:12925340
    reference_title: Phenotypic characterization of hereditary hearing impairment linked to DFNA25.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mode of inheritance is autosomal dominant with age-dependent penetrance.
    explanation: >-
      Inheritance mode and the penetrance qualifier together.

  - reference: PMID:12925340
    reference_title: Phenotypic characterization of hereditary hearing impairment linked to DFNA25.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In those inheriting the DFNA25-associated haplotype from an affected mother, hearing
      loss invariably developed by the second decade of life, whereas those inheriting the
      DFNA25 haplotype from an affected father often maintained hearing levels comparable to
      those of age-matched control subjects, even into the seventh decade of life.
    explanation: >-
      The parent-of-origin observation, quoted in full so the size and source of the claim
      travel with it.
  - reference: PMID:12925340
    reference_title: Phenotypic characterization of hereditary hearing impairment linked to DFNA25.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      None of 4 deafness-associated mitochondrial mutations screened (1555A>G, 7445A>G,
      Cins7472, and 7511T>C) were found to segregate in the family.
    explanation: >-
      Only the four tested mitochondrial variants were excluded; the study did not sequence the mitochondrial
      genome or establish the cause of the parent-of-origin pattern.

  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews&reg; - 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: >-
      General autosomal dominant transmission probability, distinct from penetrance.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
animal_models:
- name: Slc17a8 null mouse
  species: Mouse
  genotype: Slc17a8 (Vglut3) exon 2 targeted deletion, homozygous null
  publication: PMID:18674745
  description: >-
    Homozygous Slc17a8 null mice model complete loss of vesicular glutamate transmission with profound
    hearing loss and extra-cochlear effects including seizures. The published vestibular study found strongly
    reduced quantal transmission but relatively preserved spontaneous vestibular nerve activity and most
    balance tests, with some assay differences. Nonquantal compensation is proposed; this is not proof
    of normal human vestibular function.
  modeled_mechanisms:
  - target: Impaired Glutamate Release at the Inner Hair Cell Ribbon Synapse
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The release failure and its localisation to vesicle content rather than fusion, both
      measured directly in the correct cell type.
    limitations: >-
      Homozygous null mice model complete VGLUT3 loss, not the heterozygous human genotypes. Congenital
      profound deafness and mouse epilepsy do not reproduce the typical progressive nonsyndromic presentation.
    readouts:
    - name: Calcium-triggered synaptic vesicle turnover in inner hair cells
      target: Impaired Glutamate Release at the Inner Hair Cell Ribbon Synapse
      direction: UNCHANGED
      interpretation: >-
        Exocytosis itself is normal. A deliberate negative result, and the one that makes the
        defect a cargo defect rather than a release-machinery defect.
      evidence:
      - reference: PMID:18674745
        reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Ca(2+)-triggered synaptic-vesicle turnover was normal in IHCs of Slc17a8 null mice
          when probed by membrane capacitance measurements at 2 weeks of age.
        explanation: >-
          The capacitance measurement behind this readout.
    - name: Ribbon synapse ultrastructure at three months
      target: Impaired Glutamate Release at the Inner Hair Cell Ribbon Synapse
      direction: UNCHANGED
      interpretation: >-
        Surviving ribbons appeared normal in this line at three months despite reduced synapse numbers.
        Other null-model studies reported altered ribbon shape; this result is specific to this study.
      evidence:
      - reference: PMID:18674745
        reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Ribbon synapses remaining by 3 months of age had a normal ultrastructural
          appearance.
        explanation: >-
          The electron-microscopy observation behind this readout.
    evidence:
    - reference: PMID:18215623
      reference_title: Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We now report that mice lacking VGLUT3 are profoundly deaf due to the absence of
        glutamate release from hair cells at the first synapse in the auditory pathway.
      explanation: >-
        Supports treating this model as informative for the release node.
  - target: Failure of Auditory Nerve Activation with Preserved Cochlear Amplification
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The three-way dissociation - no acoustic neural response, intact emissions, intact
      electrically evoked brainstem response - measured in one animal.
    limitations: >-
      Detailed human OAE/ABR testing in the 2003 report concerns one proband. The mouse dissociation cannot
      establish the physiology of all carriers or clinical implant outcomes.
    readouts:
    - name: Otoacoustic emissions
      target: Failure of Auditory Nerve Activation with Preserved Cochlear Amplification
      direction: UNCHANGED
      interpretation: >-
        Outer hair cell amplification is preserved, placing the lesion downstream of the
        cochlear amplifier. A negative result, and the load-bearing one.
      evidence:
      - reference: PMID:18674745
        reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          robust otoacoustic emissions were recorded
        explanation: >-
          The emissions measurement behind this readout.
    - name: Electrically evoked auditory brainstem response
      target: Failure of Auditory Nerve Activation with Preserved Cochlear Amplification
      direction: UNCHANGED
      interpretation: >-
        The ascending auditory pathway can still be driven when the defective synapse is
        bypassed, which is the observation that makes cochlear implantation biologically
        plausible in this disease.
      evidence:
      - reference: PMID:18674745
        reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          although auditory brainstem responses could be elicited by electrical stimuli
        explanation: >-
          The electrical-stimulation measurement behind this readout.
    evidence:
    - reference: PMID:18674745
      reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Null mice with a targeted deletion of Slc17a8 exon 2 lacked auditory-nerve responses
        to acoustic stimuli, although auditory brainstem responses could be elicited by
        electrical stimuli, and robust otoacoustic emissions were recorded.
      explanation: >-
        Supports treating this model as informative for the dissociation node.
  - target: Secondary Deafferentation of the Inner Hair Cell
    relationship: RECAPITULATES
    fidelity: LOW
    description: >-
      The afferent synapses, spiral ganglion neurons and lateral efferent endings decline
      after the functional deficit is established.
    limitations: >-
      The null model has complete congenital loss of signaling and developmental neuronal effects. Human
      onset is variable and usually later; human synapse-count evidence is lacking in the reviewed sources.
    readouts:
    - name: Afferent synapse and spiral ganglion neuron counts
      target: Secondary Deafferentation of the Inner Hair Cell
      direction: DECREASED
      interpretation: >-
        The afferent population beneath the inner hair cell falls over time in the null
        animal.
      evidence:
      - reference: PMID:18674745
        reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Later, the number of afferent synapses, spiral ganglion neurons, and lateral
          efferent endings below sensory IHCs declined.
        explanation: >-
          The counting result behind this readout.
    evidence:
    - reference: PMID:18215623
      reference_title: Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The early degeneration of some cochlear ganglion neurons in knockout mice also
        indicates an important developmental role for the glutamate released by hair cells
        before the onset of hearing.
      explanation: >-
        Supports the model for this node while naming the developmental confound that limits
        its fidelity.

