Autosomal Recessive Nonsyndromic Hearing Loss 93

Mendelian MONDO:0013963 Pathograph 11 Show in embeddings browser Autosomal Recessive Nonsyndromic Hearing Loss Hereditary Hearing Loss

Prelingual, symmetric, moderate-to-severe sensorineural hearing loss caused by biallelic variants in CABP2, which encodes calcium-binding protein 2. The lesion is at one synapse. CaBP2 sits presynaptically in the cochlear inner hair cell and holds the CaV1.3 calcium channel open: it suppresses the channel's inactivation, so that a hair cell depolarised continuously by an ongoing sound keeps enough channels available to keep releasing transmitter. Remove CaBP2 and the channels inactivate; the sustained component of exocytosis collapses; the spiral ganglion neurons downstream fire less, spontaneously and to sound. What follows from that is the feature which makes this entry worth separating from the rest of the DFNB series. Outer hair cells are untouched, so cochlear amplification is preserved and otoacoustic emissions are present while the auditory brainstem response is abnormal. That combination is the definition of auditory synaptopathy, and the mouse paper that established the mechanism says so in its own conclusion. DFNB93 is therefore a synaptopathy that happens to sit in the nonsyndromic-deafness nomenclature, and it belongs beside OTOF rather than beside the hair-bundle genes it is numbered among. Clinically this matters twice over. Amplification addresses sensitivity, and sensitivity is not the deficit here. And because the organ of Corti is structurally intact, DFNB93 is a named candidate for cochlear gene replacement, with a mouse rescue already demonstrated.

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1
Inheritance
6
Pathophys.
8
Phenotypes
2
Gaps
11
Pathograph
1
Genes
2
Medical Actions
2
Differentials
3
Models
11
References
1
Deep Research
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Inheritance

1
Autosomal recessive HP:0000007
Every reported proband is homozygous and heterozygous relatives are unaffected. The founding families were consanguineous Iranian kindreds; the Danish and Finnish cases were not consanguineous, and in the Danish case a run of homozygosity spanning CABP2 pointed to a distant shared ancestor instead.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:22981119 SUPPORT Human Clinical
"we identified a splice-site mutation (c.637+1G>T) in Ca(2+)-binding protein 2 (CABP2) in three consanguineous Iranian families affected by moderate-to-severe hearing loss."
Homozygosity in consanguineous kindreds, the founding recessive observation.
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Discussions and Knowledge Gaps

2
Do DFNB93 patients benefit from amplification, given that auditory synaptopathy as a class is described as responding poorly to it?
KNOWLEDGE GAP OPEN gap_hearing_aid_benefit_in_dfnb93
Attached to
treatments#Hearing Aids pathophysiology#Auditory Synaptopathy with Preserved Cochlear Amplification
The entry cites both halves of a genuine tension. Auditory synaptopathy and auditory neuropathy patients are described in the review literature as gaining little from hearing aids, because amplification addresses sensitivity and the deficit is neural encoding. Yet the individual DFNB93 case reports describe amplification being fitted and outcomes being good, and the disease is milder than the synaptopathies that generalisation was built on. Both readings are defensible from what is published. DFNB93 may be the mild corner of the class where partial synaptic function leaves enough encoding for amplification to work with; or the reported good outcomes may reflect early fitting and small numbers rather than genuine class-atypical benefit. Nobody has measured speech perception in a DFNB93 cohort against aided thresholds, which is what would separate the two. The stake is immediate and clinical. If amplification genuinely works here, the class generalisation should not be applied to these patients when counselling. If it does not, the reported positive prognoses are measuring the wrong thing and cochlear implantation should be discussed earlier.
Proposed experiments
Aided speech perception versus aided threshold in a genotyped DFNB93 cohort
dfnb93_aided_speech_perception
Assemble the reported CABP2-biallelic patients through the existing patient registry and measure speech perception in noise against aided pure-tone thresholds, comparing against OTOF-related synaptopathy patients and against sensitivity-matched cochlear hearing loss.
Would support
treatments#Hearing Aids
Supporting outcome
  • Aided speech perception in DFNB93 tracks aided threshold in the way it does for cochlear hearing loss, which would mean amplification does the expected work here and the class generalisation does not apply.
Refuting outcome
  • Speech perception is disproportionately poor for the aided threshold, matching the OTOF pattern, which would mean the reported positive prognoses rest on audiometric gain that is not translating into communication and would move cochlear implantation earlier in counselling.
Is DFNB93 hearing loss stable after onset, or does it progress?
KNOWLEDGE GAP OPEN gap_dfnb93_progression
Attached to
phenotypes#Prelingual Moderate-to-Severe Sensorineural Hearing Loss
The mouse is described as having early-onset progressive hearing impairment. The human reports are cross-sectional - a proband is described at the age they were assessed - and none of the published families has serial audiometry across years. So the entry asserts prelingual onset and a severity band and deliberately asserts no clinical course, because the only progression evidence available is from the model. This is not a technicality. Progression determines whether a moderate childhood loss will still be moderate in adulthood, and it determines when a gene replacement therapy would have to be given to be worth giving. A disease that is stable at moderate thresholds has a very different therapeutic window from one that is sliding.
Proposed experiments
Longitudinal audiometry across the reported CABP2 families
dfnb93_longitudinal_audiometry
Retrieve serial audiograms from the Iranian, Turkish, Pakistani, Italian, Danish, Finnish and North American probands and their affected relatives, and plot threshold against age by allele class.
Would support
phenotypes#Prelingual Moderate-to-Severe Sensorineural Hearing Loss
Supporting outcome
  • Thresholds are stable across decades, confirming the disease as a fixed prelingual loss and making the mouse progression a species difference to record.
Refuting outcome
  • Thresholds worsen with age in humans as they do in the mouse, which would add a progressive clinical course to the phenotype and make the timing of any future gene therapy the central clinical question.
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Pathophysiology

6
Biallelic CABP2 Loss-of-Function Variant
The recurrent allele, and the one that accounts for most reported families, is the splice-donor variant c.637+1G>T. It causes skipping of exon 6 and a frameshift, p.Phe164Serfs*4, truncating the protein. Nonsense and missense alleles have also been reported. The truncated product is not simply absent from the cell: it was made and tested, and it binds calcium abnormally and regulates CaV1.3 less effectively than wild type. The functional claim of this entry therefore rests on a measured hypomorph, not only on an inferred null.
Genetic context CABP2 hgnc:1385 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns CABP2 (hgnc:1385). hgnc:1385 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Homozygous in every reported family. The founding families were consanguineous; the Danish and Finnish cases were not, and reflect a shared founder haplotype instead.
Downstream
Loss of CaBP2 Function at the Inner Hair Cell Ribbon Synapse The truncated protein cannot perform the CaV1.3 regulation that is CaBP2's job in the inner hair cell.
Show evidence (2 references)
PMID:22981119 SUPPORT Human Clinical
"we identified a splice-site mutation (c.637+1G>T) in Ca(2+)-binding protein 2 (CABP2) in three consanguineous Iranian families affected by moderate-to-severe hearing loss."
The founding families and the recurrent allele.
PMID:22981119 SUPPORT In Vitro
"Compared with wild-type CaBP2, the truncated CaBP2 showed altered Ca(2+) binding in isothermal titration calorimetry and less potent regulation of Ca(v)1.3 Ca(2+) channels."
The biochemical and channel-regulation consequence of the truncation, measured outside an organism, which is why this item is graded IN_VITRO while the family report above from the same paper is HUMAN_CLINICAL.
Loss of CaBP2 Function at the Inner Hair Cell Ribbon Synapse
CaBP2 is expressed by cochlear hair cells and preferentially by inner hair cells. It is not in the postsynaptic spiral ganglion neuron, which fixes the lesion on the presynaptic side of the synapse and is the reason this disease is a synaptopathy rather than a neuropathy of the auditory nerve itself.
cochlear inner hair cell CL:0000589 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear inner hair cell (CL:0000589). CL:0000589 is a cell type from the Cell Ontology.
CaV1.3 calcium channel regulation by CaBP2 GO:0005246 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased CaV1.3 calcium channel regulation by CaBP2, annotated with calcium channel regulator activity (GO:0005246). GO:0005246 is a molecular function from the Gene Ontology. ↓ DECREASED
Animal models
Cabp2 knockout mouse with AAV-mediated Cabp2 gene replacement Mouse rescues Delivering the Cabp2 coding sequence into inner hair cells restores the missing channel regulator in the genotype that matches the human disease, recovering the non-inactivating CaV1.3 current and improving hearing.
Downstream
Enhanced CaV1.3 Calcium-Channel Inactivation CaBP2's specific action is to suppress inactivation; without it the suppression is lifted.
Show evidence (1 reference)
PMID:28183797 SUPPORT Model Organism
"CaBP2 was expressed by cochlear hair cells, preferentially in inner hair cells (IHCs), and was lacking from the postsynaptic spiral ganglion neurons (SGNs)."
Localises the protein to the presynaptic side, which is what makes the rest of the chain a presynaptic account.
Enhanced CaV1.3 Calcium-Channel Inactivation
In inner hair cells lacking CaBP2 the CaV1.3 current inactivates more than it should. The channels are not fewer and they do not open at the wrong voltage - channel number and the voltage dependence of activation are normal, and so is the ribbon synapse count. What changes is availability over time. A hair cell responding to a continuing sound is held depolarised, and under that condition an inactivating channel population steadily withdraws from service.
cochlear inner hair cell CL:0000589 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear inner hair cell (CL:0000589). CL:0000589 is a cell type from the Cell Ontology.
available presynaptic CaV1.3 current GO:0005245 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased available presynaptic CaV1.3 current, annotated with voltage-gated calcium channel activity (GO:0005245). GO:0005245 is a molecular function from the Gene Ontology. ↓ DECREASED
Animal models
Cabp2 knockout mouse Mouse recapitulates The defining channel defect, measured directly by patch clamp in the correct cell type.
Downstream
Impaired Sustained Exocytosis at the Inner Hair Cell Ribbon Synapse Transmitter release at this synapse is driven by the calcium that enters through these channels, so a shrinking available current is a shrinking release drive.
Show evidence (2 references)
PMID:28183797 SUPPORT Model Organism
"Patch-clamp recordings from Cabp2LacZ/LacZ IHCs revealed enhanced Ca2+-channel inactivation."
The direct measurement of the inactivation defect in the cell type that matters.
PMID:28183797 SUPPORT Model Organism
"We propose that CaBP2 inhibits CaV1.3 Ca2+-channel inactivation, and thus sustains the availability of CaV1.3 Ca2+ channels for synaptic sound encoding."
States the mechanism in the availability terms this node uses.
Impaired Sustained Exocytosis at the Inner Hair Cell Ribbon Synapse
The consequence of reduced channel availability is that the sustained component of vesicle release fails. In the double-knockout preparation, where the phenotype is most severe because the partially redundant CaBP1 is removed as well, even mild activation reduces the channel pool enough that synapses may be effectively silenced.
cochlear inner hair cell CL:0000589 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear inner hair cell (CL:0000589). CL:0000589 is a cell type from the Cell Ontology.
sustained synaptic vesicle exocytosis at the hair cell ribbon synapse GO:0016079 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased sustained synaptic vesicle exocytosis at the hair cell ribbon synapse, annotated with synaptic vesicle exocytosis (GO:0016079). GO:0016079 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Cabp1/Cabp2 double-knockout mouse with AAV CaBP2 rescue Mouse recapitulates The sustained component of exocytosis fails, and afferent responses become strongly rate-dependent.
Downstream
Reduced Spiral Ganglion Neuron Firing Less transmitter released onto the afferent terminal means less afferent drive.
Show evidence (1 reference)
PMID:39718549 SUPPORT Model Organism
"In Cabp1/2 double-knockout mice, we find strongly enhanced CaV1.3 inactivation, slowed recovery from inactivation and impaired sustained exocytosis."
Links the channel defect to the exocytosis defect in the same preparation. Note this is the double knockout, so it overstates what loss of CaBP2 alone does; the single-knockout severity is recorded on the animal model entry.
Reduced Spiral Ganglion Neuron Firing
Single-unit recordings from spiral ganglion neurons show reduced spontaneous and sound-evoked firing. The neurons themselves are not the lesion - CaBP2 is not expressed in them - so this is a readout of presynaptic failure, and it is the step at which the defect becomes something an auditory brainstem response can see.
spiral ganglion neuron CL:0011113 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves spiral ganglion neuron (CL:0011113). CL:0011113 is a cell type from the Cell Ontology.
afferent auditory nerve firing GO:0019228 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased afferent auditory nerve firing, annotated with neuronal action potential (GO:0019228). GO:0019228 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Auditory Synaptopathy with Preserved Cochlear Amplification Degraded afferent encoding with an intact cochlear amplifier upstream of it.
Show evidence (2 references)
PMID:28183797 SUPPORT Model Organism
"Recordings from single SGNs showed reduced spontaneous and sound-evoked firing rates."
The afferent firing measurement itself.
PMID:39718549 SUPPORT Model Organism
"Spontaneous and sound-evoked responses of spiral ganglion neurons in vivo are strikingly reduced and strongly depend on stimulation rates."
Adds the rate dependence, which is the in vivo signature of a channel pool that recovers too slowly from inactivation.
Auditory Synaptopathy with Preserved Cochlear Amplification
The end state is a dissociation. Outer hair cells never enter the mechanism, so otoacoustic emissions are present and cochlear amplification is intact, while the auditory brainstem response is abnormal because what reaches the brainstem has been degraded at the synapse. That pattern is the operational definition of auditory synaptopathy, and both the mouse work and the clinical perspective paper state the classification explicitly rather than leaving it to be inferred.
sensory perception of sound GO:0007605 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased sensory perception of sound (GO:0007605). GO:0007605 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Cabp2 knockout mouse Mouse recapitulates The mouse shows the same dissociation as the patients: the cochlear amplifier works and the brainstem response does not.
Cabp1/Cabp2 double-knockout mouse with AAV CaBP2 rescue Mouse rescues Transgenic re-expression of CaBP2 in the inner ear substantially restores synaptic function and hearing sensitivity, showing that the deficit is reversible by replacing the missing protein and not the consequence of an irreversible developmental defect.
Show evidence (3 references)
PMID:28183797 SUPPORT Model Organism
"Therefore, we conclude that human deafness DFNB93 is an auditory synaptopathy."
The classification stated by the paper that established the mechanism.
PMID:40927552 SUPPORT Human Clinical
"Otoacoustic emissions have been observed in an Italian family with a homozygous CABP2 variant, indicating preservation of outer hair cell-mediated cochlear amplification."
The human observation of preserved outer hair cell function, which is what makes the mouse classification transferable rather than assumed.
PMID:40927552 SUPPORT Human Clinical
"Hence, DFNB93 belongs to the hearing disorders caused by impairment of IHC synapses, termed auditory synaptopathy."
States the classification for the human disease.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Autosomal Recessive Nonsyndromic Hearing Loss 93 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

8
Prelingual Moderate-to-Severe Sensorineural Hearing Loss OBLIGATE Otologic HP:0008504 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Moderate sensorineural hearing impairment (HP:0008504). HP:0008504 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:22981119 SUPPORT Human Clinical
"We show that genetic defects in CABP2 cause moderate-to-severe sensorineural hearing impairment."
The severity range stated by the founding report.
PMID:33666369 SUPPORT Human Clinical
"The hearing loss was in these cases described as prelingual, symmetrical, and moderate to severe."
Confirms prelingual onset and symmetry alongside the severity band.
Prelingual Onset OBLIGATE Otologic HP:0000399 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prelingual sensorineural hearing impairment (HP:0000399). HP:0000399 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33666369 SUPPORT Human Clinical
"We report the first Northern European individual with CABP2-related hearing loss: an 8-year-old Danish Caucasian boy with non-syndromic, prelingual, and sensorineural hearing loss, who is homozygous for the splice site variant CABP2: c."
A case with prelingual onset explicitly stated.
Bilateral Symmetric Involvement OBLIGATE Otologic HP:0008619 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral sensorineural hearing impairment (HP:0008619). HP:0008619 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33666369 SUPPORT Human Clinical
"The hearing loss was in these cases described as prelingual, symmetrical, and moderate to severe."
States symmetry across the previously reported families.
Severe Hearing Loss in a Subset of Families OCCASIONAL Otologic HP:0008625 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe sensorineural hearing impairment (HP:0008625). HP:0008625 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31661684 SUPPORT Human Clinical
"Our results show that CABP2variantsalso cause severe ARNSHL, adding CABP2to the growing list of genes that exhibit phenotypic heterogeneity."
Reports the severe end of the range. The missing spaces are in the source text.
Abnormal Auditory Brainstem Response FREQUENT Otologic HP:0006958 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal auditory evoked potentials (HP:0006958). HP:0006958 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40927552 SUPPORT Human Clinical
"This finding indicated preserved outer hair cell function, identifying the first individual with DFNB93 precisely diagnosed with an auditory synaptopathy."
The human anchor: a genetically confirmed DFNB93 child diagnosed with auditory synaptopathy, which is by definition an abnormal auditory brainstem response alongside preserved emissions.
PMID:40927552 SUPPORT Model Organism
"reduced auditory brainstem responses and increased hearing thresholds despite preserved distortion product otoacoustic emissions corroborating auditory synaptopathy"
The direction of the threshold change, and where the polarity of the model readout comes from. Graded MODEL_ORGANISM because the sentence it is cut from describes a mouse with a deletion of Cabp2 exons 3 and 4; it corroborates the human phenotype above rather than being the evidence for it.
Preserved Otoacoustic Emissions OCCASIONAL Otologic
No phenotype_term binding. HPO codes the negation - HP:6000182 Absent otoacoustic emissions - and has no term for emissions being present, so binding this finding to any existing HP term would assert the opposite of what the node claims. Left as a free-text preferred_term rather than mis-bound; an NTR for a preserved-emissions term would be the right upstream fix.
Show evidence (2 references)
PMID:40927552 SUPPORT Human Clinical
"Otoacoustic emissions have been observed in an Italian family with a homozygous CABP2 variant, indicating preservation of outer hair cell-mediated cochlear amplification."
The human observation of preserved emissions, in the one family where it is reported.
PMID:40927552 SUPPORT Human Clinical
"Measurement of otoacoustic emissions, so far, have been rarely done (Table 2), making comprehensive auditory phenotyping a high priority for further investigations."
Qualifies the frequency: emissions are the discriminating test for this disease and have seldom been performed, so OCCASIONAL records the evidence rather than the expectation.
U-Shaped (Mid-Frequency) Audiometric Configuration FREQUENT Otologic HP:0012781 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mid-frequency hearing loss (HP:0012781). HP:0012781 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:40927552 SUPPORT Human Clinical
"in three consanguineous Iranian families presenting moderate to severe autosomal recessive hearing impairment with characteristic U‐shaped audiograms"
The rule stated directly of the founding families, rather than inferred from a report of an exception to it.
PMID:40927552 SUPPORT Human Clinical
"revealed mid‐frequency, moderate‐to‐severe hearing loss, and transitory evoked otoacoustic emissions"
An independent case with mid-frequency loss, which is the audiometric description this phenotype's HP term names.
PMID:42448438 SUPPORT Human Clinical
"Audiological testing revealed a reverse-slope pattern of hearing loss, differing from the U-shaped pattern associated with previous reports of DFNB93."
Confirms the U-shaped pattern as the previously reported norm, from the report of the one case that departs from it.
Reverse-Slope Audiometric Configuration OCCASIONAL Otologic HP:0008542 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low-frequency hearing loss (HP:0008542). HP:0008542 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42448438 SUPPORT Human Clinical
"Audiological testing revealed a reverse-slope pattern of hearing loss, differing from the U-shaped pattern associated with previous reports of DFNB93."
Reports the configuration and explicitly contrasts it with the previously reported one.
🧬

Genetic Associations

1
CABP2
Gene: CABP2 hgnc:1385 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CABP2 (hgnc:1385). hgnc:1385 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:35150090 SUPPORT Human Clinical
"In both Finnish families, we identified a homozygous pathogenic splice site variant c.637+1G>T in CAPB2 that is known to cause autosomal recessive nonsyndromic hearing impairment."
Independent replication of the recurrent allele in a further population. The gene symbol is transposed in the source.
CGGV:assertion_20de88d2-6681-4522-9e11-26cdf66a2c15-2020-02-06T170000.000Z SUPPORT Other
"Variants in this gene segregated with disease in at least 12 additional family members."
The segregation total behind the Definitive classification.
🗃️

External Assertions

1
ClinGen CABP2-nonsyndromic hearing loss gene-disease validity assertion
ClinGen gene disease validity CGGV:assertion_20de88d2-6681-4522-9e11-26cdf66a2c15-2020-02-06T170000.000Z
The ClinGen Hearing Loss Gene Curation Expert Panel classifies the autosomal recessive CABP2-nonsyndromic hearing loss relationship as Definitive. This is the strongest of the four possible classifications and is stated here explicitly because three of the other DFN loci curated alongside this one are not: the same expert panel rates TSPEAR (DFNB98) and GJB3 (DFNA2B) as Disputed and MET (DFNB97) as Limited.
Show evidence (2 references)
CGGV:assertion_20de88d2-6681-4522-9e11-26cdf66a2c15-2020-02-06T170000.000Z SUPPORT Other
"CABP2 | HGNC:1385 | nonsyndromic genetic hearing loss | MONDO:0019497 | AR | Definitive"
The expert-panel classification row itself, with gene, disease, inheritance mode and verdict.
CGGV:assertion_20de88d2-6681-4522-9e11-26cdf66a2c15-2020-02-06T170000.000Z SUPPORT Other
"In summary, CABP2 is definitively associated with autosomal recessive nonsyndromic hearing loss."
The panel's own summary sentence, which is the conclusion of a scored review of case, segregation and experimental evidence.
💊

Medical Actions

2
Hearing Aids
Amplification is what patients receive in practice, and the reported outcomes are good - the North American case describes a positive prognosis with hearing aids and multidisciplinary follow-up. It is worth stating the tension rather than smoothing it. As a class, auditory synaptopathy patients are described as gaining little from amplification, because the problem is neural encoding rather than sensitivity. DFNB93 sits at the mild end of that class - moderate thresholds and a partial rather than abolished synaptic function - and the individual reports are of benefit. Both statements are cited below; neither is dropped.
Mechanism Target:
Auditory Synaptopathy with Preserved Cochlear Amplification — Amplification raises the stimulus reaching an inner hair cell whose transmitter release is reduced. It compensates for the consequence and does nothing to the channel defect that produces it.
Show evidence (1 reference)
PMID:42448438 SUPPORT Human Clinical
"Hearing aids and multidisciplinary follow-up have led to a positive prognosis."
A reported outcome of amplification in a genetically confirmed DFNB93 patient.
Show evidence (1 reference)
PMID:40927552 SUPPORT Human Clinical
"Patients with auditory synaptopathy and auditory neuropathy typically gain little benefit from using hearing aids, as the functional problem is not hearing sensitivity but neural sound processing."
Graded PARTIAL because it is the general statement about the disease class this entry places DFNB93 in, and it qualifies rather than supports the use of amplification here.
Cochlear Gene Replacement (investigational)
Action: gene therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is gene therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. Ontology label: Gene Therapy NCIT:C15238
Not available to patients. It is listed because the preclinical case is specific and published: CaBP2 re-expression in the double-knockout mouse restores synaptic function and hearing sensitivity, the cochlea is structurally intact in this disease so there is something left to rescue, and a patient registry has been set up to support future trials. The read-across from the otoferlin trials is the field's own argument, and it is an argument about a disease class rather than a result in DFNB93 patients.
Mechanism Target:
Loss of CaBP2 Function at the Inner Hair Cell Ribbon Synapse — Delivering a functional CABP2 coding sequence to inner hair cells restores the missing channel regulator, which is the one node in this pathograph that a replacement therapy can act on directly.
Show evidence (2 references)
PMID:34489639 SUPPORT Model Organism
"We used AAV2/1 and AAV-PHP.eB viral vectors to deliver the Cabp2 coding sequence into IHCs of early postnatal Cabp2-/- mice and assessed the level of restoration of hair cell function and hearing."
The intervention this treatment describes, performed in the single-knockout genotype that matches the human disease.
PMID:39718549 SUPPORT Model Organism
"Transgenic expression of CaBP2 leads to substantial recovery of IHC synaptic function and hearing sensitivity."
A second rescue result, in the double knockout, supporting the same target.
Show evidence (1 reference)
PMID:40927552 SUPPORT Model Organism
"Furthermore, preclinical studies have demonstrated feasibility of gene therapy."
States the preclinical feasibility that is the whole basis for listing this treatment.
🔬

Diagnosis

2
Genetic testing for biallelic CABP2 variants
The diagnosis is molecular. CABP2 is small and is on comprehensive hearing-loss gene panels and exome pipelines; in every reported case the finding was a homozygous variant, most often c.637+1G>T. Ancestry matters to the pretest probability: the allele is a founder in Iranian, Turkish and Pakistani families and is enriched in Finland.
Show evidence (1 reference)
PMID:32860223 SUPPORT Human Clinical
"Other genes (AIFM1, CABP2, DIAPH1, PTPRQ, RDX, SLC26A4, TBC1D24, TECTA, TMC1) that explained the cause of hearing impairment were further detected in only one patient for each gene."
A measured panel/exome yield: CABP2 explained one of the 54 solved cases in an unselected Czech prelingual hearing-loss cohort, which is the diagnostic frequency to expect from this test rather than a general statement about sequencing.
Audiological testing including otoacoustic emissions
Because the outer hair cells are spared, emissions testing is the discriminating study. Emissions present alongside an abnormal auditory brainstem response places the patient in the synaptopathy group and changes what to expect from amplification. Recording emissions is not optional in a suspected DFNB93 case; it is the finding that distinguishes it.
Show evidence (1 reference)
PMID:40927552 SUPPORT Human Clinical
"Otoacoustic emissions have been observed in an Italian family with a homozygous CABP2 variant, indicating preservation of outer hair cell-mediated cochlear amplification."
The human emissions finding this test is looking for.
📊

Prevalence

2
Worldwide
Cases In Literature Not yet documented
Fewer than a dozen families were on record when the most recent count was published: four variants across eight families from Iran, Turkey, Pakistan, Italy and Denmark, subsequently joined by two Finnish families and a first North American case. No population prevalence estimate exists and none would be meaningful at this evidence base. The one place where a rate has been measured is the Finnish founder allele, which is recorded separately below.
Show evidence (1 reference)
PMID:35150090 SUPPORT Human Clinical
"Four CABP2 variants have been reported to underlie autosomal recessive nonsyndromic hearing impairment in eight families from Iran, Turkey, Pakistan, Italy, and Denmark."
The published family count and its geographic spread at the time of writing.
Finland
Carrier Frequency Unknown
The recurrent splice allele c.637+1G>T is enriched in the Finnish population by founder effect, where it is reported as the second most frequent autosomal recessive nonsyndromic hearing impairment allele after GJB2. The source gives an allele frequency rather than a disease rate, so no prevalence class is asserted.
Show evidence (1 reference)
PMID:35150090 SUPPORT Human Clinical
"The c.637+1G>T variant is enriched in the Finnish population, which has undergone multiple bottlenecks that can lead to the higher frequency of certain variants including those involved in disease."
States the enrichment and attributes it to the Finnish population bottleneck.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Autosomal Recessive Nonsyndromic Hearing Loss 93:

🐁

Animal Models

3
Cabp2 knockout mouse
The single-gene knockout, matching the human genotype in kind. It is the source of the mechanism: the localisation of CaBP2 to inner hair cells, the enhanced channel inactivation, the normal channel number and ribbon count, and the reduced afferent firing. Crucially it also reproduces the human dissociation - intact cochlear amplification with abnormal brainstem responses - which is what licenses reading the mouse mechanism across to the patients.
Species
Mouse
Genotype
Cabp2 LacZ/LacZ (constitutive knockout, homozygous)
Publication
PMID:28183797
Pathograph links
Enhanced CaV1.3 Calcium-Channel Inactivation recapitulates fidelity: high The defining channel defect, measured directly by patch clamp in the correct cell type.
Limitations: A constitutive null, whereas the commonest human allele produces a truncated protein with residual, weakened CaV1.3 regulation rather than none. The mouse therefore models the severe end of the allelic range. The cochlear apex is also mildly affected relative to more basal positions, so a whole-cochlea statement flattens a tonotopic gradient.
Readouts
CaV1.3 calcium-current inactivation in inner hair cells
Direction: INCREASED
Interpretation: Inactivation of the presynaptic calcium current is increased in the absence of CaBP2, which is the primary channel-level defect of this disease.
Show evidence (1 reference)
PMID:28183797 SUPPORT Model Organism
"Patch-clamp recordings from Cabp2LacZ/LacZ IHCs revealed enhanced Ca2+-channel inactivation."
The patch-clamp measurement behind this readout.
Show evidence (1 reference)
PMID:28183797 SUPPORT Model Organism
"We propose that CaBP2 inhibits CaV1.3 Ca2+-channel inactivation, and thus sustains the availability of CaV1.3 Ca2+ channels for synaptic sound encoding."
Supports treating this model as the definitional system for the channel node.
Auditory Synaptopathy with Preserved Cochlear Amplification recapitulates fidelity: high The mouse shows the same dissociation as the patients: the cochlear amplifier works and the brainstem response does not.
Limitations: Cochlear amplification is assayed in the mouse by distortion-product otoacoustic emissions and in patients by clinical emissions testing; the two are analogous rather than identical measurements, and the human observation comes from a single family.
Readouts
Cochlear amplification (otoacoustic emissions)
Direction: UNCHANGED
Interpretation: Outer hair cell amplification is preserved, establishing that the lesion is downstream of the cochlear amplifier. A deliberate negative result.
Show evidence (1 reference)
PMID:28183797 SUPPORT Model Organism
"Cabp2LacZ/LacZ mice displayed intact cochlear amplification but impaired auditory brainstem responses."
The measurement of preserved amplification.
Auditory brainstem response threshold
Direction: INCREASED
Interpretation: Brainstem response thresholds are elevated despite the intact amplifier, which is the synaptopathic pattern. The direction is INCREASED because the readout is a threshold: an impaired ABR means more sound is needed to evoke a response, and the review literature describes the human finding the same way - reduced responses with increased thresholds.
Show evidence (1 reference)
PMID:28183797 SUPPORT Model Organism
"Cabp2LacZ/LacZ mice displayed intact cochlear amplification but impaired auditory brainstem responses."
The same sentence reports both halves of the dissociation.
Show evidence (1 reference)
PMID:40927552 SUPPORT Model Organism
"DFNB93 mouse models have recapitulated findings and demonstrated that lack of CaBP2 impairs synaptic sound encoding by enhanced steady-state inactivation of CaV1.3 Ca2+ channels."
An independent statement that the mouse models recapitulate the human findings, which is the claim this link makes.
Cabp1/Cabp2 double-knockout mouse with AAV CaBP2 rescue
Removing the partially redundant paralogue CaBP1 as well produces a much more severe synaptic phenotype than the single knockout, and that severity is the point: it makes the exocytosis deficit and the afferent-firing deficit large enough to measure cleanly, and it provides a window in which a rescue can be seen. Delivering Cabp2 into the inner ear substantially recovers both synaptic function and hearing sensitivity, which is the experiment underlying the claim that DFNB93 is a gene-therapy candidate.
Species
Mouse
Genotype
Cabp1-/-; Cabp2-/- double knockout, with and without AAV-PHP.eB-mediated Cabp2 transgene delivery
Publication
PMID:39718549
Pathograph links
Impaired Sustained Exocytosis at the Inner Hair Cell Ribbon Synapse recapitulates fidelity: moderate The sustained component of exocytosis fails, and afferent responses become strongly rate-dependent.
Limitations: Two genes are removed, not one. Human DFNB93 patients are CABP2-biallelic with intact CABP1, so this animal is more severely affected than the disease it stands for and its quantitative deficits should not be read as DFNB93 magnitudes. It earns its place by isolating the mechanism, not by matching the genotype.
Readouts
Sustained exocytosis in inner hair cells
Direction: DECREASED
Interpretation: Sustained vesicle release is reduced when CaV1.3 inactivation is unopposed.
Show evidence (1 reference)
PMID:39718549 SUPPORT Model Organism
"In Cabp1/2 double-knockout mice, we find strongly enhanced CaV1.3 inactivation, slowed recovery from inactivation and impaired sustained exocytosis."
The exocytosis measurement behind this readout.
Show evidence (1 reference)
PMID:39718549 SUPPORT Model Organism
"To encode continuous sound stimuli, the inner hair cell (IHC) ribbon synapses utilize calcium-binding proteins (CaBPs), which reduce the inactivation of their CaV1.3 calcium channels."
States the function this model was built to interrogate.
Auditory Synaptopathy with Preserved Cochlear Amplification rescues fidelity: moderate Transgenic re-expression of CaBP2 in the inner ear substantially restores synaptic function and hearing sensitivity, showing that the deficit is reversible by replacing the missing protein and not the consequence of an irreversible developmental defect.
Limitations: Recovery is substantial but partial, the rescue restores only CaBP2 in an animal lacking both paralogues, and the voltage shift in channel activation persists after re-expression. Timing relative to the human therapeutic window is not addressed.
Readouts
Hearing sensitivity and inner hair cell synaptic function after Cabp2 delivery
Direction: RESTORED
Interpretation: Both synaptic function and hearing sensitivity improve after gene delivery, which is the preclinical basis for treating DFNB93 as a gene replacement target.
Show evidence (1 reference)
PMID:39718549 SUPPORT Model Organism
"Transgenic expression of CaBP2 leads to substantial recovery of IHC synaptic function and hearing sensitivity."
The rescue result behind this readout.
Show evidence (1 reference)
PMID:40927552 SUPPORT Model Organism
"Furthermore, preclinical studies have demonstrated feasibility of gene therapy."
Independent confirmation that the rescue is read by the field as preclinical feasibility evidence.
Cabp2 knockout mouse with AAV-mediated Cabp2 gene replacement
The gene therapy experiment done in the right genotype. Unlike the double knockout, this is the single Cabp2 null - the animal that matches the human disease - and the intervention is a cochlear delivery route that could plausibly be used in a patient: a round-window injection of AAV carrying the Cabp2 coding sequence, given in the first week of life. It is the strongest preclinical result this entity has, and it is why the disease is named as a gene therapy candidate rather than merely speculated about. The paper also states the property that makes the window wide: hair cells in these mice develop normally and do not degenerate early, so there is intact cochlea left to rescue.
Species
Mouse
Genotype
Cabp2-/- (constitutive knockout) with AAV2/1 or AAV-PHP.eB Cabp2 delivered by round-window injection at postnatal day 5-7
Publication
PMID:34489639
Pathograph links
Loss of CaBP2 Function at the Inner Hair Cell Ribbon Synapse rescues fidelity: moderate Delivering the Cabp2 coding sequence into inner hair cells restores the missing channel regulator in the genotype that matches the human disease, recovering the non-inactivating CaV1.3 current and improving hearing.
Limitations: The rescue is partial rather than complete, and it was given at postnatal day 5 to 7 - before hearing onset in the mouse, and therefore earlier in auditory development than a human infant diagnosed on newborn screening would be treated. Hearing was assessed at 5 to 8 weeks, so durability beyond that is not addressed. Transduction was unilateral, with the contralateral ear as the internal control.
Readouts
Restored CaBP2 function, read out as inner hair cell CaV1.3 current inactivation
Direction: RESTORED
Interpretation: CaBP2 function is not measured directly; it is measured by its only known effect, the non-inactivating character of the CaV1.3 current, which is restored after delivery. That is the molecular defect of this disease being reversed rather than compensated for. The readout repeats the link's target because restoring the protein is what the intervention does; the channel is the instrument.
Show evidence (1 reference)
PMID:34489639 SUPPORT Model Organism
"we observed high transduction efficiency, and restoration of IHC CaV1.3 function resulting in improved hearing of Cabp2-/- mice."
The channel and hearing measurements behind this readout.
Show evidence (1 reference)
PMID:34489639 SUPPORT Model Organism
"These preclinical results prove the feasibility of DFNB93 gene therapy."
The paper's own conclusion, which is the claim this link makes.
{ }