  evidence:
  - reference: DOI:10.1038/s41598-026-43836-7
    reference_title: Persistence of vestibular function in the absence of glutamatergic transmission from hair cells
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We propose that non-quantal transmission is sufficient to support vestibular nerve physiology and
      behavioral function in Vglut3 −/− mice.
    explanation: >-
      The published study proposes a compensatory explanation from mouse physiology and behavioral tests;
      some assay differences and limited sampling preclude universal normality.
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
- name: VGLUT3 A224V knock-in mouse
  species: Mouse
  genotype: Slc17a8 p.A224V knock-in (mouse equivalent of human p.A211V), homozygous
  publication: PMID:34783032
  description: >-
    The allele-matched model, and the reason this entry carries two hypothesis groups. A
    single point mutation was introduced into exon 5 of mouse Slc17a8, exchanging the codon
    for the alanine that corresponds to human A211. It reproduces the progressive course the
    null mouse does not, and it reaches a different conclusion about where the disease starts.
  modeled_mechanisms:
  - target: Inner Hair Cell Stereocilia Bundle Disruption
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Collapse and fusion of the inner hair cell stereocilia bundles, with outer hair cell
      bundles spared - the model's primary structural finding.
    limitations: >-
      Homozygosity differs from human dominant inheritance. The C57BL/6J Cdh23 background may modify the
      bundle phenotype; this has not been separated experimentally. No corresponding human cochlear morphology
      was demonstrated.
    readouts:
    - name: Inner hair cell stereocilia bundle morphology by scanning electron microscopy
      target: Inner Hair Cell Stereocilia Bundle Disruption
      direction: ALTERED
      interpretation: >-
        Inner hair cell bundles collapse; outer hair cell bundles do not. The contrast within
        the same cochlea is what makes this a cell-type-specific lesion rather than general
        degeneration.
      evidence:
      - reference: PMID:34783032
        reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Scanning electron microscopy examinations demonstrated the collapse of stereocilia
          bundles in IHCs, leaving those from outer hair cells unaffected.
        explanation: >-
          The microscopy result behind this readout.
    evidence:
    - reference: PMID:34783032
      reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These results suggest that DFNA25 stems from a failure in the mechano-transduction
        followed by a change in synaptic transfer.
      explanation: >-
        The authors' claim that this model's structural finding is the disease's starting
        point, which is what makes the model informative for this node.
  - target: Reduced Inner Hair Cell Receptor Potential
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The functional counterpart of the bundle collapse, measured as a reduced summating
      potential in an animal whose cochlear amplifier is intact.
    limitations: >-
      The summating potential is a gross cochlear potential and an indirect index of the
      inner hair cell receptor potential rather than a recording from the cell. It is not
      measured clinically in DFNA25 patients, so there is no human comparison.
    readouts:
    - name: Summating potential
      target: Reduced Inner Hair Cell Receptor Potential
      direction: DECREASED
      interpretation: >-
        A smaller receptor-potential correlate from a mechanically normal input, consistent
        with a transduction rather than an amplification deficit.
      evidence:
      - reference: PMID:34783032
        reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          The summating potential was reduced, indicating the alteration of inner hair cell
          (IHC) receptor potential.
        explanation: >-
          The measurement behind this readout.
    evidence:
    - reference: PMID:34783032
      reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The summating potential was reduced, indicating the alteration of inner hair cell (IHC) receptor
        potential.
      explanation: >-
        Measured cochlear potential supports the model-to-mechanism link, with the indirect nature of
        the receptor-potential readout stated in its limitations.
  - target: Synaptic Ribbon Enlargement
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Ribbon enlargement at four to six months in the homozygous knock-in.
    limitations: >-
      Elongated and enlarged ribbons are not necessarily opposite findings. Morphology differs between
      studies and models; compensation, pathogenic contribution and relevance to human heterozygotes remain
      unresolved.
    readouts:
    - name: Synaptic ribbon size by super-resolution microscopy
      target: Synaptic Ribbon Enlargement
      direction: INCREASED
      interpretation: >-
        Ribbons are larger than wild type in the knock-in animal.
      evidence:
      - reference: PMID:34783032
        reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Using super-resolution microscopy, we observed oversized synaptic ribbons
        explanation: >-
          The imaging result behind this readout.
    evidence:
    - reference: PMID:34783032
      reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In addition, IHC ribbon synapses underwent structural and functional modifications at
        later stages.
      explanation: >-
        Supports the model for this node and fixes its position late in the sequence.
  - target: Increased Sustained Inner Hair Cell Exocytosis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Increased sustained exocytic capacitance response at six months.
    limitations: >-
      An ex-vivo membrane-fusion readout, not a direct measure of glutamate release or evidence that increased
      secretion causes the hearing deficit.
    readouts:
    - name: Sustained releasable pool exocytosis rate
      target: Increased Sustained Inner Hair Cell Exocytosis
      direction: INCREASED
      interpretation: >-
        Sustained vesicle fusion is increased under imposed depolarization; glutamate quantal content
        was not measured.
      evidence:
      - reference: PMID:34783032
        reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          patch-clamp membrane capacitance measurements showed an increase in the rate of the
          sustained releasable pool exocytosis
        explanation: >-
          The capacitance measurement behind this readout.
    evidence:
    - reference: PMID:34783032
      reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        patch-clamp membrane capacitance measurements showed an increase in the rate of the sustained
        releasable pool exocytosis
      explanation: >-
        Ex-vivo patch-clamp measurements in isolated mouse organs of Corti; membrane fusion does not determine
        glutamate quantal content.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  - target: Progressive High-Frequency Sensorineural Hearing Loss
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Progressive hearing loss with intact cochlear amplification, which is the human course
      in outline.
    limitations: >-
      Homozygotes progress, whereas heterozygotes have only mild impairment over the studied interval.
      Human dominant inheritance, audiogram configuration and limited human OAE findings are not fully
      reproduced. Lifespan and background effects remain hypotheses.
    readouts:
    - name: Auditory brainstem response threshold
      target: Progressive High-Frequency Sensorineural Hearing Loss
      direction: INCREASED
      interpretation: >-
        Thresholds rise progressively with age. The direction is INCREASED because the
        readout is a threshold - worse hearing means more sound is required to evoke a
        response.
      evidence:
      - reference: PMID:34783032
        reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Mutant mice carrying the VGLUT3-p.A211V variant show progressive hearing loss.
        explanation: >-
          The progressive threshold shift behind this readout, stated in the paper's key
          points.
    - name: Distortion-product otoacoustic emissions
      target: Progressive High-Frequency Sensorineural Hearing Loss
      direction: UNCHANGED
      interpretation: >-
        Cochlear amplification is intact while brainstem responses deteriorate. A negative
        result that separates this from an outer-hair-cell hearing loss.
      evidence:
      - reference: PMID:34783032
        reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          we showed progressive hearing loss with intact cochlear amplification in the
          VGLUT3A224V/A224V mouse
        explanation: >-
          The emissions measurement behind this readout.
    evidence:
    - reference: PMID:34783032
      reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our data show that the VGLUT3A224V/A224V mice phenocopy human progressive hearing
        loss.
      explanation: >-
        The authors' own claim that this model matches the human course, which is what
        licenses using it for the clinical phenotype node.
    - reference: PMID:34783032
      reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      snippet: >-
        the mouse model harbouring the VGLUT3-p.A224V variant mimics a progressive hearing loss
        with auditory neuropathy features, but might be arguable so far as to consider it as a
        faithful model of DFNA25
      explanation: >-
        The same authors' qualification of the sentence above, in the discussion rather than the
        abstract. It is recorded as REFUTE against the link's claim of fidelity, and it is why
        this relationship is PARTIALLY_RECAPITULATES.
    - reference: PMID:34783032
      reference_title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        However, the mild hearing impairment in the VGLUT3+/A224V heterozygotes contrasts with
        the dominant transmission in DFNA25
      explanation: >-
        The zygosity mismatch measured rather than assumed: the genotype that matches a patient
        is only mildly affected in this animal.

diagnosis:
- name: Pure-Tone Audiometry
  description: >-
    Audiometric assessment documents and tracks the delayed-onset,
    progressive, high-frequency-predominant sensorineural hearing loss that
    defines DFNA25, as a step separate from the molecular testing described
    in the row below.
  diagnosis_term:
    preferred_term: audiometric test
    term:
      id: NCIT:C38036
      label: Audiometric Test
  measurements:
  - preferred_term: pure-tone threshold audiometry
    term:
      id: LOINC:89015-2
      label: Pure tone threshold audiometry panel
  - preferred_term: hearing threshold, left ear, 500 Hz
    term:
      id: LOINC:89024-4
      label: Hearing threshold Ear - left --500 Hz
  - preferred_term: hearing threshold, right ear, 500 Hz
    term:
      id: LOINC:89025-1
      label: Hearing threshold Ear - right --500 Hz
  - preferred_term: hearing threshold, left ear, 1000 Hz
    term:
      id: LOINC:89016-0
      label: Hearing threshold Ear - left --1000 Hz
  - preferred_term: hearing threshold, right ear, 1000 Hz
    term:
      id: LOINC:89017-8
      label: Hearing threshold Ear - right --1000 Hz
  - preferred_term: hearing threshold, left ear, 2000 Hz
    term:
      id: LOINC:89018-6
      label: Hearing threshold Ear - left --2000 Hz
  - preferred_term: hearing threshold, right ear, 2000 Hz
    term:
      id: LOINC:89019-4
      label: Hearing threshold Ear - right --2000 Hz
  - preferred_term: hearing threshold, left ear, 4000 Hz
    term:
      id: LOINC:89022-8
      label: Hearing threshold Ear - left --4000 Hz
  - preferred_term: hearing threshold, right ear, 4000 Hz
    term:
      id: LOINC:89023-6
      label: Hearing threshold Ear - right --4000 Hz
  notes: >-
    No reference range is recorded: the cited founding-locus report states
    the loss is progressive and high-frequency-predominant but gives no
    severity grade or dB cut-off specific to DFNA25.
  evidence:
  - reference: PMID:11115382
    reference_title: "DFNA25, a novel locus for dominant nonsyndromic hereditary hearing impairment, maps to 12q21-24."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified a novel dominant locus, DFNA25, for delayed-onset, progressive,
      high-frequency, nonsyndromic sensorineural hearing loss in a large, multigenerational
      United States family of Czech descent.
    explanation: >-
      States the progressive, high-frequency-predominant audiometric pattern
      that these measurements document and track over serial audiograms.
- name: Molecular testing of SLC17A8
  description: >-
    Combine audiologic assessment, examination for syndromic findings, family history and molecular testing.
    A hearing-loss multigene panel or genomic testing can identify SLC17A8 alongside overlapping causes.
    Testing a known familial pathogenic variant clarifies carrier status; audiometry independently measures
    current hearing and progression.
  evidence:
  - reference: PMID:28647561
    reference_title: Identification of a novel splicing mutation within SLC17A8 in a Korean family with hearing loss by whole-exome sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To identify a causative mutation of HL in this family, we performed whole-exome
      sequencing of 4 family members, 3 affected and an unaffected.
    explanation: >-
      Family exome sequencing identified the splice-site variant; the paper does not state that linkage
      was unavailable.
  - reference: PMID:26797701
    reference_title: Screening of the SLC17A8 gene as a causative factor for autosomal dominant non-syndromic hearing loss in Koreans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this study, we performed a genetic analysis of 87 unrelated Korean patients with
      ADNSHL to determine whether the SLC17A8 gene affects hearing ability in the Korean
      population.
    explanation: >-
      The screened cohort comprised 87 unrelated dominant-hearing-loss probands; the single candidate
      frameshift does not provide a general diagnostic yield.