Source YAML

click to show 
name: Autosomal Recessive Nonsyndromic Hearing Loss 93
creation_date: "2026-08-28T19:30:00Z"
category: Mendelian
disease_term:
  preferred_term: autosomal recessive nonsyndromic hearing loss 93
  term:
    id: MONDO:0013963
    label: autosomal recessive nonsyndromic hearing loss 93
synonyms:
- DFNB93
- deafness, autosomal recessive 93
- CABP2-related autosomal recessive nonsyndromic hearing loss
- autosomal recessive nonsyndromic deafness 93
description: >-
  Prelingual, symmetric, moderate-to-severe sensorineural hearing loss caused by biallelic
  variants in CABP2, which encodes calcium-binding protein 2. The lesion is at one synapse.
  CaBP2 sits presynaptically in the cochlear inner hair cell and holds the CaV1.3 calcium
  channel open: it suppresses the channel's inactivation, so that a hair cell depolarised
  continuously by an ongoing sound keeps enough channels available to keep releasing
  transmitter. Remove CaBP2 and the channels inactivate; the sustained component of
  exocytosis collapses; the spiral ganglion neurons downstream fire less, spontaneously and
  to sound.

  What follows from that is the feature which makes this entry worth separating from the
  rest of the DFNB series. Outer hair cells are untouched, so cochlear amplification is
  preserved and otoacoustic emissions are present while the auditory brainstem response is
  abnormal. That combination is the definition of auditory synaptopathy, and the mouse
  paper that established the mechanism says so in its own conclusion. DFNB93 is therefore a
  synaptopathy that happens to sit in the nonsyndromic-deafness nomenclature, and it belongs
  beside OTOF rather than beside the hair-bundle genes it is numbered among.

  Clinically this matters twice over. Amplification addresses sensitivity, and sensitivity
  is not the deficit here. And because the organ of Corti is structurally intact, DFNB93 is
  a named candidate for cochlear gene replacement, with a mouse rescue already demonstrated.

parents:
- Autosomal Recessive Nonsyndromic Hearing Loss
- Hereditary Hearing Loss

external_assertions:
- name: ClinGen CABP2-nonsyndromic hearing loss gene-disease validity assertion
  source: ClinGen
  assertion_type: gene_disease_validity
  external_id: CGGV:assertion_20de88d2-6681-4522-9e11-26cdf66a2c15-2020-02-06T170000.000Z
  url: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_20de88d2-6681-4522-9e11-26cdf66a2c15-2020-02-06T170000.000Z
  description: >-
    The ClinGen Hearing Loss Gene Curation Expert Panel classifies the autosomal recessive
    CABP2-nonsyndromic hearing loss relationship as Definitive. This is the strongest of the
    four possible classifications and is stated here explicitly because three of the other
    DFN loci curated alongside this one are not: the same expert panel rates TSPEAR
    (DFNB98) and GJB3 (DFNA2B) as Disputed and MET (DFNB97) as Limited.
  evidence:
  - reference: CGGV:assertion_20de88d2-6681-4522-9e11-26cdf66a2c15-2020-02-06T170000.000Z
    reference_title: CABP2 / nonsyndromic genetic hearing loss (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CABP2 | HGNC:1385 | nonsyndromic genetic hearing loss | MONDO:0019497 | AR | Definitive"
    explanation: >-
      The expert-panel classification row itself, with gene, disease, inheritance mode and
      verdict.
  - reference: CGGV:assertion_20de88d2-6681-4522-9e11-26cdf66a2c15-2020-02-06T170000.000Z
    reference_title: CABP2 / nonsyndromic genetic hearing loss (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In summary, CABP2 is definitively associated with autosomal recessive nonsyndromic
      hearing loss.
    explanation: >-
      The panel's own summary sentence, which is the conclusion of a scored review of case,
      segregation and experimental evidence.

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    Fewer than a dozen families were on record when the most recent count was published:
    four variants across eight families from Iran, Turkey, Pakistan, Italy and Denmark,
    subsequently joined by two Finnish families and a first North American case. No
    population prevalence estimate exists and none would be meaningful at this evidence
    base. The one place where a rate has been measured is the Finnish founder allele, which
    is recorded separately below.
  evidence:
  - reference: PMID:35150090
    reference_title: "Autosomal recessive nonsyndromic hearing impairment in two Finnish families due to the population enriched CABP2 c.637+1G>T variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four CABP2 variants have been reported to underlie autosomal recessive nonsyndromic
      hearing impairment in eight families from Iran, Turkey, Pakistan, Italy, and Denmark.
    explanation: >-
      The published family count and its geographic spread at the time of writing.

- population: Finland
  measure_type: CARRIER_FREQUENCY
  prevalence_class: UNKNOWN
  notes: >-
    The recurrent splice allele c.637+1G>T is enriched in the Finnish population by founder
    effect, where it is reported as the second most frequent autosomal recessive
    nonsyndromic hearing impairment allele after GJB2. The source gives an allele frequency
    rather than a disease rate, so no prevalence class is asserted.
  evidence:
  - reference: PMID:35150090
    reference_title: "Autosomal recessive nonsyndromic hearing impairment in two Finnish families due to the population enriched CABP2 c.637+1G>T variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The c.637+1G>T variant is enriched in the Finnish population, which has undergone
      multiple bottlenecks that can lead to the higher frequency of certain variants
      including those involved in disease.
    explanation: >-
      States the enrichment and attributes it to the Finnish population bottleneck.

pathophysiology:

- name: Biallelic CABP2 Loss-of-Function Variant
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    The recurrent allele, and the one that accounts for most reported families, is the
    splice-donor variant c.637+1G>T. It causes skipping of exon 6 and a frameshift,
    p.Phe164Serfs*4, truncating the protein. Nonsense and missense alleles have also been
    reported.

    The truncated product is not simply absent from the cell: it was made and tested, and it
    binds calcium abnormally and regulates CaV1.3 less effectively than wild type. The
    functional claim of this entry therefore rests on a measured hypomorph, not only on an
    inferred null.
  genetic_context:
    gene:
      preferred_term: CABP2
      term:
        id: hgnc:1385
        label: CABP2
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Homozygous in every reported family. The founding families were consanguineous; the
      Danish and Finnish cases were not, and reflect a shared founder haplotype instead.
  downstream:
  - target: Loss of CaBP2 Function at the Inner Hair Cell Ribbon Synapse
    causal_link_type: DIRECT
    description: >-
      The truncated protein cannot perform the CaV1.3 regulation that is CaBP2's job in the
      inner hair cell.
  evidence:
  - reference: PMID:22981119
    reference_title: "A mutation in CABP2, expressed in cochlear hair cells, causes autosomal-recessive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified a splice-site mutation (c.637+1G>T) in Ca(2+)-binding protein 2 (CABP2)
      in three consanguineous Iranian families affected by moderate-to-severe hearing loss.
    explanation: >-
      The founding families and the recurrent allele.
  - reference: PMID:22981119
    reference_title: "A mutation in CABP2, expressed in cochlear hair cells, causes autosomal-recessive hearing impairment."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Compared with wild-type CaBP2, the truncated CaBP2 showed altered Ca(2+) binding in
      isothermal titration calorimetry and less potent regulation of Ca(v)1.3 Ca(2+)
      channels.
    explanation: >-
      The biochemical and channel-regulation consequence of the truncation, measured outside
      an organism, which is why this item is graded IN_VITRO while the family report above
      from the same paper is HUMAN_CLINICAL.

- name: Loss of CaBP2 Function at the Inner Hair Cell Ribbon Synapse
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    CaBP2 is expressed by cochlear hair cells and preferentially by inner hair cells. It is
    not in the postsynaptic spiral ganglion neuron, which fixes the lesion on the presynaptic
    side of the synapse and is the reason this disease is a synaptopathy rather than a
    neuropathy of the auditory nerve itself.
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  molecular_functions:
  - preferred_term: CaV1.3 calcium channel regulation by CaBP2
    term:
      id: GO:0005246
      label: calcium channel regulator activity
    modifier: DECREASED
  downstream:
  - target: Enhanced CaV1.3 Calcium-Channel Inactivation
    causal_link_type: DIRECT
    description: >-
      CaBP2's specific action is to suppress inactivation; without it the suppression is
      lifted.
  evidence:
  - reference: PMID:28183797
    reference_title: Ca(2+)-binding protein 2 inhibits Ca(2+)-channel inactivation in mouse inner hair cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      CaBP2 was expressed by cochlear hair cells, preferentially in inner hair cells (IHCs),
      and was lacking from the postsynaptic spiral ganglion neurons (SGNs).
    explanation: >-
      Localises the protein to the presynaptic side, which is what makes the rest of the
      chain a presynaptic account.

- name: Enhanced CaV1.3 Calcium-Channel Inactivation
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    In inner hair cells lacking CaBP2 the CaV1.3 current inactivates more than it should.
    The channels are not fewer and they do not open at the wrong voltage - channel number
    and the voltage dependence of activation are normal, and so is the ribbon synapse count.
    What changes is availability over time. A hair cell responding to a continuing sound is
    held depolarised, and under that condition an inactivating channel population steadily
    withdraws from service.
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  molecular_functions:
  - preferred_term: available presynaptic CaV1.3 current
    term:
      id: GO:0005245
      label: voltage-gated calcium channel activity
    modifier: DECREASED
  downstream:
  - target: Impaired Sustained Exocytosis at the Inner Hair Cell Ribbon Synapse
    causal_link_type: DIRECT
    description: >-
      Transmitter release at this synapse is driven by the calcium that enters through these
      channels, so a shrinking available current is a shrinking release drive.
  evidence:
  - reference: PMID:28183797
    reference_title: Ca(2+)-binding protein 2 inhibits Ca(2+)-channel inactivation in mouse inner hair cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Patch-clamp recordings from Cabp2LacZ/LacZ IHCs revealed enhanced Ca2+-channel
      inactivation.
    explanation: >-
      The direct measurement of the inactivation defect in the cell type that matters.
  - reference: PMID:28183797
    reference_title: Ca(2+)-binding protein 2 inhibits Ca(2+)-channel inactivation in mouse inner hair cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We propose that CaBP2 inhibits CaV1.3 Ca2+-channel inactivation, and thus sustains the
      availability of CaV1.3 Ca2+ channels for synaptic sound encoding.
    explanation: >-
      States the mechanism in the availability terms this node uses.

- name: Impaired Sustained Exocytosis at the Inner Hair Cell Ribbon Synapse
  role: central_effector
  biological_scale: CELLULAR
  description: >-
    The consequence of reduced channel availability is that the sustained component of
    vesicle release fails. In the double-knockout preparation, where the phenotype is most
    severe because the partially redundant CaBP1 is removed as well, even mild activation
    reduces the channel pool enough that synapses may be effectively silenced.
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  biological_processes:
  - preferred_term: sustained synaptic vesicle exocytosis at the hair cell ribbon synapse
    term:
      id: GO:0016079
      label: synaptic vesicle exocytosis
    modifier: DECREASED
  downstream:
  - target: Reduced Spiral Ganglion Neuron Firing
    causal_link_type: DIRECT
    description: >-
      Less transmitter released onto the afferent terminal means less afferent drive.
  evidence:
  - reference: PMID:39718549
    reference_title: CaBP1 and 2 enable sustained Ca(V)1.3 calcium currents and synaptic transmission in inner hair cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In Cabp1/2 double-knockout mice, we find strongly enhanced CaV1.3 inactivation, slowed
      recovery from inactivation and impaired sustained exocytosis.
    explanation: >-
      Links the channel defect to the exocytosis defect in the same preparation. Note this
      is the double knockout, so it overstates what loss of CaBP2 alone does; the
      single-knockout severity is recorded on the animal model entry.

- name: Reduced Spiral Ganglion Neuron Firing
  role: consequence
  biological_scale: CELLULAR
  description: >-
    Single-unit recordings from spiral ganglion neurons show reduced spontaneous and
    sound-evoked firing. The neurons themselves are not the lesion - CaBP2 is not expressed
    in them - so this is a readout of presynaptic failure, and it is the step at which the
    defect becomes something an auditory brainstem response can see.
  cell_types:
  - preferred_term: spiral ganglion neuron
    term:
      id: CL:0011113
      label: spiral ganglion neuron
  biological_processes:
  - preferred_term: afferent auditory nerve firing
    term:
      id: GO:0019228
      label: neuronal action potential
    modifier: DECREASED
  downstream:
  - target: Auditory Synaptopathy with Preserved Cochlear Amplification
    causal_link_type: DIRECT
    description: >-
      Degraded afferent encoding with an intact cochlear amplifier upstream of it.
  evidence:
  - reference: PMID:28183797
    reference_title: Ca(2+)-binding protein 2 inhibits Ca(2+)-channel inactivation in mouse inner hair cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Recordings from single SGNs showed reduced spontaneous and sound-evoked firing rates.
    explanation: >-
      The afferent firing measurement itself.
  - reference: PMID:39718549
    reference_title: CaBP1 and 2 enable sustained Ca(V)1.3 calcium currents and synaptic transmission in inner hair cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Spontaneous and sound-evoked responses of spiral ganglion neurons in vivo are
      strikingly reduced and strongly depend on stimulation rates.
    explanation: >-
      Adds the rate dependence, which is the in vivo signature of a channel pool that
      recovers too slowly from inactivation.

- name: Auditory Synaptopathy with Preserved Cochlear Amplification
  role: consequence
  biological_scale: ORGANISM
  description: >-
    The end state is a dissociation. Outer hair cells never enter the mechanism, so
    otoacoustic emissions are present and cochlear amplification is intact, while the
    auditory brainstem response is abnormal because what reaches the brainstem has been
    degraded at the synapse. That pattern is the operational definition of auditory
    synaptopathy, and both the mouse work and the clinical perspective paper state the
    classification explicitly rather than leaving it to be inferred.
  biological_processes:
  - preferred_term: sensory perception of sound
    term:
      id: GO:0007605
      label: sensory perception of sound
    modifier: DECREASED
  evidence:
  - reference: PMID:28183797
    reference_title: Ca(2+)-binding protein 2 inhibits Ca(2+)-channel inactivation in mouse inner hair cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Therefore, we conclude that human deafness DFNB93 is an auditory synaptopathy.
    explanation: >-
      The classification stated by the paper that established the mechanism.
  - 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: >-
      The human observation of preserved outer hair cell function, which is what makes the
      mouse classification transferable rather than assumed.
  - 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: >-
      Hence, DFNB93 belongs to the hearing disorders caused by impairment of IHC synapses,
      termed auditory synaptopathy.
    explanation: >-
      States the classification for the human disease.

phenotypes:

- category: Otologic
  name: Prelingual Moderate-to-Severe Sensorineural Hearing Loss
  frequency: OBLIGATE
  severity: MODERATE
  description: >-
    The characteristic presentation is bilateral, symmetric, prelingual and in the
    moderate-to-severe range - milder than most DFNB forms, which is itself a diagnostic
    clue. Severity is not uniform: one Iranian family is reported with severe loss, and the
    entry records that separately rather than flattening the range.
  phenotype_term:
    preferred_term: Moderate sensorineural hearing impairment
    term:
      id: HP:0008504
      label: Moderate sensorineural hearing impairment
  evidence:
  - reference: PMID:22981119
    reference_title: "A mutation in CABP2, expressed in cochlear hair cells, causes autosomal-recessive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We show that genetic defects in CABP2 cause moderate-to-severe sensorineural hearing
      impairment.
    explanation: >-
      The severity range stated by the founding report.
  - reference: PMID:33666369
    reference_title: First reported CABP2-related non-syndromic hearing loss in Northern Europe.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The hearing loss was in these cases described as prelingual, symmetrical, and moderate
      to severe.
    explanation: >-
      Confirms prelingual onset and symmetry alongside the severity band.