  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews&reg; - 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 initial diagnostic strategy; targeted testing for a known familial variant is a separate
      indication.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
- name: Variant interpretation as a distinct problem in this gene
  description: >-
    Evaluate each variant using segregation, population data, phenotype and functional evidence. A VUS
    does not confirm or exclude DFNA25. The 2016 full text found I78V did not cosegregate and A374S also
    occurred in normal-hearing controls, illustrating why conservation and predictions alone are insufficient.
    Cell-culture effects of c.616dupA and c.824C>A are functional support, not proof of a shared mechanism
    or clinical pathogenicity.
  evidence:
  - reference: PMID:34145196
    reference_title: "The c.824C>A and c.616dupA mutations in the SLC17a8 gene are associated with auditory neuropathy and lead to defective expression of VGluT3."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Although several suspected pathogenic mutations of the SLC17a8 gene have been
      identified in humans, few studies have confirmed their pathogenicity.
    explanation: >-
      The interpretation problem stated by the authors as their motivation.
  - reference: PMID:34145196
    reference_title: "The c.824C>A and c.616dupA mutations in the SLC17a8 gene are associated with auditory neuropathy and lead to defective expression of VGluT3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The c.616dupA mutation in the SLC17a8 gene resulted in a significant decrease in
      transcriptional activity of mRNA, and the expression of VGluT3 was also reduced. The
      c.824C>A mutation in the SLC17a8 gene resulted in abnormal VGluT3, although this
      mutation did not affect the transcriptional activity of mRNA.
    explanation: >-
      Two alleles in one gene with two different molecular consequences, measured in cell
      culture.