- category: Otologic
  name: Prelingual Onset
  frequency: OBLIGATE
  description: >-
    Onset before speech acquisition. This is what puts the diagnosis inside the newborn and
    infant screening window and makes the choice of habilitation an early decision rather
    than a later one.
  phenotype_term:
    preferred_term: Prelingual sensorineural hearing impairment
    term:
      id: HP:0000399
      label: Prelingual sensorineural hearing impairment
  evidence:
  - reference: PMID:33666369
    reference_title: First reported CABP2-related non-syndromic hearing loss in Northern Europe.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report the first Northern European individual with CABP2-related hearing loss: an
      8-year-old Danish Caucasian boy with non-syndromic, prelingual, and sensorineural
      hearing loss, who is homozygous for the splice site variant CABP2: c.
    explanation: >-
      A case with prelingual onset explicitly stated.

- category: Otologic
  name: Bilateral Symmetric Involvement
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Bilateral sensorineural hearing impairment
    term:
      id: HP:0008619
      label: Bilateral sensorineural hearing impairment
  description: >-
    Both ears, and to a similar degree. Asymmetry should prompt a search for a different
    cause.
  evidence:
  - reference: PMID:33666369
    reference_title: First reported CABP2-related non-syndromic hearing loss in Northern Europe.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The hearing loss was in these cases described as prelingual, symmetrical, and moderate
      to severe.
    explanation: >-
      States symmetry across the previously reported families.

- category: Otologic
  name: Severe Hearing Loss in a Subset of Families
  frequency: OCCASIONAL
  severity: SEVERE
  description: >-
    A missense allele, c.311G>A, was reported in an Iranian family with severe rather than
    moderate loss. The report frames this as widening the CABP2 phenotypic range, so the
    moderate band above should be read as typical rather than defining.
  phenotype_term:
    preferred_term: Severe sensorineural hearing impairment
    term:
      id: HP:0008625
      label: Severe sensorineural hearing impairment
  evidence:
  - reference: PMID:31661684
    reference_title: A Novel Pathogenic Variant in the CABP2 Gene Causes Severe Nonsyndromic Hearing Loss in a Consanguineous Iranian Family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results show that CABP2variantsalso cause severe ARNSHL, adding CABP2to the growing
      list of genes that exhibit phenotypic heterogeneity.
    explanation: >-
      Reports the severe end of the range. The missing spaces are in the source text.

- category: Otologic
  name: Abnormal Auditory Brainstem Response
  frequency: FREQUENT
  description: >-
    Brainstem responses are degraded because what reaches the brainstem has been degraded at
    the synapse. Together with the preserved emissions recorded separately below, this is the
    dissociation that defines the disease as a synaptopathy.
  phenotype_term:
    preferred_term: Abnormal auditory evoked potentials
    term:
      id: HP:0006958
      label: Abnormal auditory evoked potentials
  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: >-
      This finding indicated preserved outer hair cell function, identifying the first
      individual with DFNB93 precisely diagnosed with an auditory synaptopathy.
    explanation: >-
      The human anchor: a genetically confirmed DFNB93 child diagnosed with auditory
      synaptopathy, which is by definition an abnormal auditory brainstem response alongside
      preserved emissions.
  - reference: PMID:40927552
    reference_title: "Is CABP2-Associated Hearing Loss (DFNB93) a Gene Therapy Target? Preclinical Progress and Patient Registry."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      reduced auditory brainstem responses and increased hearing thresholds despite preserved
      distortion product otoacoustic emissions corroborating auditory synaptopathy
    explanation: >-
      The direction of the threshold change, and where the polarity of the model readout comes
      from. Graded MODEL_ORGANISM because the sentence it is cut from describes a mouse with a
      deletion of Cabp2 exons 3 and 4; it corroborates the human phenotype above rather than
      being the evidence for it.

- category: Otologic
  name: Preserved Otoacoustic Emissions
  frequency: OCCASIONAL
  description: >-
    Emissions are present because the outer hair cells are not part of the mechanism. This is
    the finding that separates DFNB93 from a cochlear hair-cell deafness at the audiology
    bench, and it is why the entry classifies the disease as a synaptopathy.

    Frequency is OCCASIONAL because it reflects what has been measured, not what is believed.
    Emissions have been reported in one Italian family, and the review that reports them says
    in the same table that emissions testing has rarely been done in DFNB93 at all. The
    mechanism predicts they should usually be present; the evidence base does not yet say so.
  phenotype_term:
    preferred_term: Preserved otoacoustic emissions
  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: >-
      The human observation of preserved emissions, in the one family where it is reported.
  - 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: >-
      Measurement of otoacoustic emissions, so far, have been rarely done (Table 2), making
      comprehensive auditory phenotyping a high priority for further investigations.
    explanation: >-
      Qualifies the frequency: emissions are the discriminating test for this disease and have
      seldom been performed, so OCCASIONAL records the evidence rather than the expectation.
  notes: >-
    No phenotype_term binding. HPO codes the negation - HP:6000182 Absent otoacoustic
    emissions - and has no term for emissions being present, so binding this finding to any
    existing HP term would assert the opposite of what the node claims. Left as a free-text
    preferred_term rather than mis-bound; an NTR for a preserved-emissions term would be the
    right upstream fix.

- category: Otologic
  name: U-Shaped (Mid-Frequency) Audiometric Configuration
  frequency: FREQUENT
  description: >-
    The audiogram shape usually reported in DFNB93 is U-shaped, with mid frequencies worst
    affected. Audiogram shape is used in practice to decide which genes to sequence, so the
    characteristic pattern belongs in the entry alongside the one atypical case recorded
    below - curating the exception without the rule would invert the diagnostic signal.
  phenotype_term:
    preferred_term: Mid-frequency hearing loss
    term:
      id: HP:0012781
      label: Mid-frequency hearing loss
  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: "in three consanguineous Iranian families presenting moderate to severe autosomal recessive hearing impairment with characteristic U‐shaped audiograms"
    explanation: >-
      The rule stated directly of the founding families, rather than inferred from a report of
      an exception to it.
  - 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: "revealed mid‐frequency, moderate‐to‐severe hearing loss, and transitory evoked otoacoustic emissions"
    explanation: >-
      An independent case with mid-frequency loss, which is the audiometric description this
      phenotype's HP term names.
  - reference: PMID:42448438
    reference_title: First reported North American calcium binding protein 2-related non-syndromic hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Audiological testing revealed a reverse-slope pattern of hearing loss, differing from
      the U-shaped pattern associated with previous reports of DFNB93.
    explanation: >-
      Confirms the U-shaped pattern as the previously reported norm, from the report of the one
      case that departs from it.

- category: Otologic
  name: Reverse-Slope Audiometric Configuration
  frequency: OCCASIONAL
  description: >-
    The audiogram shape reported in DFNB93 has usually been U-shaped. The first North
    American case had a reverse-slope configuration instead, with low frequencies worse
    affected. One case is not a pattern, but it is recorded because audiogram shape is used
    in practice to decide which genes to sequence.
  phenotype_term:
    preferred_term: Low-frequency hearing loss
    term:
      id: HP:0008542
      label: Low-frequency hearing loss
  evidence:
  - reference: PMID:42448438
    reference_title: First reported North American calcium binding protein 2-related non-syndromic hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Audiological testing revealed a reverse-slope pattern of hearing loss, differing from
      the U-shaped pattern associated with previous reports of DFNB93.
    explanation: >-
      Reports the configuration and explicitly contrasts it with the previously reported one.

genetic:

- name: CABP2
  gene_term:
    preferred_term: CABP2
    term:
      id: hgnc:1385
      label: CABP2
  relationship_type: CAUSATIVE
  notes: >-
    The single causal gene. It encodes calcium-binding protein 2, a calmodulin-related
    EF-hand protein of the CaBP family expressed in the cochlea and retina, whose relevant
    effector here is the CaV1.3 channel of the inner hair cell.

    Four variants across eight families were on record at the last published count; the
    splice-donor allele c.637+1G>T recurs across most of them and is a founder allele in
    both the Middle Eastern and the Northern European families, where a shared haplotype was
    demonstrated rather than assumed.
  evidence:
  - reference: PMID:35150090
    reference_title: "Autosomal recessive nonsyndromic hearing impairment in two Finnish families due to the population enriched CABP2 c.637+1G>T variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In both Finnish families, we identified a homozygous pathogenic splice site variant
      c.637+1G>T in CAPB2 that is known to cause autosomal recessive nonsyndromic hearing
      impairment.
    explanation: >-
      Independent replication of the recurrent allele in a further population. The gene
      symbol is transposed in the source.
  - reference: CGGV:assertion_20de88d2-6681-4522-9e11-26cdf66a2c15-2020-02-06T170000.000Z
    reference_title: CABP2 / nonsyndromic genetic hearing loss (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Variants in this gene segregated with disease in at least 12 additional family
      members.
    explanation: >-
      The segregation total behind the Definitive classification.

inheritance:

- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Every reported proband is homozygous and heterozygous relatives are unaffected. The
    founding families were consanguineous Iranian kindreds; the Danish and Finnish cases were
    not consanguineous, and in the Danish case a run of homozygosity spanning CABP2 pointed
    to a distant shared ancestor instead.
  evidence:
  - reference: PMID:22981119
    reference_title: "A mutation in CABP2, expressed in cochlear hair cells, causes autosomal-recessive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified a splice-site mutation (c.637+1G>T) in Ca(2+)-binding protein 2 (CABP2)
      in three consanguineous Iranian families affected by moderate-to-severe hearing loss.
    explanation: >-
      Homozygosity in consanguineous kindreds, the founding recessive observation.

animal_models:

- name: Cabp2 knockout mouse
  species: Mouse
  genotype: Cabp2 LacZ/LacZ (constitutive knockout, homozygous)
  publication: PMID:28183797
  description: >-
    The single-gene knockout, matching the human genotype in kind. It is the source of the
    mechanism: the localisation of CaBP2 to inner hair cells, the enhanced channel
    inactivation, the normal channel number and ribbon count, and the reduced afferent
    firing. Crucially it also reproduces the human dissociation - intact cochlear
    amplification with abnormal brainstem responses - which is what licenses reading the
    mouse mechanism across to the patients.
  modeled_mechanisms:
  - target: Enhanced CaV1.3 Calcium-Channel Inactivation
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      The defining channel defect, measured directly by patch clamp in the correct cell
      type.
    limitations: >-
      A constitutive null, whereas the commonest human allele produces a truncated protein
      with residual, weakened CaV1.3 regulation rather than none. The mouse therefore models
      the severe end of the allelic range. The cochlear apex is also mildly affected relative
      to more basal positions, so a whole-cochlea statement flattens a tonotopic gradient.
    readouts:
    - name: CaV1.3 calcium-current inactivation in inner hair cells
      target: Enhanced CaV1.3 Calcium-Channel Inactivation
      direction: INCREASED
      interpretation: >-
        Inactivation of the presynaptic calcium current is increased in the absence of
        CaBP2, which is the primary channel-level defect of this disease.
      evidence:
      - reference: PMID:28183797
        reference_title: Ca(2+)-binding protein 2 inhibits Ca(2+)-channel inactivation in mouse inner hair cells.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Patch-clamp recordings from Cabp2LacZ/LacZ IHCs revealed enhanced Ca2+-channel
          inactivation.
        explanation: >-
          The patch-clamp measurement behind this readout.
    evidence:
    - reference: PMID:28183797
      reference_title: Ca(2+)-binding protein 2 inhibits Ca(2+)-channel inactivation in mouse inner hair cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We propose that CaBP2 inhibits CaV1.3 Ca2+-channel inactivation, and thus sustains
        the availability of CaV1.3 Ca2+ channels for synaptic sound encoding.
      explanation: >-
        Supports treating this model as the definitional system for the channel node.
  - target: Auditory Synaptopathy with Preserved Cochlear Amplification
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      The mouse shows the same dissociation as the patients: the cochlear amplifier works
      and the brainstem response does not.
    limitations: >-
      Cochlear amplification is assayed in the mouse by distortion-product otoacoustic
      emissions and in patients by clinical emissions testing; the two are analogous rather
      than identical measurements, and the human observation comes from a single family.
    readouts:
    - name: Cochlear amplification (otoacoustic emissions)
      target: Auditory Synaptopathy with Preserved Cochlear Amplification
      direction: UNCHANGED
      interpretation: >-
        Outer hair cell amplification is preserved, establishing that the lesion is
        downstream of the cochlear amplifier. A deliberate negative result.
      evidence:
      - reference: PMID:28183797
        reference_title: Ca(2+)-binding protein 2 inhibits Ca(2+)-channel inactivation in mouse inner hair cells.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Cabp2LacZ/LacZ mice displayed intact cochlear amplification but impaired auditory
          brainstem responses.
        explanation: >-
          The measurement of preserved amplification.
    - name: Auditory brainstem response threshold
      target: Auditory Synaptopathy with Preserved Cochlear Amplification
      direction: INCREASED
      interpretation: >-
        Brainstem response thresholds are elevated despite the intact amplifier, which is the
        synaptopathic pattern. The direction is INCREASED because the readout is a threshold:
        an impaired ABR means more sound is needed to evoke a response, and the review
        literature describes the human finding the same way - reduced responses with
        increased thresholds.
      evidence:
      - reference: PMID:28183797
        reference_title: Ca(2+)-binding protein 2 inhibits Ca(2+)-channel inactivation in mouse inner hair cells.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Cabp2LacZ/LacZ mice displayed intact cochlear amplification but impaired auditory
          brainstem responses.
        explanation: >-
          The same sentence reports both halves of the dissociation.
    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: MODEL_ORGANISM
      snippet: >-
        DFNB93 mouse models have recapitulated findings and demonstrated that lack of CaBP2
        impairs synaptic sound encoding by enhanced steady-state inactivation of CaV1.3 Ca2+
        channels.
      explanation: >-
        An independent statement that the mouse models recapitulate the human findings, which
        is the claim this link makes.

- name: Cabp1/Cabp2 double-knockout mouse with AAV CaBP2 rescue
  species: Mouse
  genotype: Cabp1-/-; Cabp2-/- double knockout, with and without AAV-PHP.eB-mediated Cabp2 transgene delivery
  publication: PMID:39718549
  description: >-
    Removing the partially redundant paralogue CaBP1 as well produces a much more severe
    synaptic phenotype than the single knockout, and that severity is the point: it makes
    the exocytosis deficit and the afferent-firing deficit large enough to measure cleanly,
    and it provides a window in which a rescue can be seen. Delivering Cabp2 into the inner
    ear substantially recovers both synaptic function and hearing sensitivity, which is the
    experiment underlying the claim that DFNB93 is a gene-therapy candidate.
  modeled_mechanisms:
  - target: Impaired Sustained Exocytosis at the Inner Hair Cell Ribbon Synapse
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The sustained component of exocytosis fails, and afferent responses become strongly
      rate-dependent.
    limitations: >-
      Two genes are removed, not one. Human DFNB93 patients are CABP2-biallelic with intact
      CABP1, so this animal is more severely affected than the disease it stands for and its
      quantitative deficits should not be read as DFNB93 magnitudes. It earns its place by
      isolating the mechanism, not by matching the genotype.
    readouts:
    - name: Sustained exocytosis in inner hair cells
      target: Impaired Sustained Exocytosis at the Inner Hair Cell Ribbon Synapse
      direction: DECREASED
      interpretation: >-
        Sustained vesicle release is reduced when CaV1.3 inactivation is unopposed.
      evidence:
      - reference: PMID:39718549
        reference_title: CaBP1 and 2 enable sustained Ca(V)1.3 calcium currents and synaptic transmission in inner hair cells.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In Cabp1/2 double-knockout mice, we find strongly enhanced CaV1.3 inactivation,
          slowed recovery from inactivation and impaired sustained exocytosis.
        explanation: >-
          The exocytosis measurement behind this readout.
    evidence:
    - reference: PMID:39718549
      reference_title: CaBP1 and 2 enable sustained Ca(V)1.3 calcium currents and synaptic transmission in inner hair cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        To encode continuous sound stimuli, the inner hair cell (IHC) ribbon synapses utilize
        calcium-binding proteins (CaBPs), which reduce the inactivation of their CaV1.3
        calcium channels.
      explanation: >-
        States the function this model was built to interrogate.
  - target: Auditory Synaptopathy with Preserved Cochlear Amplification
    relationship: RESCUES
    fidelity: MODERATE
    description: >-
      Transgenic re-expression of CaBP2 in the inner ear substantially restores synaptic
      function and hearing sensitivity, showing that the deficit is reversible by replacing
      the missing protein and not the consequence of an irreversible developmental defect.
    limitations: >-
      Recovery is substantial but partial, the rescue restores only CaBP2 in an animal
      lacking both paralogues, and the voltage shift in channel activation persists after
      re-expression. Timing relative to the human therapeutic window is not addressed.
    readouts:
    - name: Hearing sensitivity and inner hair cell synaptic function after Cabp2 delivery
      target: Auditory Synaptopathy with Preserved Cochlear Amplification
      direction: RESTORED
      interpretation: >-
        Both synaptic function and hearing sensitivity improve after gene delivery, which is
        the preclinical basis for treating DFNB93 as a gene replacement target.
      evidence:
      - reference: PMID:39718549
        reference_title: CaBP1 and 2 enable sustained Ca(V)1.3 calcium currents and synaptic transmission in inner hair cells.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Transgenic expression of CaBP2 leads to substantial recovery of IHC synaptic
          function and hearing sensitivity.
        explanation: >-
          The rescue result behind this readout.
    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: MODEL_ORGANISM
      snippet: >-
        Furthermore, preclinical studies have demonstrated feasibility of gene therapy.
      explanation: >-
        Independent confirmation that the rescue is read by the field as preclinical
        feasibility evidence.