  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews&reg; - 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 variant-interpretation guidance.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
treatments:
- name: Hearing Aids
  therapeutic_modality: DEVICE
  description: >-
    Offer audiologist-fitted amplification and communication support according to hearing thresholds,
    speech testing and individual preferences. This follows general genetic hearing-loss care; genotype-specific
    benefit cannot be predicted from the null mouse or an isolated OAE finding.
  treatment_term:
    preferred_term: hearing aid fitting
    term:
      id: NCIT:C15315
      label: Rehabilitation
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: hearing aid
        term:
          id: NCIT:C183182
          label: Hearing Aid

  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews&reg; - 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-aid guidance, not a DFNA25 outcome estimate.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
- name: Cochlear Implantation
  therapeutic_modality: DEVICE
  description: >-
    Consider cochlear implantation under standard audiologic candidacy assessment when amplification provides
    insufficient benefit. Preserved electrically evoked responses in null mice provide mechanistic plausibility,
    but do not establish human DFNA25 implant efficacy or guarantee preservation of the neural target.
  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
  target_mechanisms:
  - target: Failure of Auditory Nerve Activation with Preserved Cochlear Amplification
    treatment_effect: BYPASSES
    description: >-
      Direct electrical stimulation of the spiral ganglion substitutes for the defective
      inner hair cell synapse.
    evidence:
    - reference: PMID:18674745
      reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        although auditory brainstem responses could be elicited by electrical stimuli
      explanation: >-
        The preserved electrical responsiveness that an implant would exploit. Model evidence
        for a human intervention, so the claim in the description is plausibility rather than
        efficacy.

  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Habilitation for hearing loss includes improved access to sound through hearing aids or cochlear
      implants
    explanation: >-
      General habilitation options; no SLC17A8-specific outcome is asserted.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
- name: AAV-mediated VGLUT3 Gene Replacement
  therapeutic_modality: GENE_THERAPY
  description: >-
    Preclinical gene replacement has restored auditory responses in homozygous null mice after neonatal
    cochlear AAV1 delivery, adult intracisternal delivery through the cochlear aqueduct, and AAV8 injection
    at five weeks with assessment 27 weeks later. The latter does not demonstrate reversal after treatment
    of already aged animals. These interventions have not established efficacy in dominant A211V disease;
    augmentation, suppression or combined strategies require variant-specific testing. No human SLC17A8
    interventional study was identified in the reviewed research; the registered NCT01802190 study is
    observational.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Altered VGLUT3 Function in the Inner Hair Cell
    treatment_effect: RESTORES
    description: >-
      Restoring VGLUT3 protein to the inner hair cell addresses the molecular lesion rather
      than its consequences - in an animal that has none of the protein to begin with.
    evidence:
    - reference: PMID:22841313
      reference_title: Restoration of hearing in the VGLUT3 knockout mouse using virally mediated gene therapy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Within 2 weeks of AAV1-VGLUT3 delivery, auditory brainstem response (ABR) thresholds
        normalize, along with partial rescue of the startle response.
      explanation: >-
        The functional rescue, in the null mouse.
    - reference: PMID:40841774
      reference_title: Gene therapy restores auditory function and rescues damaged inner hair cells in an aged Vglut3 knockout mouse model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Auditory brainstem response (ABR) testing demonstrated restoration of auditory
        function following gene therapy.
      explanation: >-
        Mice were injected at five weeks and evaluated 27 weeks later, so the aged endpoint does not establish
        efficacy when treatment starts in aged animals.
  evidence:
  - reference: PMID:22841313
    reference_title: Restoration of hearing in the VGLUT3 knockout mouse using virally mediated gene therapy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These findings represent a successful restoration of hearing by gene replacement in
      mice, which is a significant advance toward gene therapy of human deafness.
    explanation: >-
      The authors' own framing of how far the result reaches - toward human therapy, not to
      it.

  - reference: DOI:10.1126/scitranslmed.abq3916
    reference_title: Delivery of gene therapy through a cerebrospinal fluid conduit to rescue hearing in adult mice
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      rescued hearing in adult deaf Slc17A8 −/− mice by restoring VGLUT3 protein expression in inner hair
      cells
    explanation: >-
      Primary 2023 adult-null-mouse rescue supporting the CSF-delivery theme in the research report.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Audiologic surveillance and noise protection
  description: >-
    Follow hearing serially and adjust rehabilitation as needed. Avoid repeated loud-noise overexposure
    using general hearing-loss guidance. No SLC17A8-specific surveillance interval or proven genotype-specific
    noise susceptibility is inferred.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Regular follow up is recommended for all individuals with genetic hearing loss
    explanation: >-
      General surveillance baseline.
    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&reg; - 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 precaution; no demonstrated DFNA25-specific disease-modifying effect.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
- name: Genetic counseling
  description: >-
    Discuss 50% variant transmission per pregnancy, variable onset and penetrance, familial testing and
    reproductive options. Counseling should respect individual communication and reproductive preferences.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews&reg; - 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: >-
      General autosomal dominant transmission probability, distinct from penetrance.
    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&reg; - 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 identification of the familial variant.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
differential_diagnoses:
- name: Presbycusis and noise-induced hearing loss
  description: >-
    Age-related and noise-related hearing loss can resemble DFNA25. Pedigree information and molecular
    testing help distinguish causes, while acquired exposures and genetic disease may coexist. Audiogram
    shape alone is insufficient.
  evidence:
  - reference: PMID:12925340
    reference_title: Phenotypic characterization of hereditary hearing impairment linked to DFNA25.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is difficult to differentiate delayed-onset high-frequency sensorineural hearing
      loss inherited as a simple mendelian trait like DFNA25-associated hearing loss from
      that due to noise exposure or presbycusis, disorders that may also have a genetic
      component.
    explanation: >-
      The difficulty stated as the study's own conclusion.
  - reference: PMID:18674745
    reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal-dominant sensorineural hearing loss is genetically heterogeneous, with a
      phenotype closely resembling presbycusis, the most common sensory defect associated
      with aging in humans.
    explanation: >-
      The same resemblance stated for the dominant class DFNA25 belongs to.

    quote_role: BACKGROUND
- name: OTOF-related auditory neuropathy (DFNB9)
  description: >-
    OTOF-related hearing loss is a presynaptic disorder with recessive inheritance, contrasting with dominant
    SLC17A8 disease. Typical clinical patterns can guide testing, but overlapping and atypical presentations
    require molecular interpretation. Null-mouse physiology and sparse human emission data do not reliably
    distinguish every patient.
  evidence:
  - reference: PMID:18674745
    reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Null mice with a targeted deletion of Slc17a8 exon 2 lacked auditory-nerve responses to
      acoustic stimuli, although auditory brainstem responses could be elicited by electrical
      stimuli, and robust otoacoustic emissions were recorded.
    explanation: >-
      The physiological pattern DFNA25's null mouse shares with the OTOF synaptopathies, which
      is what makes DFNB9 the mechanistic differential.

- name: CABP2-related nonsyndromic hearing loss (DFNB93)
  description: >-
    CABP2-related DFNB93 is recessive and involves regulation of presynaptic calcium channels. Preserved
    emissions in a reported CABP2 patient support a synaptopathy in that case; comprehensive emission
    phenotyping remains limited. The isolated absent-emission observation in DFNA25 is insufficient for
    a universal mechanistic contrast.
  evidence:
  - reference: PMID:40927552
    reference_title: "Is CABP2-Associated Hearing Loss (DFNB93) a Gene Therapy Target? Preclinical Progress and Patient Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Otoacoustic emissions have been observed in an Italian family with a homozygous CABP2
      variant, indicating preservation of outer hair cell-mediated cochlear amplification.
    explanation: >-
      A review summarizes a human CABP2 observation; it does not establish uniform emissions across either
      disease.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  - reference: PMID:18674745
    reference_title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified SLC17A8, which encodes the vesicular glutamate transporter-3
      (VGLUT3), as the gene responsible for DFNA25, an autosomal-dominant form of
      progressive, high-frequency nonsyndromic deafness.
    explanation: >-
      Dominant inheritance and the characteristic high-frequency pattern help frame the differential;
      the quote does not establish universal postlingual onset.