- name: Cabp2 knockout mouse with AAV-mediated Cabp2 gene replacement
  species: Mouse
  genotype: Cabp2-/- (constitutive knockout) with AAV2/1 or AAV-PHP.eB Cabp2 delivered by round-window injection at postnatal day 5-7
  publication: PMID:34489639
  description: >-
    The gene therapy experiment done in the right genotype. Unlike the double knockout, this
    is the single Cabp2 null - the animal that matches the human disease - and the
    intervention is a cochlear delivery route that could plausibly be used in a patient: a
    round-window injection of AAV carrying the Cabp2 coding sequence, given in the first week
    of life.

    It is the strongest preclinical result this entity has, and it is why the disease is named
    as a gene therapy candidate rather than merely speculated about. The paper also states the
    property that makes the window wide: hair cells in these mice develop normally and do not
    degenerate early, so there is intact cochlea left to rescue.
  modeled_mechanisms:
  - target: Loss of CaBP2 Function at the Inner Hair Cell Ribbon Synapse
    relationship: RESCUES
    fidelity: MODERATE
    description: >-
      Delivering the Cabp2 coding sequence into inner hair cells restores the missing channel
      regulator in the genotype that matches the human disease, recovering the
      non-inactivating CaV1.3 current and improving hearing.
    limitations: >-
      The rescue is partial rather than complete, and it was given at postnatal day 5 to 7 -
      before hearing onset in the mouse, and therefore earlier in auditory development than a
      human infant diagnosed on newborn screening would be treated. Hearing was assessed at 5
      to 8 weeks, so durability beyond that is not addressed. Transduction was unilateral,
      with the contralateral ear as the internal control.
    readouts:
    - name: Restored CaBP2 function, read out as inner hair cell CaV1.3 current inactivation
      target: Loss of CaBP2 Function at the Inner Hair Cell Ribbon Synapse
      direction: RESTORED
      interpretation: >-
        CaBP2 function is not measured directly; it is measured by its only known effect, the
        non-inactivating character of the CaV1.3 current, which is restored after delivery.
        That is the molecular defect of this disease being reversed rather than compensated
        for. The readout repeats the link's target because restoring the protein is what the
        intervention does; the channel is the instrument.
      evidence:
      - reference: PMID:34489639
        reference_title: Cabp2-Gene Therapy Restores Inner Hair Cell Calcium Currents and Improves Hearing in a DFNB93 Mouse Model.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          we observed high transduction efficiency, and restoration of IHC CaV1.3 function
          resulting in improved hearing of Cabp2-/- mice.
        explanation: >-
          The channel and hearing measurements behind this readout.
    evidence:
    - reference: PMID:34489639
      reference_title: Cabp2-Gene Therapy Restores Inner Hair Cell Calcium Currents and Improves Hearing in a DFNB93 Mouse Model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These preclinical results prove the feasibility of DFNB93 gene therapy.
      explanation: >-
        The paper's own conclusion, which is the claim this link makes.

diagnosis:
- name: Genetic testing for biallelic CABP2 variants
  description: >-
    The diagnosis is molecular. CABP2 is small and is on comprehensive hearing-loss gene
    panels and exome pipelines; in every reported case the finding was a homozygous variant,
    most often c.637+1G>T. Ancestry matters to the pretest probability: the allele is a
    founder in Iranian, Turkish and Pakistani families and is enriched in Finland.
  evidence:
  - reference: PMID:32860223
    reference_title: "Spectrum and frequencies of non GJB2 gene mutations in Czech patients with early non-syndromic hearing loss detected by gene panel NGS and whole-exome sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other genes (AIFM1, CABP2, DIAPH1, PTPRQ, RDX, SLC26A4, TBC1D24, TECTA, TMC1) that
      explained the cause of hearing impairment were further detected in only one patient
      for each gene.
    explanation: >-
      A measured panel/exome yield: CABP2 explained one of the 54 solved cases in an
      unselected Czech prelingual hearing-loss cohort, which is the diagnostic frequency to
      expect from this test rather than a general statement about sequencing.

- name: Audiological testing including otoacoustic emissions
  description: >-
    Because the outer hair cells are spared, emissions testing is the discriminating study.
    Emissions present alongside an abnormal auditory brainstem response places the patient in
    the synaptopathy group and changes what to expect from amplification. Recording
    emissions is not optional in a suspected DFNB93 case; it is the finding that
    distinguishes it.
  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: >-
      The human emissions finding this test is looking for.

treatments:

- name: Hearing Aids
  therapeutic_modality: DEVICE
  description: >-
    Amplification is what patients receive in practice, and the reported outcomes are good -
    the North American case describes a positive prognosis with hearing aids and
    multidisciplinary follow-up.

    It is worth stating the tension rather than smoothing it. As a class, auditory
    synaptopathy patients are described as gaining little from amplification, because the
    problem is neural encoding rather than sensitivity. DFNB93 sits at the mild end of that
    class - moderate thresholds and a partial rather than abolished synaptic function - and
    the individual reports are of benefit. Both statements are cited below; neither is
    dropped.
  treatment_term:
    preferred_term: hearing aid usage
  target_mechanisms:
  - target: Auditory Synaptopathy with Preserved Cochlear Amplification
    description: >-
      Amplification raises the stimulus reaching an inner hair cell whose transmitter release
      is reduced. It compensates for the consequence and does nothing to the channel defect
      that produces it.
    evidence:
    - reference: PMID:42448438
      reference_title: First reported North American calcium binding protein 2-related non-syndromic hearing loss.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hearing aids and multidisciplinary follow-up have led to a positive prognosis.
      explanation: >-
        A reported outcome of amplification in a genetically confirmed DFNB93 patient.
  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: >-
      Patients with auditory synaptopathy and auditory neuropathy typically gain little
      benefit from using hearing aids, as the functional problem is not hearing sensitivity
      but neural sound processing.
    explanation: >-
      Graded PARTIAL because it is the general statement about the disease class this entry
      places DFNB93 in, and it qualifies rather than supports the use of amplification here.

- name: Cochlear Gene Replacement (investigational)
  therapeutic_modality: GENE_THERAPY
  description: >-
    Not available to patients. It is listed because the preclinical case is specific and
    published: CaBP2 re-expression in the double-knockout mouse restores synaptic function
    and hearing sensitivity, the cochlea is structurally intact in this disease so there is
    something left to rescue, and a patient registry has been set up to support future
    trials. The read-across from the otoferlin trials is the field's own argument, and it is
    an argument about a disease class rather than a result in DFNB93 patients.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Loss of CaBP2 Function at the Inner Hair Cell Ribbon Synapse
    description: >-
      Delivering a functional CABP2 coding sequence to inner hair cells restores the missing
      channel regulator, which is the one node in this pathograph that a replacement therapy
      can act on directly.
    evidence:
    - reference: PMID:34489639
      reference_title: Cabp2-Gene Therapy Restores Inner Hair Cell Calcium Currents and Improves Hearing in a DFNB93 Mouse Model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We used AAV2/1 and AAV-PHP.eB viral vectors to deliver the Cabp2 coding sequence into
        IHCs of early postnatal Cabp2-/- mice and assessed the level of restoration of hair
        cell function and hearing.
      explanation: >-
        The intervention this treatment describes, performed in the single-knockout genotype
        that matches the human disease.
    - reference: PMID:39718549
      reference_title: CaBP1 and 2 enable sustained Ca(V)1.3 calcium currents and synaptic transmission in inner hair cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Transgenic expression of CaBP2 leads to substantial recovery of IHC synaptic function
        and hearing sensitivity.
      explanation: >-
        A second rescue result, in the double knockout, supporting the same target.
  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: MODEL_ORGANISM
    snippet: >-
      Furthermore, preclinical studies have demonstrated feasibility of gene therapy.
    explanation: >-
      States the preclinical feasibility that is the whole basis for listing this treatment.

differential_diagnoses:
- name: OTOF-related auditory neuropathy (DFNB9)
  description: >-
    The other genetic auditory synaptopathy, and the one DFNB93 is repeatedly compared to.
    Both present with preserved otoacoustic emissions and abnormal brainstem responses, and
    both are presynaptic inner hair cell disorders. OTOF is usually profound and congenital
    where DFNB93 is moderate, and OTOF is the one with an approved gene therapy. Separation
    is by sequencing, not by audiology.
  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: >-
      As growing evidence from OTOF clinical trials confirms synaptopathies as promising
      therapeutic targets for hearing restoration, CABP2 ranks highly among the candidate
      genes for virus-mediated gene therapy to restore hearing.
    explanation: >-
      Places the two diseases in the same mechanistic class, which is why OTOF is the
      differential that matters.

- name: GJB2-related nonsyndromic hearing loss (DFNB1)
  description: >-
    The commonest cause of autosomal recessive nonsyndromic hearing loss, and the one that
    is excluded first in every reported DFNB93 family before the CABP2 finding is accepted.
    It is a gap-junction disease of the cochlear supporting-cell network, not a synaptopathy,
    and otoacoustic emissions are absent.
  evidence:
  - reference: PMID:31661684
    reference_title: A Novel Pathogenic Variant in the CABP2 Gene Causes Severe Nonsyndromic Hearing Loss in a Consanguineous Iranian Family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After excluding mutations in the GJB2 gene and 7 other most common autosomal recessive
      nonsyndromic HL (ARNSHL) genes via Sanger sequencing and genetic linkage analysis in the
      family, WES was utilized to find the possible etiology of the disease.
    explanation: >-
      Records that GJB2 and seven other common recessive deafness genes were excluded before
      the CABP2 diagnosis was accepted in this family.

discussions:

- discussion_id: gap_hearing_aid_benefit_in_dfnb93
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#Hearing Aids
  - pathophysiology#Auditory Synaptopathy with Preserved Cochlear Amplification
  prompt: >-
    Do DFNB93 patients benefit from amplification, given that auditory synaptopathy as a
    class is described as responding poorly to it?
  rationale: >-
    The entry cites both halves of a genuine tension. Auditory synaptopathy and auditory
    neuropathy patients are described in the review literature as gaining little from hearing
    aids, because amplification addresses sensitivity and the deficit is neural encoding. Yet
    the individual DFNB93 case reports describe amplification being fitted and outcomes
    being good, and the disease is milder than the synaptopathies that generalisation was
    built on.

    Both readings are defensible from what is published. DFNB93 may be the mild corner of
    the class where partial synaptic function leaves enough encoding for amplification to
    work with; or the reported good outcomes may reflect early fitting and small numbers
    rather than genuine class-atypical benefit. Nobody has measured speech perception in a
    DFNB93 cohort against aided thresholds, which is what would separate the two.

    The stake is immediate and clinical. If amplification genuinely works here, the class
    generalisation should not be applied to these patients when counselling. If it does not,
    the reported positive prognoses are measuring the wrong thing and cochlear implantation
    should be discussed earlier.
  proposed_experiments:
  - experiment_id: dfnb93_aided_speech_perception
    name: Aided speech perception versus aided threshold in a genotyped DFNB93 cohort
    description: >-
      Assemble the reported CABP2-biallelic patients through the existing patient registry
      and measure speech perception in noise against aided pure-tone thresholds, comparing
      against OTOF-related synaptopathy patients and against sensitivity-matched cochlear
      hearing loss.
    would_support:
    - treatments#Hearing Aids
    supporting_outcome:
    - >-
      Aided speech perception in DFNB93 tracks aided threshold in the way it does for
      cochlear hearing loss, which would mean amplification does the expected work here and
      the class generalisation does not apply.
    refuting_outcome:
    - >-
      Speech perception is disproportionately poor for the aided threshold, matching the
      OTOF pattern, which would mean the reported positive prognoses rest on audiometric
      gain that is not translating into communication and would move cochlear implantation
      earlier in counselling.

- discussion_id: gap_dfnb93_progression
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Prelingual Moderate-to-Severe Sensorineural Hearing Loss
  prompt: >-
    Is DFNB93 hearing loss stable after onset, or does it progress?
  rationale: >-
    The mouse is described as having early-onset progressive hearing impairment. The human
    reports are cross-sectional - a proband is described at the age they were assessed - and
    none of the published families has serial audiometry across years. So the entry asserts
    prelingual onset and a severity band and deliberately asserts no clinical course, because
    the only progression evidence available is from the model.

    This is not a technicality. Progression determines whether a moderate childhood loss will
    still be moderate in adulthood, and it determines when a gene replacement therapy would
    have to be given to be worth giving. A disease that is stable at moderate thresholds has
    a very different therapeutic window from one that is sliding.
  proposed_experiments:
  - experiment_id: dfnb93_longitudinal_audiometry
    name: Longitudinal audiometry across the reported CABP2 families
    description: >-
      Retrieve serial audiograms from the Iranian, Turkish, Pakistani, Italian, Danish,
      Finnish and North American probands and their affected relatives, and plot threshold
      against age by allele class.
    would_support:
    - phenotypes#Prelingual Moderate-to-Severe Sensorineural Hearing Loss
    supporting_outcome:
    - >-
      Thresholds are stable across decades, confirming the disease as a fixed prelingual loss
      and making the mouse progression a species difference to record.
    refuting_outcome:
    - >-
      Thresholds worsen with age in humans as they do in the mouse, which would add a
      progressive clinical course to the phenotype and make the timing of any future gene
      therapy the central clinical question.

notes: >-
  Named entity check. CABP2 causes one disease. There is no second CABP2 phenotype to be
  confused with, unlike the other three loci curated in this batch, and nothing in the
  knowledge base mentioned CABP2 before this entry. The related gene CABP4 causes a
  congenital stationary night blindness and is not curated here; the CaBP1 knockout appears
  only inside the double-knockout model, where it is part of the animal's genotype rather
  than a disease claim.

  Relationship to Auditory Neuropathy. DFNB93 is a genetic auditory synaptopathy and belongs
  inside the mechanism that the Auditory Neuropathy entry describes: presynaptic inner hair
  cell failure with preserved outer hair cell function. It is recorded here rather than as a
  subtype of that entry because MONDO carries it as its own disease with its own OMIM entry
  and the DFNB numbering, and because the pathograph is gene-specific down to the CaV1.3
  channel. The classification is asserted in the pathophysiology section with the two
  citations that state it, so the relationship is machine-visible rather than left in prose.

  Evidence grading. The mechanism is mouse. Every step from channel inactivation to afferent
  firing is graded MODEL_ORGANISM, and the two human anchors - the moderate-to-severe
  phenotype and the preserved otoacoustic emissions - are the only things holding the mouse
  account to the patients. Human inner ear tissue is not obtainable, so this is a permanent
  feature of the evidence base rather than a curation shortcut. The founding paper's
  biochemistry on the truncated protein is graded IN_VITRO rather than HUMAN_CLINICAL even
  though it appears in a clinical genetics paper, because evidence_source describes the
  experiment and not the paper it sits in.

  What is deliberately absent. No progression, because only the mouse has it. No
  clinical_trials, because there are none. No datasets, because no CABP2-specific omics
  dataset was found and a gene-symbol search would return the retinal CaBP literature.

references:
- reference: PMID:22981119
  title: "A mutation in CABP2, expressed in cochlear hair cells, causes autosomal-recessive hearing impairment."
- reference: PMID:28183797
  title: Ca(2+)-binding protein 2 inhibits Ca(2+)-channel inactivation in mouse inner hair cells.
- reference: PMID:39718549
  title: CaBP1 and 2 enable sustained Ca(V)1.3 calcium currents and synaptic transmission in inner hair cells.
- reference: PMID:34489639
  title: Cabp2-Gene Therapy Restores Inner Hair Cell Calcium Currents and Improves Hearing in a DFNB93 Mouse Model.
- reference: PMID:40927552
  title: "Is CABP2-Associated Hearing Loss (DFNB93) a Gene Therapy Target? Preclinical Progress and Patient Registry."
- reference: PMID:35150090
  title: "Autosomal recessive nonsyndromic hearing impairment in two Finnish families due to the population enriched CABP2 c.637+1G>T variant."
- reference: PMID:33666369
  title: First reported CABP2-related non-syndromic hearing loss in Northern Europe.
- reference: PMID:31661684
  title: A Novel Pathogenic Variant in the CABP2 Gene Causes Severe Nonsyndromic Hearing Loss in a Consanguineous Iranian Family.
- reference: PMID:42448438
  title: First reported North American calcium binding protein 2-related non-syndromic hearing loss.
- reference: PMID:32860223
  title: "Spectrum and frequencies of non GJB2 gene mutations in Czech patients with early non-syndromic hearing loss detected by gene panel NGS and whole-exome sequencing."
- reference: CGGV:assertion_20de88d2-6681-4522-9e11-26cdf66a2c15-2020-02-06T170000.000Z
  title: CABP2 / nonsyndromic genetic hearing loss (Definitive)
📚

References & Deep Research

References

11
PMID:22981119
A mutation in CABP2, expressed in cochlear hair cells, causes autosomal-recessive hearing impairment.
No top-level findings curated for this source.
PMID:28183797
Ca(2+)-binding protein 2 inhibits Ca(2+)-channel inactivation in mouse inner hair cells.
No top-level findings curated for this source.
PMID:39718549
CaBP1 and 2 enable sustained Ca(V)1.3 calcium currents and synaptic transmission in inner hair cells.
No top-level findings curated for this source.
PMID:34489639
Cabp2-Gene Therapy Restores Inner Hair Cell Calcium Currents and Improves Hearing in a DFNB93 Mouse Model.
No top-level findings curated for this source.
PMID:40927552
Is CABP2-Associated Hearing Loss (DFNB93) a Gene Therapy Target? Preclinical Progress and Patient Registry.
No top-level findings curated for this source.
PMID:35150090
Autosomal recessive nonsyndromic hearing impairment in two Finnish families due to the population enriched CABP2 c.637+1G>T variant.
No top-level findings curated for this source.
PMID:33666369
First reported CABP2-related non-syndromic hearing loss in Northern Europe.
No top-level findings curated for this source.
PMID:31661684
A Novel Pathogenic Variant in the CABP2 Gene Causes Severe Nonsyndromic Hearing Loss in a Consanguineous Iranian Family.
No top-level findings curated for this source.
PMID:42448438
First reported North American calcium binding protein 2-related non-syndromic hearing loss.
No top-level findings curated for this source.
PMID:32860223
Spectrum and frequencies of non GJB2 gene mutations in Czech patients with early non-syndromic hearing loss detected by gene panel NGS and whole-exome sequencing.
No top-level findings curated for this source.
CGGV:assertion_20de88d2-6681-4522-9e11-26cdf66a2c15-2020-02-06T170000.000Z
CABP2 / nonsyndromic genetic hearing loss (Definitive)
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 26 citations 2026-08-28T19:14:02.445148

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Autosomal Recessive Nonsyndromic Hearing Loss 93 (DFNB93, CABP2-related)
  • MONDO ID: MONDO:0013963 (if available)
  • Category: Genetic

Research Objectives

Please provide a comprehensive research report on Autosomal Recessive Nonsyndromic Hearing Loss 93 (DFNB93, CABP2-related) covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
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For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
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  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

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    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

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14. Other Species / Natural Disease

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    Search first: VBO (Vertebrate Breed Ontology)

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    Search first: NCBI Gene

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15. Model Organisms

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  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Autosomal-recessive nonsyndromic hearing loss 93 (DFNB93; CABP2-related)

Executive summary

DFNB93 is an exceptionally rare, autosomal-recessive, usually prelingual sensorineural hearing disorder caused by biallelic pathogenic variants in CABP2, encoding calcium-binding protein 2 (CaBP2). The best-supported phenotype is bilateral, symmetric, moderate-to-severe hearing loss, often greatest at middle frequencies; severe loss also occurs. Physiologically, DFNB93 is best classified as a presynaptic auditory synaptopathy: outer-hair-cell amplification and cochlear architecture can remain relatively preserved, while excessive inactivation of inner-hair-cell (IHC) CaV1.3 calcium channels limits sustained glutamate release to spiral-ganglion neurons (SGNs). Human evidence remains limited to a small number of families, so prevalence, penetrance, progression, and genotype–phenotype relationships are not yet quantified reliably. (picher2017ca2+bindingprotein2 pages 1-2, schrauwen2012amutationin pages 1-2, picher2017ca2+bindingprotein2 pages 2-3)

The principal recent advance is the December 24, 2024 eLife study showing that CaBP1 and CaBP2 cooperate to suppress voltage- and calcium-dependent CaV1.3 inactivation and sustain IHC exocytosis. A dedicated CABP2 registry, NCT06680934, began August 16, 2024 and is recruiting, representing the first disease-specific real-world natural-history infrastructure. AAV-mediated Cabp2 augmentation has improved hearing in mice, but no CABP2-directed human interventional trial or approved molecular therapy was identified. (NCT06680934 chunk 1, oestreicher2024cabp1and2 pages 1-2, oestreicher2024cabp1and2 pages 11-12)

The key human, model, and translational evidence is summarized below.

Evidence/source and date Cohort/model Variant/intervention Phenotype or quantitative outcome Interpretation/evidence type
Schrauwen et al., Am J Hum Genet (2012-10-05) 3 consanguineous Iranian families (Sh10, Sh11, He) CABP2 c.637+1G>T, predicted exon 6 skipping; p.Phe164Serfs*4 Moderate-to-severe sensorineural hearing impairment; founder effect supported by shared 0.52 Mb haplotype; variant absent in 100 Iranian controls; truncated protein showed altered Ca²⁺ binding and less potent CaV1.3 regulation (schrauwen2012amutationin pages 1-2, schrauwen2012amutationin pages 7-8, schrauwen2012amutationin pages 3-4) Primary human genetics + functional in vitro evidence establishing DFNB93 mechanism via hypofunctional CaBP2
Picher et al., PNAS (2017-02) 2 affected siblings from Northern Italy + family segregation CABP2 c.466G>T (p.Glu156Ter / p.E156X) Prelingual, bilateral, symmetric moderate-to-severe hearing impairment with characteristic U-shaped/mid-frequency emphasis affecting communication; no syndromic features on clinical exam; variant absent in 225 white controls and not reported in ExAC in cited study context (picher2017ca2+bindingprotein2 pages 1-2) Primary human clinical-genetic evidence for an independent CABP2 loss-of-function DFNB93 family
Koohiyan et al., Audiol Neurotol (2019-10) Consanguineous Iranian family; 2 affected relatives/siblings in multigenerational pedigree CABP2 c.311G>A (p.Gly104Asp) Prelingual bilateral severe sensorineural hearing loss; segregated homozygously in affected relatives; absent in 50 normal-hearing controls from same population; study states zero frequency in 1000 Genomes and ExAC (koohiyan2019anovelpathogenic pages 4-5, koohiyan2019anovelpathogenic pages 3-4, koohiyan2019anovelpathogenic pages 1-2) Primary human genetics showing phenotypic heterogeneity, extending CABP2 from moderate/severe to severe DFNB93
Nawaz et al., Heliyon (available online 2023-12-14; 2024 issue) Egyptian family A; 2 affected siblings with DASS background due to separate LTBP3 defect CABP2 c.590T>C (p.Ile197Thr) Hearing impairment in Egyptian siblings was reported as having a separate transmission mechanism independent of LTBP3; both siblings homozygous for CABP2 missense variant while mother heterozygous (nawaz2024brachyolmiadentalanomalies pages 1-2) Recent blended-phenotype report; supports CABP2 as contributor to hearing loss but not isolated DFNB93-only family ascertainment
Picher et al., PNAS (2017-02) Cabp2 knockout mouse (Cabp2LacZ/LacZ) Genetic disruption of Cabp2 Elevated ABR thresholds and reduced amplitudes at 6–24 kHz; DPOAE thresholds/amplitudes comparable to controls; reduced and more jittered SGN firing; preserved IHC/OHC anatomy and normal synapses with SGNs; expression stronger in IHCs than OHCs, also vestibular hair cells/outer retina (picher2017ca2+bindingprotein2 pages 2-3, picher2017ca2+bindingprotein2 pages 1-2, picher2017ca2+bindingprotein2 pages 7-8) Primary model-organism evidence for auditory synaptopathy with preserved outer hair cell/cochlear amplification
Oestreicher et al., Front Mol Neurosci (2021-08) Postnatal Cabp2−/− mice treated at P5–P7 AAV2/1-Cabp2 or AAV-PHP.eB-Cabp2 round-window gene therapy Hearing improved in 16/24 (67%) treated animals with ≥20 dB SPL improvement at tested frequencies (p<0.0001); ABR wave I amplitude increased from 0.8±0.1 µV to 1.3±0.2 µV at 80 dB SPL (p<0.001); PHP.eB achieved about 98% IHC transduction; DPOAEs largely unaffected in mutants (oestreicher2021cabp2genetherapyrestores pages 2-4, oestreicher2021cabp2genetherapyrestores pages 5-7, oestreicher2021cabp2genetherapyrestores pages 7-8, oestreicher2021cabp2genetherapyrestores pages 1-2) Preclinical translational proof-of-concept that CABP2 deficiency is at least partially reversible by inner-ear gene augmentation
Oestreicher et al., eLife Version of Record (2024-12-24) Cabp1/2 double-knockout mice Loss of CaBP1 + CaBP2; rescue by transgenic/AAV-mediated CaBP2 re-expression Severe auditory dysfunction: click ABR threshold 59±2 dB SPL vs 30±2 WT at 3–4 weeks (N=8–9), worsening to 68±5 dB SPL vs 30±1 WT by 7–13 weeks (N=7); preserved ribbon density 12.9±0.2 WT vs 12.8±0.8 DKO synapses/cell; SGN adaptation ratio 12.5±3.0 vs 3.4±0.2 WT, p<0.00001; sound-responsive neuron yield 0.3/h vs 2.5/h WT; rescue substantially recovered IHC synaptic function, ABR wave I amplitudes, and thresholds (oestreicher2024cabp1and2 pages 1-2, oestreicher2024cabp1and2 pages 11-12, oestreicher2024cabp1and2 pages 7-9, oestreicher2024cabp1and2 pages 13-14) Latest mechanistic refinement: CaBP1 and CaBP2 cooperatively suppress CaV1.3 inactivation needed for sustained exocytosis and sound encoding
ClinicalTrials.gov NCT06680934 (first posted 2024-11-08; recruiting) Human registry/natural history study; estimated n=100; University Medical Center Goettingen CABP2 Patient Registry and Natural History Study Observational case-only patient registry for individuals with biallelic CABP2 variants; actual start 2024-08-16; primary outcomes include pure-tone audiometry and speech audiometry; secondary outcomes otoacoustic emissions and auditory brainstem response; estimated completion 2049-08-16 (NCT06680934 chunk 1) Current real-world implementation creating disease-specific natural-history infrastructure for diagnostics, phenotyping, and future trial readiness

Table: This table summarizes the main human, model-organism, translational, and registry evidence for CABP2-related DFNB93. It highlights reported variants, core phenotypes, quantitative rescue/model findings, and the distinction between isolated DFNB93 evidence and broader/blended presentations.

1. Disease information

Definition and identifiers

  • Preferred name: autosomal-recessive nonsyndromic hearing loss 93.
  • Synonyms: DFNB93; deafness, autosomal recessive 93; CABP2-related hearing loss; CABP2-associated hearing impairment; CABP2-related auditory synaptopathy.
  • Disease OMIM: 614899 (DFNB93). Gene OMIM/MIM: CABP2, 607314. The locus was mapped to chromosome 11q13.3. (schrauwen2012amutationin pages 1-2, koohiyan2019anovelpathogenic pages 1-2)
  • MONDO: the supplied identifier MONDO:0013963 should be retained, but its current label/cross-references should be verified directly in the live MONDO release before production ingestion.
  • Gene: CABP2, seven exons in the transcript used by the original reports, encoding a 220-amino-acid Ca²⁺-binding protein. The 2012 HGVS descriptions used NM_016366.2/NP_057450.2. (schrauwen2012amutationin pages 1-2, koohiyan2019anovelpathogenic pages 2-3)
  • MeSH: no disease-specific MeSH term was identified. Use the broader Hearing Loss, Sensorineural where appropriate; ClinicalTrials.gov maps the registry to Hearing Loss, D034381. (NCT06680934 chunk 1)
  • ICD-10/ICD-11: there is no CABP2-specific billing code. Code the clinical hearing phenotype under the applicable bilateral sensorineural hearing-loss category and retain the molecular diagnosis separately. Exact national ICD-10-CM/ICD-11 coding should be jurisdictionally validated.
  • Orphanet: no confidently verified disease-specific Orphanet identifier was recovered; do not assign one without checking the current Orphanet release.

This report is based on aggregated disease-level literature and registry resources, not individual EHR data. Nevertheless, the human evidence itself consists largely of family-level case ascertainment, pedigrees, audiograms, and molecular testing rather than population cohorts.

2. Etiology, risk, protection, and environment

Causal factor

The necessary cause is biallelic germline CABP2 dysfunction. Established disease mechanisms include nonsense-mediated decay, splice-induced truncation, defective Ca²⁺ binding, reduced protein abundance, and impaired modulation of CaV1.3 channels. Heterozygous relatives and heterozygous mice were reported as hearing-normal, supporting recessive inheritance. (schrauwen2012amutationin pages 1-2, picher2017ca2+bindingprotein2 pages 1-2, schrauwen2012amutationin pages 6-7)

Genetic risk factors

Reported variants with primary evidence include:

  1. c.637+1G>T; p.Phe164Serfs*4: splice-donor disruption, predicted exon 6 skipping and loss of EF hands 3–4; found in three consanguineous Iranian families on a shared 0.52-Mb haplotype, consistent with a founder allele. It was absent from 100 Iranian controls. The truncated protein had approximately tenfold lower expression and less effective CaV1.3 regulation in experimental assays. (schrauwen2012amutationin pages 7-8, schrauwen2012amutationin pages 6-7, schrauwen2012amutationin pages 3-4)
  2. c.466G>T; p.Glu156Ter (reported as p.E156X): homozygous in two Northern Italian siblings; likely nonsense-mediated decay. It was absent from 225 White controls and was not represented in ExAC at the time. (picher2017ca2+bindingprotein2 pages 1-2)
  3. c.311G>A; p.Gly104Asp: homozygous in two affected relatives from a consanguineous Iranian family; classified as pathogenic by the reporting authors under ACMG/AMP criteria, absent from 50 local controls, 1000 Genomes, and ExAC. It affects a conserved EF-hand region, but the retrieved evidence is primarily segregation, rarity, prediction, and structural modeling rather than a direct electrophysiological assay. (koohiyan2019anovelpathogenic pages 4-5, koohiyan2019anovelpathogenic pages 3-4, koohiyan2019anovelpathogenic pages 1-2)
  4. c.590T>C; p.Ile197Thr: reported in two Egyptian siblings with hearing impairment. Their skeletal/dental DASS phenotype was independently caused by biallelic LTBP3 variation; the authors described the CABP2-associated hearing phenotype as having a separate transmission mechanism. This is a blended diagnosis, not evidence that CABP2 causes DASS. (nawaz2024brachyolmiadentalanomalies pages 1-2)

Current ClinVar classifications and present-day gnomAD frequencies were not directly retrieved and should be checked variant-by-variant against the current databases before clinical interpretation. No somatic mechanism is implicated.

Other factors

  • Family history, consanguinity, and founder ancestry increase the probability of biallelic inheritance; they are ascertainment/risk factors rather than biological triggers.
  • No validated susceptibility loci, protective CABP2 alleles, environmental protective factors, modifier genes, epigenetic determinants, or human gene–environment interactions have been established.
  • Noise, ototoxic drugs, infection, smoking, diet, alcohol, occupation, age, and sex are not demonstrated causes of DFNB93. Avoiding ordinary acquired auditory injury remains prudent but cannot prevent a congenital CABP2 defect.
  • CaBP1 provides partial functional redundancy in mice and is therefore a plausible biological modifier, but no human CABP1 modifier association has been demonstrated. (oestreicher2024cabp1and2 pages 1-2, oestreicher2024cabp1and2 pages 11-12)

3. Phenotypes

Core auditory phenotype

Phenotype Characteristics and evidence Suggested HPO
Bilateral sensorineural hearing impairment Symmetric, prelingual, generally moderate-to-severe; severe loss occurred with p.Gly104Asp HP:0000407 Sensorineural hearing impairment; HP:0000365 Hearing impairment; HP:0012715 Bilateral hearing impairment
Mid-frequency-predominant/U-shaped audiogram Especially clear in the Italian siblings; hearing was impaired across frequencies but preferentially in the middle range HP:0000408 Progressive sensorineural hearing impairment is not appropriate unless progression is documented; use an audiogram-shape annotation if available locally
Prelingual onset Reported in Italian and Iranian patients and affected communication HP:0011592 Selective mutism is inappropriate; use HP:0003623 Neonatal onset or HP:0011463 Childhood onset only when patient-specific age is known; otherwise encode “prelingual onset” textually
Auditory synaptopathy physiology Reduced/abnormal neural responses with potentially preserved otoacoustic emissions, localizing dysfunction downstream of outer-hair-cell amplification HP:0012718 Auditory neuropathy spectrum disorder, if supported by the individual’s electrophysiology
Speech/communication difficulty Explicitly reported in the Italian family; expected functional consequence of prelingual hearing loss HP:0002167 Speech articulation difficulties or HP:0000750 Delayed speech and language development only when clinically documented

The 2017 primary report states that affected siblings had “prelingual hearing impairment affecting their communication” and “symmetrical moderate-to-severe hearing impairment across all frequencies, preferentially affecting the middle-frequency range (‘U shape’).” (picher2017ca2+bindingprotein2 pages 1-2)

Frequency, progression, and extra-auditory findings

Reliable percentages cannot be calculated: published families are too few, ascertainment differs, and case reports are not a denominator-based cohort. Bilaterality and prelingual onset appear recurrent, but their penetrance should not be represented as 100% in a knowledge base. Longitudinal progression is unresolved. The mouse double knockout worsened with age, but this must not be translated directly into a human progression rate. (oestreicher2024cabp1and2 pages 7-9)

Comprehensive examinations in the Italian family excluded syndromic features. The original Iranian study performed ophthalmologic and cardiovascular evaluations; CABP2 expression in retina and vestibular hair cells has not translated into a reproducible human retinal, cardiac, or vestibular syndrome. The Egyptian DASS findings belong to the separate LTBP3 diagnosis. (picher2017ca2+bindingprotein2 pages 1-2, schrauwen2012amutationin pages 1-2, nawaz2024brachyolmiadentalanomalies pages 1-2)

Quality of life

No DFNB93-specific EQ-5D, SF-36, PROMIS, educational, employment, or caregiver-burden study was identified. Likely effects concern speech perception, communication, language acquisition, education, and social participation, but disease-specific effect sizes are unavailable.

4. Genetic and molecular information

CABP2 encodes a calmodulin-related EF-hand Ca²⁺-binding protein. CaBP2 binds/modulates presynaptic L-type CaV1.3, whose pore-forming subunit is encoded by CACNA1D. CaBP2-alt is the predominant murine cochlear isoform, although rescue studies also used the conventional long isoform. (koohiyan2019anovelpathogenic pages 4-5, oestreicher2024cabp1and2 pages 11-12)

Variant consequences should be represented as follows:

  • c.637+1G>T: germline splice loss → frameshift/truncation → loss of C-terminal EF hands, altered Ca²⁺ binding, reduced protein expression, hypomorphic/functional loss.
  • c.466G>T: germline nonsense → anticipated NMD → loss of function.
  • c.311G>A and c.590T>C: germline missense; likely impaired protein structure/function, but direct variant-specific electrophysiology was not recovered, so “loss of function” should be qualified rather than asserted as experimentally proven.

No validated dominant-negative or gain-of-function CABP2 mechanism, large recurrent deletion, translocation, aneuploidy, repeat expansion, mitochondrial mechanism, somatic mosaicism, germline mosaicism, or disease-specific methylation/chromatin abnormality has been reported. No robust transcriptomic, human single-cell, spatial-transcriptomic, proteomic, metabolomic, or lipidomic disease signature is established.

5. Environmental information

DFNB93 is genetic, not infectious, toxic, nutritional, occupational, or lifestyle-mediated. No pathogen, toxin, radiation exposure, pollutant, smoking behavior, diet, exercise pattern, or alcohol exposure is known to trigger it. General hearing conservation and avoidance of ototoxic exposure may preserve residual hearing but are tertiary risk-reduction measures, not disease-specific prevention.

6. Mechanism and pathophysiology

Causal chain

  1. Upstream genetic lesion: biallelic CABP2 loss or dysfunction reduces effective CaBP2 in cochlear hair cells.
  2. Channel dysregulation: CaBP2 normally restrains voltage- and/or calcium-dependent inactivation of IHC CaV1.3 channels. Its absence leaves fewer channels available during sustained or repeated depolarization.
  3. Presynaptic failure: reduced sustained Ca²⁺ entry impairs ribbon-synapse vesicle exocytosis and glutamate release.
  4. Neural coding defect: SGNs fire less, adapt excessively, and show poorer temporal precision/jitter.
  5. Systems phenotype: ABR thresholds rise and wave amplitudes fall despite relatively preserved DPOAEs and cochlear mechanics, producing bilateral sensorineural hearing impairment/auditory synaptopathy. (picher2017ca2+bindingprotein2 pages 1-2, brotto2024autosomalrecessivenonsyndromic pages 8-9, picher2017ca2+bindingprotein2 pages 7-8)

The 2012 abstract described the mutant protein as “a hypofunctional CaBP2 defective in Ca²⁺ sensing and effector regulation in the inner ear.” (schrauwen2012amutationin pages 1-2)

The latest mechanistic refinement comes from the 2024 eLife Version of Record: CaBP1/2 double-null IHCs exhibited “strongly enhanced CaV1.3 inactivation, slowed recovery from inactivation and impaired sustained exocytosis”; the authors concluded that both proteins support “fast, temporally precise and indefatigable sound encoding.” (oestreicher2024cabp1and2 pages 1-2)

Ontology-ready annotations

  • GO biological processes: calcium ion transmembrane transport; regulation of voltage-gated calcium-channel activity; regulation of membrane depolarization; synaptic vesicle exocytosis; chemical synaptic transmission; sensory perception of sound; calcium-ion homeostasis.
  • GO molecular functions: calcium-ion binding; voltage-gated calcium-channel regulator activity; protein binding.
  • GO cellular components: cytosol; presynaptic active zone; ribbon synapse; plasma membrane/voltage-gated calcium-channel complex. Exact GO accessions should be validated in the live GO release.
  • Cell Ontology suggestions: inner hair cell (CL term to be release-validated), outer hair cell, spiral-ganglion neuron/auditory neuron, vestibular hair cell.
  • CHEBI: calcium(2+) (CHEBI:29108) and glutamate should be annotated only as mechanistic entities, not treatments.

No primary metabolic, immune, inflammatory, fibrotic, ischemic, lysosomal, mitochondrial, or apoptotic disease mechanism is established. The major lesion is channel regulation and synaptic transmission, not early hair-cell death.

7. Anatomical structures affected

  • Organ/system: inner ear, specifically the cochlear auditory system; no established secondary-organ involvement.
  • Primary cells: cochlear IHCs, where CaBP2 strongly regulates CaV1.3; OHC expression occurs but amplification is comparatively preserved. SGN abnormalities are downstream of impaired IHC output. (picher2017ca2+bindingprotein2 pages 2-3)
  • Subcellular site: presynaptic ribbon active zone, CaV1.3 channel complex, cytosolic Ca²⁺-buffering/modulatory environment, and synaptic-vesicle release machinery.
  • Suggested UBERON: inner ear; cochlea; organ of Corti/spiral organ; cochlear hair cell layer; spiral ganglion. Validate exact accessions against the current UBERON release.
  • Laterality: typically bilateral and symmetric in documented patients. (picher2017ca2+bindingprotein2 pages 1-2)

Mouse expression also occurs in vestibular hair cells and retinal cells, but scotopic electroretinography was intact and consistent human vestibular/retinal disease has not been established. (picher2017ca2+bindingprotein2 pages 2-3)

8. Temporal development

The best-supported onset is congenital or prelingual, with a chronic, lifelong course. Available reports do not define discrete stages, remission, episodic attacks, or spontaneous recovery. Human longitudinal data are insufficient to label DFNB93 uniformly stable or progressive.

The clinically important intervention window is inferred from preserved early cochlear morphology in mice: development, stereocilia, ribbons, and SGNs remain initially intact, potentially permitting functional rescue before secondary damage. This is a translational hypothesis, not a validated human treatment window. (oestreicher2021cabp2genetherapyrestores pages 7-8, oestreicher2021cabp2genetherapyrestores pages 1-2)

9. Inheritance and population

Inheritance is autosomal recessive. If both parents carry the same pathogenic CABP2 allele, each pregnancy has an expected 25% affected, 50% carrier, and 25% non-carrier/unaffected probability under standard Mendelian assumptions. Male and female siblings have been affected; no sex bias is known.

Evidence supports a founder effect for c.637+1G>T in southern/southwestern Iranian families and identity-by-descent for c.466G>T in the Italian pedigree. Consanguinity was prominent in Iranian and Egyptian reports. (schrauwen2012amutationin pages 1-2, picher2017ca2+bindingprotein2 pages 2-3, nawaz2024brachyolmiadentalanomalies pages 1-2)

There is no defensible prevalence, annual incidence, carrier frequency, geographic prevalence, sex ratio, penetrance estimate, or age distribution. The published families demonstrate occurrence in Iranian, Northern Italian, and Egyptian ancestry but do not establish ethnic restriction. Apparent geographic clustering is heavily affected by consanguinity and ascertainment.

10. Diagnostics

Clinical evaluation

Recommended phenotype definition includes:

  1. Age-appropriate pure-tone or visual-reinforcement audiometry, with air and bone conduction.
  2. Speech audiometry, including speech-in-noise where feasible.
  3. Tympanometry to exclude conductive middle-ear disease.
  4. OAEs to evaluate OHC function.
  5. ABR, including wave-I amplitude/latency where technically available, to assess auditory-neural transmission.
  6. Otologic, vestibular, ophthalmologic, and syndromic review guided by presentation. The dedicated registry uses pure-tone and speech audiometry as primary outcomes and OAEs and ABR as secondary outcomes. (NCT06680934 chunk 1, schrauwen2012amutationin pages 1-2)

A characteristic clue is bilateral symmetric mid-frequency loss with preserved OAEs or unexpectedly abnormal ABR, but neither feature is diagnostic in isolation.

Molecular diagnosis

A practical sequence is:

  • comprehensive hearing-loss multigene panel including CABP2, with copy-number analysis;
  • exome or genome sequencing if panel testing is negative or the phenotype is blended/atypical;
  • confirm candidate variants and phase them by parental/segregation testing;
  • interpret under current ACMG/AMP specifications, ClinVar, ClinGen, gnomAD, and phenotype concordance;
  • consider RNA analysis for uncertain splice variants where clinically accessible.

WES discovered p.Gly104Asp after GJB2 and several common ARNSHL genes were excluded; exome sequencing also resolved the dual LTBP3/CABP2 diagnosis in the Egyptian family. (koohiyan2019anovelpathogenic pages 2-3, nawaz2024brachyolmiadentalanomalies pages 1-2)

Single-gene CABP2 sequencing is reasonable in a known family or highly characteristic phenotype. WGS may detect noncoding or structural variants missed by exome/panels, but no CABP2-specific diagnostic-yield comparison exists. CMA, conventional karyotyping, FISH, mtDNA sequencing, and repeat-expansion assays are not first-line for isolated suspected DFNB93 unless another clinical indication exists. No blood biomarker, enzyme assay, biopsy, imaging signature, proteomic, metabolomic, epigenomic, or liquid-biopsy test diagnoses DFNB93.

Differential diagnosis and screening

Differentials include other nonsyndromic hearing-loss genes producing mid-frequency loss (TECTA, STRC) and auditory synaptopathy genes such as OTOF, as well as broader congenital genetic, infectious, structural, and acquired causes. TECTA and CABP2 were specifically considered in the Italian U-shaped-audiogram family. (picher2017ca2+bindingprotein2 pages 1-2)

Universal newborn hearing screening can detect hearing impairment but does not establish CABP2 etiology. Cascade testing should be offered after a familial variant is established. The current natural-history study requires a molecular diagnosis involving biallelic CABP2 variants and audiometry. (NCT06680934 chunk 1)

11. Outcome and prognosis

DFNB93 is not known to reduce survival or life expectancy, and no disease-specific mortality has been reported. Five- or ten-year survival statistics are therefore not meaningful. Morbidity is principally auditory and communicative.

Residual hearing may remain in the moderate-to-severe range, but severe hearing loss is documented. Prognostic factors are not validated; plausible candidates—variant class, residual CaBP2 activity, audiometric severity, OAEs, ABR wave I, age, and CaBP1 compensation—remain unproven in humans. No prognostic biomarker or validated risk calculator exists.

Recovery without hearing technology is not documented. Because early anatomy is preserved in mice, functional restoration may be biologically feasible, but human durability and therapeutic window remain unknown. (oestreicher2021cabp2genetherapyrestores pages 7-8, oestreicher2021cabp2genetherapyrestores pages 1-2)

12. Treatment and real-world implementation

Current standard care

There is no approved CABP2-specific pharmacotherapy. Management follows individualized pediatric/adult sensorineural hearing-loss care:

  • appropriately fitted hearing aids when audibility and speech benefit are adequate;
  • cochlear-implant assessment when severe loss or poor aided speech understanding meets local criteria;
  • early speech-language/auditory habilitation, educational accommodations, assistive listening technology, and communication support;
  • serial audiology to track thresholds, speech performance, OAEs, and ABR as indicated.

The primary preclinical paper notes that present management of auditory synaptopathies is limited to hearing aids or cochlear implants, but it provides no CABP2-specific response rate. (oestreicher2021cabp2genetherapyrestores pages 1-2)

Suggested NCIT concepts, with identifiers to be release-validated, include Hearing Aid, Cochlear Implantation, Speech Therapy, Audiologic Rehabilitation, Genetic Counseling, and Gene Therapy.

Experimental gene therapy

In Cabp2-null mice, round-window delivery at postnatal days 5–7 of AAV2/1-Cabp2 or AAV-PHP.eB-Cabp2 restored IHC CaV1.3 function and partially improved hearing. Sixteen of 24 treated mice met a reported ≥20-dB improvement criterion at tested frequencies; wave-I amplitude rose from 0.8±0.1 to 1.3±0.2 µV at 80 dB SPL, and PHP.eB produced approximately 98% IHC transduction. (oestreicher2021cabp2genetherapyrestores pages 2-4)

Limitations include partial rather than complete rescue, cross-ear transduction, possible toxicity or physiological disruption from vector/eGFP overexpression, imperfect promoter/dose matching, postnatal mouse delivery, and uncertain human translation. Some treated wild-type mice developed modest threshold/DPOAE abnormalities, emphasizing the importance of cell-specific, physiological expression. (oestreicher2021cabp2genetherapyrestores pages 5-7, oestreicher2021cabp2genetherapyrestores pages 7-8)

No CABP2-directed drug, ASO, siRNA, CRISPR/editing, cell therapy, immunotherapy, or human gene-therapy trial was identified. NCT06680934 is observational, not therapeutic.

Registry implementation

NCT06680934, sponsored by University Medical Center Göttingen, is a recruiting, case-only, non-probability registry targeting 100 participants of any sex and age with biallelic CABP2 variants. It began August 16, 2024, was first posted November 8, 2024, and has an estimated 25-year duration. Registry URL: https://clinicaltrials.gov/study/NCT06680934; study site: http://www.auditory-neuroscience.uni-goettingen.de/cabp2_registry_en.html. (NCT06680934 chunk 1)

13. Prevention

Primary prevention by lifestyle, vaccine, or medication is not possible for an inherited biallelic disorder. Reproductive prevention options after identifying familial variants include carrier testing, cascade screening, prenatal diagnosis, and preimplantation genetic testing, following nondirective genetic counseling and local ethical/legal standards.

Secondary prevention consists of newborn hearing screening, prompt diagnostic audiology, early molecular diagnosis, and rapid habilitation during language-development windows. Tertiary prevention includes hearing conservation, avoidance of unnecessary ototoxins, optimized hearing technology, speech-language services, and educational support. No immunization or pharmacologic prophylaxis specifically prevents DFNB93.

14. Other species and natural disease

The principal comparative species is Mus musculus (NCBI Taxonomy 10090) with ortholog Cabp2. CaBP2’s cochlear expression and calcium-channel regulatory role are conserved sufficiently for mouse models to reproduce the human synaptopathy mechanism. No naturally occurring companion-animal, livestock, or wildlife CABP2-associated hearing disorder, breed predisposition, VBO term, cross-species transmission, or zoonotic potential was identified. DFNB93 is noninfectious and cannot be transmitted between animals or humans.

15. Model organisms and experimental systems

Cabp2-null mouse

The KOMP-derived Cabp2LacZ/LacZ model replaces/disrupts Cabp2 exons and shows elevated ABR thresholds, reduced amplitudes, prolonged latencies, and reduced/jittered SGN firing, with normal DPOAEs and preserved IHC/OHC and synaptic anatomy. It is suited to studying IHC CaV1.3 gating, ribbon-synapse transmission, neural temporal coding, and gene replacement. (picher2017ca2+bindingprotein2 pages 7-8, picher2017ca2+bindingprotein2 pages 2-3)

Cabp1/Cabp2 double knockout

This model exposes functional redundancy. At 3–4 weeks, click thresholds were 59±2 versus 30±2 dB SPL in controls; by 7–13 weeks they were 68±5 versus 30±1 dB SPL. Ribbon number remained essentially unchanged (12.8±0.8 versus 12.9±0.2 synapses/IHC), while SGN adaptation increased markedly (12.5±3.0 versus 3.4±0.2). These data localize failure to synaptic physiology rather than synapse loss. (oestreicher2024cabp1and2 pages 11-12, oestreicher2024cabp1and2 pages 7-9)

Cellular/in-vitro systems

HEK293-derived heterologous expression, calcium-binding calorimetry, cochlear explants, perforated-patch electrophysiology, exocytosis measurements, immunohistochemistry, ABR/DPOAE, and in-vivo SGN recordings have been used. Such systems isolate channel effects but cannot reproduce the complete human tonotopic, developmental, and perceptual phenotype.

Limitations

The Cabp2 single knockout has a milder SGN phenotype than many affected humans; mice have different audible-frequency ranges, developmental timing, and CaBP redundancy. The double knockout models combined CABP1/CABP2 deficiency rather than human DFNB93 itself and may exaggerate severity. AAV rescue in neonatal mice does not establish safety, dose, surgical route, durability, or efficacy in humans. (oestreicher2024cabp1and2 pages 13-14)

Evidence gaps and expert interpretation

The authoritative interpretation emerging from the primary studies is that DFNB93 is a function-first, structurally preserved presynaptic disorder, making it unusually attractive for gene augmentation. That conclusion is supported by preserved OAEs/anatomy, reversible CaV1.3 inactivation, and successful mouse rescue—not by human therapeutic data. (brotto2024autosomalrecessivenonsyndromic pages 8-9, oestreicher2021cabp2genetherapyrestores pages 1-2)

Major knowledge-base fields should presently be marked unknown rather than negative: population prevalence and incidence; age-dependent penetrance; longitudinal progression; carrier frequency; validated modifier genes; environmental interaction; disease-specific quality-of-life scores; hearing-aid/cochlear-implant outcomes; human therapeutic window; and variant-specific treatment response. The dedicated registry is designed to close several of these gaps by collecting molecular diagnoses, pure-tone and speech audiometry, OAEs, and ABRs. (NCT06680934 chunk 1)

Principal sources and publication dates

  • Schrauwen I, et al. “A Mutation in CABP2, Expressed in Cochlear Hair Cells, Causes Autosomal-Recessive Hearing Impairment.” American Journal of Human Genetics. October 5, 2012. DOI/URL: https://doi.org/10.1016/j.ajhg.2012.08.018. (schrauwen2012amutationin pages 1-2)
  • Picher MM, et al. “Ca²⁺-binding protein 2 inhibits Ca²⁺-channel inactivation in mouse inner hair cells.” PNAS. February 2017. DOI/URL: https://doi.org/10.1073/pnas.1617533114. (picher2017ca2+bindingprotein2 pages 2-3)
  • Koohiyan M, et al. “A Novel Pathogenic Variant in the CABP2 Gene Causes Severe Nonsyndromic Hearing Loss in a Consanguineous Iranian Family.” Audiology and Neurotology. October 2019. DOI/URL: https://doi.org/10.1159/000502251. (koohiyan2019anovelpathogenic pages 4-5)
  • Oestreicher D, et al. “Cabp2-Gene Therapy Restores Inner Hair Cell Calcium Currents and Improves Hearing in a DFNB93 Mouse Model.” Frontiers in Molecular Neuroscience. August 2021. DOI/URL: https://doi.org/10.3389/fnmol.2021.689415. (oestreicher2021cabp2genetherapyrestores pages 1-2)
  • Nawaz H, et al. “Brachyolmia, dental anomalies and short stature (DASS): Phenotype and genotype analyses of Egyptian and Pakistani patients.” Heliyon 10:e23688; available online December 14, 2023, 2024 issue. DOI/URL: https://doi.org/10.1016/j.heliyon.2023.e23688. (nawaz2024brachyolmiadentalanomalies pages 1-2)
  • Oestreicher D, et al. “CaBP1 and 2 enable sustained CaV1.3 calcium currents and synaptic transmission in inner hair cells.” eLife 13:RP93646, Version of Record December 24, 2024. DOI/URL: https://doi.org/10.7554/eLife.93646. (oestreicher2024cabp1and2 pages 1-2)
  • ClinicalTrials.gov. “CABP2 Patient Registry and Natural History Study.” NCT06680934, first posted November 8, 2024: https://clinicaltrials.gov/study/NCT06680934. The registry record also links a 2025 review, PMID 40927552. (NCT06680934 chunk 1)

References

  1. (picher2017ca2+bindingprotein2 pages 1-2): Maria Magdalena Picher, Anna Gehrt, Sandra Meese, Aleksandra Ivanovic, Friederike Predoehl, SangYong Jung, Isabelle Schrauwen, Alberto Giulio Dragonetti, Roberto Colombo, Guy Van Camp, Nicola Strenzke, and Tobias Moser. Ca2+-binding protein 2 inhibits ca2+-channel inactivation in mouse inner hair cells. Proceedings of the National Academy of Sciences, 114:E1717-E1726, Feb 2017. URL: https://doi.org/10.1073/pnas.1617533114, doi:10.1073/pnas.1617533114. This article has 74 citations and is from a highest quality peer-reviewed journal.

  2. (schrauwen2012amutationin pages 1-2): Isabelle Schrauwen, Sarah Helfmann, Akira Inagaki, Friederike Predoehl, Mohammad Amin Tabatabaiefar, Maria Magdalena Picher, Manou Sommen, Celia Zazo Seco, Jaap Oostrik, Hannie Kremer, Annelies Dheedene, Charlotte Claes, Erik Fransen, Morteza Hashemzadeh Chaleshtori, Paul Coucke, Amy Lee, Tobias Moser, and Guy Van Camp. A mutation in cabp2, expressed in cochlear hair cells, causes autosomal-recessive hearing impairment. American journal of human genetics, 91 4:636-45, Oct 2012. URL: https://doi.org/10.1016/j.ajhg.2012.08.018, doi:10.1016/j.ajhg.2012.08.018. This article has 154 citations and is from a highest quality peer-reviewed journal.

  3. (picher2017ca2+bindingprotein2 pages 2-3): Maria Magdalena Picher, Anna Gehrt, Sandra Meese, Aleksandra Ivanovic, Friederike Predoehl, SangYong Jung, Isabelle Schrauwen, Alberto Giulio Dragonetti, Roberto Colombo, Guy Van Camp, Nicola Strenzke, and Tobias Moser. Ca2+-binding protein 2 inhibits ca2+-channel inactivation in mouse inner hair cells. Proceedings of the National Academy of Sciences, 114:E1717-E1726, Feb 2017. URL: https://doi.org/10.1073/pnas.1617533114, doi:10.1073/pnas.1617533114. This article has 74 citations and is from a highest quality peer-reviewed journal.

  4. (NCT06680934 chunk 1): Tobias Moser. CABP2 Patient Registry and Natural History Study. University Medical Center Goettingen. 2024. ClinicalTrials.gov Identifier: NCT06680934

  5. (oestreicher2024cabp1and2 pages 1-2): David Oestreicher, Shashank Chepurwar, Kathrin Kusch, Vladan Rankovic, Sangyong Jung, Nicola Strenzke, and Tina Pangrsic. Cabp1 and 2 enable sustained cav1.3 calcium currents and synaptic transmission in inner hair cells. Aug 2024. URL: https://doi.org/10.7554/elife.93646.2, doi:10.7554/elife.93646.2. This article has 12 citations.

  6. (oestreicher2024cabp1and2 pages 11-12): David Oestreicher, Shashank Chepurwar, Kathrin Kusch, Vladan Rankovic, Sangyong Jung, Nicola Strenzke, and Tina Pangrsic. Cabp1 and 2 enable sustained cav1.3 calcium currents and synaptic transmission in inner hair cells. Aug 2024. URL: https://doi.org/10.7554/elife.93646.2, doi:10.7554/elife.93646.2. This article has 12 citations.

  7. (schrauwen2012amutationin pages 7-8): Isabelle Schrauwen, Sarah Helfmann, Akira Inagaki, Friederike Predoehl, Mohammad Amin Tabatabaiefar, Maria Magdalena Picher, Manou Sommen, Celia Zazo Seco, Jaap Oostrik, Hannie Kremer, Annelies Dheedene, Charlotte Claes, Erik Fransen, Morteza Hashemzadeh Chaleshtori, Paul Coucke, Amy Lee, Tobias Moser, and Guy Van Camp. A mutation in cabp2, expressed in cochlear hair cells, causes autosomal-recessive hearing impairment. American journal of human genetics, 91 4:636-45, Oct 2012. URL: https://doi.org/10.1016/j.ajhg.2012.08.018, doi:10.1016/j.ajhg.2012.08.018. This article has 154 citations and is from a highest quality peer-reviewed journal.

  8. (schrauwen2012amutationin pages 3-4): Isabelle Schrauwen, Sarah Helfmann, Akira Inagaki, Friederike Predoehl, Mohammad Amin Tabatabaiefar, Maria Magdalena Picher, Manou Sommen, Celia Zazo Seco, Jaap Oostrik, Hannie Kremer, Annelies Dheedene, Charlotte Claes, Erik Fransen, Morteza Hashemzadeh Chaleshtori, Paul Coucke, Amy Lee, Tobias Moser, and Guy Van Camp. A mutation in cabp2, expressed in cochlear hair cells, causes autosomal-recessive hearing impairment. American journal of human genetics, 91 4:636-45, Oct 2012. URL: https://doi.org/10.1016/j.ajhg.2012.08.018, doi:10.1016/j.ajhg.2012.08.018. This article has 154 citations and is from a highest quality peer-reviewed journal.

  9. (koohiyan2019anovelpathogenic pages 4-5): Mahbobeh Koohiyan, Mohammad Reza Noori-Daloii, Morteza Hashemzadeh-Chaleshtori, Mansoor Salehi, Hamidreza Abtahi, and Mohammad Amin Tabatabaiefar. A novel pathogenic variant in the cabp2 gene causes severe nonsyndromic hearing loss in a consanguineous iranian family. Audiology and Neurotology, 24:258-263, Oct 2019. URL: https://doi.org/10.1159/000502251, doi:10.1159/000502251. This article has 18 citations.

  10. (koohiyan2019anovelpathogenic pages 3-4): Mahbobeh Koohiyan, Mohammad Reza Noori-Daloii, Morteza Hashemzadeh-Chaleshtori, Mansoor Salehi, Hamidreza Abtahi, and Mohammad Amin Tabatabaiefar. A novel pathogenic variant in the cabp2 gene causes severe nonsyndromic hearing loss in a consanguineous iranian family. Audiology and Neurotology, 24:258-263, Oct 2019. URL: https://doi.org/10.1159/000502251, doi:10.1159/000502251. This article has 18 citations.

  11. (koohiyan2019anovelpathogenic pages 1-2): Mahbobeh Koohiyan, Mohammad Reza Noori-Daloii, Morteza Hashemzadeh-Chaleshtori, Mansoor Salehi, Hamidreza Abtahi, and Mohammad Amin Tabatabaiefar. A novel pathogenic variant in the cabp2 gene causes severe nonsyndromic hearing loss in a consanguineous iranian family. Audiology and Neurotology, 24:258-263, Oct 2019. URL: https://doi.org/10.1159/000502251, doi:10.1159/000502251. This article has 18 citations.

  12. (nawaz2024brachyolmiadentalanomalies pages 1-2): Hamed Nawaz, Asia Parveen, Sher Alam Khan, Abul Khair Zalan, Muhammad Adnan Khan, Noor Muhammad, Nehal F. Hassib, Mostafa I. Mostafa, Rasha M. Elhossini, Nehal Nabil Roshdy, Asmat Ullah, Amina Arif, Saadullah Khan, Ole Ammerpohl, and Naveed Wasif. Brachyolmia, dental anomalies and short stature (dass): phenotype and genotype analyses of egyptian and pakistani patients. Jan 2024. URL: https://doi.org/10.1016/j.heliyon.2023.e23688, doi:10.1016/j.heliyon.2023.e23688. This article has 4 citations.

  13. (picher2017ca2+bindingprotein2 pages 7-8): Maria Magdalena Picher, Anna Gehrt, Sandra Meese, Aleksandra Ivanovic, Friederike Predoehl, SangYong Jung, Isabelle Schrauwen, Alberto Giulio Dragonetti, Roberto Colombo, Guy Van Camp, Nicola Strenzke, and Tobias Moser. Ca2+-binding protein 2 inhibits ca2+-channel inactivation in mouse inner hair cells. Proceedings of the National Academy of Sciences, 114:E1717-E1726, Feb 2017. URL: https://doi.org/10.1073/pnas.1617533114, doi:10.1073/pnas.1617533114. This article has 74 citations and is from a highest quality peer-reviewed journal.

  14. (oestreicher2021cabp2genetherapyrestores pages 2-4): David Oestreicher, Maria Magdalena Picher, Vladan Rankovic, Tobias Moser, and Tina Pangrsic. Cabp2-gene therapy restores inner hair cell calcium currents and improves hearing in a dfnb93 mouse model. Frontiers in Molecular Neuroscience, Aug 2021. URL: https://doi.org/10.3389/fnmol.2021.689415, doi:10.3389/fnmol.2021.689415. This article has 28 citations.

  15. (oestreicher2021cabp2genetherapyrestores pages 5-7): David Oestreicher, Maria Magdalena Picher, Vladan Rankovic, Tobias Moser, and Tina Pangrsic. Cabp2-gene therapy restores inner hair cell calcium currents and improves hearing in a dfnb93 mouse model. Frontiers in Molecular Neuroscience, Aug 2021. URL: https://doi.org/10.3389/fnmol.2021.689415, doi:10.3389/fnmol.2021.689415. This article has 28 citations.

  16. (oestreicher2021cabp2genetherapyrestores pages 7-8): David Oestreicher, Maria Magdalena Picher, Vladan Rankovic, Tobias Moser, and Tina Pangrsic. Cabp2-gene therapy restores inner hair cell calcium currents and improves hearing in a dfnb93 mouse model. Frontiers in Molecular Neuroscience, Aug 2021. URL: https://doi.org/10.3389/fnmol.2021.689415, doi:10.3389/fnmol.2021.689415. This article has 28 citations.

  17. (oestreicher2021cabp2genetherapyrestores pages 1-2): David Oestreicher, Maria Magdalena Picher, Vladan Rankovic, Tobias Moser, and Tina Pangrsic. Cabp2-gene therapy restores inner hair cell calcium currents and improves hearing in a dfnb93 mouse model. Frontiers in Molecular Neuroscience, Aug 2021. URL: https://doi.org/10.3389/fnmol.2021.689415, doi:10.3389/fnmol.2021.689415. This article has 28 citations.

  18. (oestreicher2024cabp1and2 pages 7-9): David Oestreicher, Shashank Chepurwar, Kathrin Kusch, Vladan Rankovic, Sangyong Jung, Nicola Strenzke, and Tina Pangrsic. Cabp1 and 2 enable sustained cav1.3 calcium currents and synaptic transmission in inner hair cells. Aug 2024. URL: https://doi.org/10.7554/elife.93646.2, doi:10.7554/elife.93646.2. This article has 12 citations.

  19. (oestreicher2024cabp1and2 pages 13-14): David Oestreicher, Shashank Chepurwar, Kathrin Kusch, Vladan Rankovic, Sangyong Jung, Nicola Strenzke, and Tina Pangrsic. Cabp1 and 2 enable sustained cav1.3 calcium currents and synaptic transmission in inner hair cells. Aug 2024. URL: https://doi.org/10.7554/elife.93646.2, doi:10.7554/elife.93646.2. This article has 12 citations.

  20. (koohiyan2019anovelpathogenic pages 2-3): Mahbobeh Koohiyan, Mohammad Reza Noori-Daloii, Morteza Hashemzadeh-Chaleshtori, Mansoor Salehi, Hamidreza Abtahi, and Mohammad Amin Tabatabaiefar. A novel pathogenic variant in the cabp2 gene causes severe nonsyndromic hearing loss in a consanguineous iranian family. Audiology and Neurotology, 24:258-263, Oct 2019. URL: https://doi.org/10.1159/000502251, doi:10.1159/000502251. This article has 18 citations.

  21. (schrauwen2012amutationin pages 6-7): Isabelle Schrauwen, Sarah Helfmann, Akira Inagaki, Friederike Predoehl, Mohammad Amin Tabatabaiefar, Maria Magdalena Picher, Manou Sommen, Celia Zazo Seco, Jaap Oostrik, Hannie Kremer, Annelies Dheedene, Charlotte Claes, Erik Fransen, Morteza Hashemzadeh Chaleshtori, Paul Coucke, Amy Lee, Tobias Moser, and Guy Van Camp. A mutation in cabp2, expressed in cochlear hair cells, causes autosomal-recessive hearing impairment. American journal of human genetics, 91 4:636-45, Oct 2012. URL: https://doi.org/10.1016/j.ajhg.2012.08.018, doi:10.1016/j.ajhg.2012.08.018. This article has 154 citations and is from a highest quality peer-reviewed journal.

  22. (brotto2024autosomalrecessivenonsyndromic pages 8-9): Davide Brotto, Marco Greggio, Cosimo De Filippis, and Patrizia Trevisi. Autosomal recessive non-syndromic deafness: is aav gene therapy a real chance? Audiology Research, 14:239-253, Feb 2024. URL: https://doi.org/10.3390/audiolres14020022, doi:10.3390/audiolres14020022. This article has 8 citations.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 8
Resolved 8
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 8
On topic 6
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 12
Resolved 12
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 1
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Terms named as a different term 1

Terms the report names something else

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

  • MONDO:0013963 (2 mentions) - the report calls it "if available"; MONDO calls it autosomal recessive nonsyndromic hearing loss 93