discussions:
- discussion_id: mismatch_zygosity_of_the_dfna25_mouse_models
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Heterozygous SLC17A8 Variant
  - animal_models#VGLUT3 A224V knock-in mouse
  prompt: >-
    Does either mouse model DFNA25, when both are homozygous and the heterozygote - the
    genotype a patient actually has - is only mildly affected?
  rationale: >-
    Homozygous knock-in mice have progressive impairment but heterozygotes have only mild changes over
    six months. Lifespan, allele dose, genetic background and species-specific biology may contribute.
    Null rescue does not select the optimal strategy for dominant human alleles.
  proposed_experiments:
  - experiment_id: dfna25_aged_heterozygous_knockin
    name: Lifespan-long auditory phenotyping of heterozygous VGLUT3 A224V mice
    description: >-
      Follow heterozygous A224V and wild-type littermates across age with serial ABR, emissions and bundle
      morphology, accounting for background-related hearing loss.
    would_support:
    - pathophysiology#Heterozygous SLC17A8 Variant
    supporting_outcome:
    - A widening deficit would support age-dependent expression in this mouse model, without proving that homozygous pathology transfers to humans.
    refuting_outcome:
    - A plateau would argue against continued progression under the tested conditions; it would not establish universal tolerance of one allele.
- discussion_id: gap_why_patient_emissions_are_absent
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Absent Otoacoustic Emissions
  - mechanistic_hypotheses#presynaptic_glutamate_loading_failure
  prompt: >-
    How representative is the absent-emission finding in the original DFNA25 proband?
  rationale: >-
    The detailed primary human observation concerns one proband, while both main mouse models retain emissions.
    Broader human OAE, cochlear microphonic, ABR, age and exposure data are needed to separate cochlear
    and neural contributions. Controlled mouse noise experiments can test model susceptibility but cannot
    establish the cause of human findings.
  proposed_experiments:
  - experiment_id: dfna25_noise_vulnerability_by_allele_dose
    name: Noise vulnerability in mice carrying one or two VGLUT3-p.A224V alleles
    description: >-
      Expose wild-type, heterozygous and homozygous A224V mice to a controlled acoustic
      overexposure and compare distortion-product emission loss and threshold shift against
      unexposed littermates. This is the experiment the knock-in authors name as necessary to
      determine whether acoustic injury accounts for the discrepancy between mouse and patient
      emissions.
    would_support:
    - phenotypes#Absent Otoacoustic Emissions
    supporting_outcome:
    - Greater emission loss after controlled noise would support genotype-dependent susceptibility in mice and motivate human exposure studies.
    refuting_outcome:
    - No genotype difference would weaken this model-specific noise hypothesis under the tested exposure; it would not resolve human auditory-neuropathy classification.
- discussion_id: gap_where_the_dfna25_lesion_starts
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - mechanistic_hypotheses#presynaptic_glutamate_loading_failure
  - mechanistic_hypotheses#a211v_mechanotransduction_first
  prompt: >-
    How does a vesicular glutamate transporter variant collapse the inner hair cell stereocilia
    bundle?
  rationale: >-
    A224V mice show bundle collapse despite retained transport in heterologous systems and comparable
    cochlear VGLUT3 immunofluorescence. Proteostasis, trafficking and the Cdh23 background remain candidate
    contributors. Identifying the mechanism could guide therapy, but a gene-directed intervention might
    affect both bundle and synaptic consequences.
  proposed_experiments:
  - experiment_id: dfna25_vglut3_localisation_in_knockin_hair_cells
    name: Subcellular localisation and turnover of VGLUT3-p.A224V in inner hair cells
    description: >-
      Track variant VGLUT3 in knock-in inner hair cells by immunogold electron microscopy and
      pulse-chase, testing directly whether it accumulates in the soma or apical compartment,
      whether proteostasis markers are engaged, and whether the cuticular plate cytoskeleton is
      disturbed before the bundles collapse.
    would_support:
    - mechanistic_hypotheses#a211v_mechanotransduction_first
    supporting_outcome:
    - Accumulation and proteostasis changes preceding bundle collapse would support this candidate mechanism; perturbation and rescue would be needed to test causation.
    refuting_outcome:
    - Normal localization and turnover would weaken this mechanism without excluding other allele-dependent or background effects.
- discussion_id: gap_dfna25_allele_class_heterogeneity
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - genetic#SLC17A8
  prompt: >-
    Do the truncating and splice SLC17A8 alleles cause the same disease as the missense
    founder allele?
  rationale: >-
    Missense, frameshift and splice alleles have unequal human and functional evidence. The frameshift
    and c.824C>A expression study retested reported alleles. Allelic heterogeneity does not by itself
    justify splitting a disease, and a normal heterozygous-null mouse does not resolve the human dominant
    mechanism.
  proposed_experiments:
  - experiment_id: dfna25_allele_class_audiogram_comparison
    name: Audiometric comparison of missense against truncating SLC17A8 carriers
    description: >-
      Collect audiograms and ages at onset across all published SLC17A8 heterozygotes and
      compare the founder missense families against the frameshift and splice-donor families,
      testing whether onset, progression rate and audiometric shape differ by allele class.
    would_support:
    - genetic#SLC17A8
    supporting_outcome:
    - Overlapping profiles would support shared clinical features without proving a shared molecular mechanism.
    refuting_outcome:
    - Reproducible differences would support allele-specific prognosis and further mechanistic work, without by themselves requiring separate disease entities.
notes: >-
  This is a genetic disease eligible for review despite noise exposure being a possible modifier and differential.
  SLC17A8 and the auditory brainstem response abbreviation ABR were distinguished in the research preflight;
  ABR is not a rival causal gene here. The matching research narrative, table, bibliography and citation
  sidecar were assessed. The report misidentifies PMID:22794260 as the 2012 rescue study; the correct
  PMID:22841313 is retained. Incorrect suggested HPO bindings were not imported. Normal-cell vesicle proteomics
  is background, not a disease biomarker. Adult CSF-mediated null-mouse rescue is now represented with
  the primary 2023 citation.

  The full GeneReviews Genetic Hearing Loss Overview supplies general clinical, diagnostic, management,
  surveillance and counseling context; it is not a DFNA25-specific chapter and does not establish gene-specific
  phenotype frequencies or follow-up intervals. Dated ClinGen counts are not worldwide prevalence. No
  quantitative progression rate is inferred from a single-family serial-audiogram report.

  The 2003 JAMA primary full text was inspected online. Automated cache retrieval returned 403 for HTML
  and PDF, so cached abstract quotations and the explicitly secondary OAE quotation are retained without
  inventing a full-text cache. The full text narrows the OAE/ABR denominator and documents an early-onset
  exception. Absence of emissions alone does not settle the disease classification.

  The PMID:41279968 cache combines a 2025 preprint abstract with the later published PDF. The published
  vestibular study is cited separately by DOI:10.1038/s41598-026-43836-7; its mouse findings are not human
  phenotype evidence. Full-text discussion limits apparently spared balance to the assays tested and proposes,
  rather than proves, nonquantal compensation.

references:
- reference: PMID:18674745
  title: "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice."
- reference: PMID:12925340
  title: Phenotypic characterization of hereditary hearing impairment linked to DFNA25.
- reference: PMID:11115382
  title: "DFNA25, a novel locus for dominant nonsyndromic hereditary hearing impairment, maps to 12q21-24."
- reference: PMID:34783032
  title: VGLUT3-p.A211V variant fuses stereocilia bundles and elongates synaptic ribbons.
- reference: PMID:18215623
  title: Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3.
- reference: PMID:22841313
  title: Restoration of hearing in the VGLUT3 knockout mouse using virally mediated gene therapy.
- reference: PMID:40841774
  title: Gene therapy restores auditory function and rescues damaged inner hair cells in an aged Vglut3 knockout mouse model.
- reference: PMID:26797701
  title: Screening of the SLC17A8 gene as a causative factor for autosomal dominant non-syndromic hearing loss in Koreans.
- reference: PMID:28647561
  title: Identification of a novel splicing mutation within SLC17A8 in a Korean family with hearing loss by whole-exome sequencing.
- reference: PMID:40927552
  title: "Is CABP2-Associated Hearing Loss (DFNB93) a Gene Therapy Target? Preclinical Progress and Patient Registry."
- reference: PMID:34145196
  title: "The c.824C>A and c.616dupA mutations in the SLC17a8 gene are associated with auditory neuropathy and lead to defective expression of VGluT3."
- reference: CGGV:assertion_8c399400-090a-4b2e-93ff-0c4915ce81c7-2023-06-01T160000.000Z
  title: SLC17A8 / nonsyndromic genetic hearing loss (Definitive)
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
  title: Genetic Hearing Loss Overview - GeneReviews&reg; - NCBI Bookshelf
  tags:
  - GeneReviews
- reference: DOI:10.1038/s41598-026-43836-7
  title: Persistence of vestibular function in the absence of glutamatergic transmission from hair cells
- reference: DOI:10.1126/scitranslmed.abq3916
  title: Delivery of gene therapy through a cerebrospinal fluid conduit to rescue hearing in adult mice
- reference: clinicaltrials:NCT01802190
  title: Prevalence of POU4F3 (DFNA15) and SLC17A8 (DFNA25) Genes Mutations in Dominant Autosomal Deafness and Phenotypic Characterization of Carrier Patients.
clinical_trials:
- name: NCT01802190
  phase: NOT_APPLICABLE
  description: >-
    Observational genetic screening and phenotypic characterization of SLC17A8/DFNA25 and POU4F3/DFNA15
    in dominant hearing loss. This registration does not test a therapy or establish clinical efficacy.
  evidence:
  - reference: clinicaltrials:NCT01802190
    reference_title: Prevalence of POU4F3 (DFNA15) and SLC17A8 (DFNA25) Genes Mutations in Dominant Autosomal Deafness and Phenotypic Characterization of Carrier Patients.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The study will allow to identify the prevalence of the SLC17A8 gene mutations in patients suffering
      from deafness.
    explanation: >-
      Registry summary describes an observational research aim, not a reported prevalence or treatment
      result.
  status: TERMINATED
  notes: 'ClinicalTrials.gov API checked 2026-09-23: observational study, actual enrollment 50; record last updated July 2015 and terminated with no convincing results reported as the reason. Registration is not evidence of a measured DFNA25 prevalence.'

📚

References & Deep Research

References

16

PMID:18674745

Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice.