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Inheritance

1

Autosomal recessive HP:0000007

Autosomal recessive inheritance is supported by segregation of biallelic CABP2 variants. Homozygous and compound-heterozygous genotypes are reported. Consanguinity is common in the initial families but is not required. Hearing impairment in ungenotyped relatives should not be attributed to a single CABP2 allele: the Danish mother and other maternal relatives remained genetically unresolved.

Autosomal recessive inheritance

Show evidence (3 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."

Homozygosity in consanguineous kindreds, the founding recessive observation.

PMID:40927552 SUPPORT Other

"p.(Glu78Lys) and p.?/ p.(Glu84Lys) and p.? | Comp het | Congenital | Moderate to profound"

Table 2 reports compound heterozygosity in DF326; the review is secondary evidence.

PMID:33666369 SUPPORT Human Clinical

"The patient’s mother and the remaining family members suffering from hearing loss on her side of the family remain genetically unresolved."

The family history does not establish dominant CABP2 disease.

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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#Impaired Synaptic Sound Encoding

Clinical reports describe benefit from hearing aids, whereas mechanistic work predicts that pronounced channel inactivation could limit benefit from amplification alone. Comparative aided speech-perception measurements would clarify the range of benefit and the value of signal-to-noise improvement in DFNB93.

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.

How does hearing change from childhood into adulthood across CABP2 genotypes?

KNOWLEDGE GAP OPEN gap_dfnb93_progression

Attached to

phenotypes#Bilateral Sensorineural Hearing Loss

Serial audiograms in two Finnish children demonstrate stable hearing over the reported childhood intervals. Longer-term, genotype-stratified natural-history data are needed to establish whether this stability persists across adulthood and across other alleles. Progressive mouse hearing impairment should not be treated as proof of human progression.

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#Bilateral 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

8

Biallelic CABP2 Loss-of-Function Variant

Biallelic pathogenic CABP2 variants impair CaBP2 function. Reported alleles include splice-site, nonsense and missense variants. For the recurrent c.637+1G>T allele, exon skipping was demonstrated in a minigene assay and truncation is predicted if the abnormal transcript escapes nonsense-mediated decay; endogenous mutant protein abundance in patient hair cells was not measured.

Genetic context CABP2 hgnc:1385 variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Both homozygous and compound-heterozygous CABP2 genotypes have been reported. Functional loss may be partial or complete depending on the allele; biochemical tests of an engineered truncation do not establish the amount of residual protein in patients.

Downstream

CABP2 Exon 6 Skipping The c.637+1G>T splice-donor allele causes exon 6 skipping in a COS-7 minigene assay.

Loss of CaBP2 Function at the Inner Hair Cell Ribbon Synapse Other pathogenic alleles can impair CaBP2 function through mechanisms that need not involve exon 6 skipping.

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."

The founding families and the recurrent allele.

CABP2 Exon 6 Skipping

The recurrent c.637+1G>T allele disrupts splicing in a COS-7 exon-trapping assay. Skipping exon 6 predicts a frameshift, p.Phe164Serfs*4, and loss of the last two EF hands if the RNA escapes degradation. This assay establishes a splice defect, not the abundance or stability of the transcript in human inner hair cells.

Experimental models

COS-7 CABP2 exon-trapping assay CELL LINE

Downstream

Loss of CaBP2 Function at the Inner Hair Cell Ribbon Synapse The predicted truncation removes C-terminal EF hands. An engineered p.Phe164Ter proxy has altered calcium binding and weakened, residual CaV1.3 regulation.

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3484643/ SUPPORT In Vitro

"Skipping of exon 6, if RNA is not degraded by nonsense-mediated mRNA decay, is predicted to lead to a shifted reading frame, a premature truncation of the protein"

Exon trapping and the predicted translation consequence; patient RNA and protein were not measured.

Loss of CaBP2 Function at the Inner Hair Cell Ribbon Synapse

CaBP2 regulates presynaptic calcium channels in cochlear inner hair cells. The founding truncation proxy showed altered calcium binding and weaker, but retained, inhibition of CaV1.3 inactivation. In mice, a genetic expression reporter localized Cabp2 to inner and outer hair cells but not spiral ganglion neurons, supporting a presynaptic site of the principal sound-encoding defect.

cochlear inner hair cell CL:0000589

CaV1.3 calcium channel regulation by CaBP2 GO:0005246 ↓ DECREASED

Experimental models

Heterologous CaV1.3 regulation by CABP2 CELL LINE

Purified CaBP2 calcium-binding assay OTHER

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 (2 references)

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.

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."

An engineered truncation models loss of the C-terminal EF hands; its residual activity must not be equated with the amount of mutant protein in patient hair cells.

Enhanced CaV1.3 Calcium-Channel Inactivation

Cabp2-deficient mouse inner hair cells show increased CaV1.3 inactivation despite preserved peak calcium-current amplitude and voltage dependence of activation under the tested conditions. At room temperature, the single knockout primarily increases voltage-dependent inactivation; its increase in calcium-dependent inactivation did not reach significance. Removing both CaBP1 and CaBP2 markedly enhances both components. Normal peak current does not directly measure channel number, and double-knockout effects do not establish the magnitude of a CABP2-only human defect.

cochlear inner hair cell CL:0000589

available presynaptic CaV1.3 current GO:0005245 ↓ DECREASED

Animal models

Cabp2 knockout mouse Mouse recapitulates The defining channel defect, measured directly by patch clamp in the correct cell type.

Downstream

Reduced Effective Transmission at the Inner Hair Cell Ribbon Synapse Greater steady-state inactivation is proposed to reduce the calcium-channel pool available to support presynaptic transmission in vivo.

Show evidence (3 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.

url:https://pure.mpg.de/rest/items/item_2419839_5/component/file_2419838/content SUPPORT Model Organism

"we found significantly increased VDI and a nonsignificant trend toward increased CDI in IHCs of 2- to 3-wk-old"

The single-knockout room-temperature measurements distinguish the two components of inactivation.

Reduced Effective Transmission at the Inner Hair Cell Ribbon Synapse

Reduced availability of presynaptic CaV1.3 channels is proposed to decrease effective transmitter delivery to auditory afferents. Whole-cell capacitance assays did not show reduced exocytosis in Cabp2-only knockout hair cells; some sustained responses were increased, possibly through extrasynaptic release. In contrast, combined Cabp1/Cabp2 deletion directly reduces sustained exocytosis, especially at depolarized holding potentials. The double-knockout result supports the mechanism but cannot be assigned unchanged to human DFNB93.

cochlear inner hair cell CL:0000589

sustained synaptic vesicle exocytosis at the hair cell ribbon synapse GO:0016079 ↓ 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 Reduced effective presynaptic drive is proposed to account for lower afferent firing rates.

Reduced Temporal Precision of Auditory Nerve Firing Impaired presynaptic encoding is proposed to delay and desynchronize afferent responses.

Show evidence (2 references)

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.

PMID:39718549 SUPPORT Model Organism

"Previously, patch-clamp recordings surprisingly revealed normal whole-cell exocytosis in CaBP2-deficient IHCs despite enhanced inactivation of calcium channels"

The paper explicitly contrasts preserved single-knockout capacitance responses with the double-knockout release deficit.

Reduced Spiral Ganglion Neuron Firing

Single-unit recordings in Cabp2-null mice show reduced spontaneous and sound-evoked spiral ganglion neuron firing. In the single knockout, neural frequency tuning and spike-rate thresholds can remain normal despite reduced maximal firing. The more severe rate dependence in Cabp1/Cabp2 double-knockout mice provides additional mechanistic evidence, with the limitation that some recorded units could be cochlear-nucleus neurons.

spiral ganglion neuron CL:0011113

afferent auditory nerve firing GO:0019228 ↓ DECREASED

Downstream

Impaired Synaptic Sound Encoding Reduced auditory-nerve activity degrades the neural representation of sound.

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.

Reduced Temporal Precision of Auditory Nerve Firing

In Cabp2-null mice, first spikes after sound onset occur later and with greater trial-to-trial variability. Reduced timing precision, together with lower firing rates, provides a physiological explanation for reduced auditory brainstem response amplitudes and elevated response thresholds.

spiral ganglion neuron CL:0011113

Animal models

Cabp2 knockout mouse Mouse recapitulates Single-neuron recordings show delayed and more variable first-spike timing at sound onset.

Downstream

Impaired Synaptic Sound Encoding Delayed and less synchronized auditory-nerve responses impair population sound encoding.

Show evidence (1 reference)

url:https://pure.mpg.de/rest/items/item_2419839_5/component/file_2419838/content SUPPORT Model Organism

"Rate reduction and increased jitter of SGN firing at sound onset likely explain the impaired ABR wave I amplitude and threshold."

The authors link reduced firing and temporal precision to the brainstem response phenotype.

Impaired Synaptic Sound Encoding

Impaired presynaptic encoding produces abnormal auditory brainstem responses and hearing impairment. Cabp2-null mice retain cochlear amplification under the reported conditions. Transient otoacoustic emissions were present in an Italian child, but were absent in founding Iranian cases and in two Finnish children. Preserved emissions support synaptopathy when present; their absence does not exclude genetically confirmed DFNB93.

Animal models

Cabp2 knockout mouse Mouse recapitulates The mouse combines preserved otoacoustic emissions with abnormal brainstem responses, supporting a presynaptic defect. This resembles an observed human pattern without implying that all patients retain emissions.

Cabp1/Cabp2 double-knockout mouse with AAV CaBP2 rescue Mouse rescues Cabp2 delivery at postnatal day six improves channel regulation, exocytosis and auditory responses. This demonstrates rescue after neonatal treatment, not reversal of established adult human deafness.

Downstream

Bilateral Sensorineural Hearing Loss The synaptic defect is the principal model-supported mechanism for human hearing impairment.

Abnormal Auditory Brainstem Response Reduced and desynchronized afferent activity alters evoked population responses.

Show evidence (2 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:35150090 SUPPORT Human Clinical

"At 4 months of age, TEOAE showed no responses, and ASSR (Figure 1d) and ABR results revealed responses on average at 40–55 dB levels which led to a diagnosis of moderate sensorineural HI."

A genetically confirmed Finnish infant had absent emissions and elevated evoked-response thresholds, limiting any universal preserved-emissions claim.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

8

Ear 6

Bilateral Sensorineural Hearing Loss Bilateral sensorineural hearing impairment HP:0008619

Show evidence (3 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.

PMID:35150090 SUPPORT Human Clinical

"Audiograms taken at the ages of 6.0 and 13.7 years for II:1 and at 2.4, 3.0, and 3.5 years for II:4 (Figure 1c) feature symmetrical, moderate-to-severe non-progressive HI that is more conspicuous in the mid-frequencies forming a U-shaped audiogram"

Serial childhood audiograms establish stability in these two siblings, not across all patients.

Prelingual Onset Prelingual sensorineural hearing impairment HP:0000399

Show evidence (2 references)

PMID:33666369 SUPPORT Human Clinical

"Bilateral hearing loss was detected when the patient was 3 days old by the national standardized hearing screening."

The Danish case had neonatal detection.

PMID:35150090 SUPPORT Human Clinical

"Although FINHEAR1 II:4 presented with congenital HI, we cannot confirm her brother II:1 has congenital HI since he was not diagnosed until 6 years of age."

Onset uncertainty prevents an obligatory prelingual classification.

Severe Hearing Loss in a Subset of Families Severe sensorineural hearing impairment HP:0008625

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.

U-Shaped (Mid-Frequency) Audiometric Configuration Mid-frequency hearing loss HP:0012781

Show evidence (1 reference)

PMID:35150090 SUPPORT Human Clinical

"symmetrical, moderate-to-severe non-progressive HI that is more conspicuous in the mid-frequencies forming a U-shaped audiogram"

Direct longitudinal audiometry in the Finnish family.

Reverse-Slope Audiometric Configuration Low-frequency hearing loss HP:0008542

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.

Absent Otoacoustic Emissions HP:6000182

Show evidence (1 reference)

PMID:35150090 SUPPORT Human Clinical

"FINHEAR2 has one affected member, II:3 (Figure 1a), who failed newborn screening as otoacoustic emissions were not elicited. At 4 months of age, TEOAE showed no responses"

Repeated absent emissions in an affected child.

Nervous System 1

Abnormal Auditory Brainstem Response Abnormal auditory evoked potentials HP:0006958

Show evidence (1 reference)

PMID:35150090 SUPPORT Human Clinical

"At 4 months of age, TEOAE showed no responses, and ASSR (Figure 1d) and ABR results revealed responses on average at 40–55 dB levels which led to a diagnosis of moderate sensorineural HI."

Direct human evoked-response measurements rather than an inference from the synaptopathy label.

Other 1

Preserved Otoacoustic Emissions

Show evidence (1 reference)

url:https://pure.mpg.de/rest/items/item_2419839_5/component/file_2419838/content SUPPORT Human Clinical

"a transitory evoked otoacoustic emission (TEOAE) was observed in subject III:1 in the course of clinical examination at the age of 4 y (subject III:3 was not tested for TEOAE)."

The primary report specifies the individual, age and untested sibling.

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Genetic Associations

1

CABP2

Gene: CABP2 hgnc:1385 relationship_type: CAUSATIVE

Show evidence (4 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.

PMID:35150090 SUPPORT Human Clinical

"The AF of the CABP2 c.637+1G>T variant within the Finnish population is 3.3 × 10−3"

Allele frequency is distinguished from carrier frequency.

+ 1 more reference

Variants (5)

NM_016366.3:c.637+1G>T Pathogenic

Gene: CABP2 hgnc:1385 splice donor variant

Recurrent splice-donor allele found homozygously in multiple families. Exon skipping predicts p.Phe164Serfs*4 if the transcript escapes decay; patient protein abundance is unresolved.

Show evidence (1 reference)

PMID:35150090 SUPPORT Human Clinical

"we identified a homozygous pathogenic splice site variant c.637+1G>T in CAPB2"

The recurrent allele was classified as pathogenic in the Finnish study; CAPB2 is a source typographical error.

CABP2 c.466G>T (p.Glu156Ter)

Gene: CABP2 hgnc:1385 nonsense variant

Homozygous nonsense allele in two Italian siblings. Nonsense-mediated decay was predicted, not measured in patient hair cells.

Show evidence (1 reference)

url:https://pure.mpg.de/rest/items/item_2419839_5/component/file_2419838/content SUPPORT Human Clinical

"The same CABP2 c.466G > T mutation was found in the homozygous state in the proband’s sister"

Independent affected sibling with the same nonsense allele.

CABP2 c.311G>A (p.Gly104Asp) Pathogenic

Gene: CABP2 hgnc:1385 missense variant

The Iranian severe-hearing-loss report classified this missense allele as pathogenic. No allele-specific CaV1.3 assay is reported in the cached abstract.

Show evidence (1 reference)

PMID:31661684 SUPPORT Human Clinical

"WES results showed a novel rare variant (c.311G>A) in the CABP2gene.This missense variant in the exon 4 of the CABP2gene meets the criteria of being pathogenic"

Published clinical classification; not a direct functional measurement.

NM_001318496.1:c.250G>A (p.Glu84Lys) Pathogenic

Gene: CABP2 hgnc:1385 missense variant

Reported as pathogenic in Israeli family DF326. The 2025 synthesis lists the family as compound heterozygous with a splice-site allele. Numbering of this missense allele differs on the shorter transcript, where the protein change is p.Glu78Lys.

Show evidence (1 reference)

PMID:33111345 SUPPORT Human Clinical

"CABP2 NM_001318496.1 | DF326 | AR | Mixed | chr11:67289435 | c.250G>A | Missense | Glu84Lys | 0 | 0 | 1337669 | P (PM2, PM3_S, PP1_M, PP3, PP4)"

Table 1 provides transcript, variant, family and pathogenic classification.

NM_016366.3:c.590T>C (p.Ile197Thr)

Gene: CABP2 hgnc:1385 missense variant

Reported with hearing loss in several populations. The Egyptian study attributes hearing impairment to this allele while describing it as presumably benign under its ACMG analysis, creating an unresolved interpretation conflict. Its skeletal and dental findings were attributed separately to LTBP3. This report is not sufficient to assign an unqualified pathogenic classification or a CABP2 skeletal syndrome.

Show evidence (2 references)

PMID:38192829 SUPPORT Human Clinical

"The CABP2 variant (c.590T > C; p.Ile197Thr) was declared presumably benign following the ACMG guidelines."

The paper itself reports an interpretation inconsistent with its causal narrative.

PMID:38192829 SUPPORT Human Clinical

"we believe that the CABP2 variant (NM_016366.3: c.590T > C; p.Ile197Thr) in exon-6 is causing hearing impairment in family A."

The authors nevertheless favor this allele as causal; both statements are retained as the source conflict.

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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 classified the autosomal recessive CABP2–nonsyndromic hearing loss relationship as Definitive in its February 2020 evaluation.

Show evidence (2 references)

CGGV:assertion_20de88d2-6681-4522-9e11-26cdf66a2c15-2020-02-06T170000.000Z SUPPORT Other

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.

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Medical Actions

5

Hearing Aids

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

Platform: Device

Fit and assess hearing aids according to the individual hearing profile and communication needs. A genetically confirmed North American case had a positive reported prognosis with hearing aids and multidisciplinary follow-up. This single report does not establish a response rate, and synaptic dysfunction may limit speech perception despite improved aided thresholds.

Mechanism Target:

Impaired Synaptic Sound Encoding — Amplification can improve audibility while leaving the molecular channel-regulation defect unchanged; benefit requires individual assessment.

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: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.

Cochlear Gene Replacement (investigational)

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

Platform: Gene therapy

AAV-mediated Cabp2 delivery improved inner-hair-cell calcium currents and hearing in neonatal Cabp2-null mice, and partially restored synaptic function in Cabp1/Cabp2 double-knockout mice. These are preclinical experiments. Early treatment, incomplete rescue, contralateral vector spread and adverse auditory findings in some treated wild-type mice limit extrapolation to human efficacy, durability and safety.

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 (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.

Cochlear Implantation

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

Platform: Device

Consider cochlear implant assessment for severe-to-profound hearing loss when appropriate after individualized audiological evaluation. This follows general genetic-hearing-loss guidance; CABP2-specific implant outcome rates are not established by the cited evidence.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK1434/ SUPPORT INDIRECT Other

"Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months."

General guidance supports considering implantation after clinical assessment; this is not a DFNB93-specific efficacy claim.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Counseling addresses recessive inheritance, variant interpretation, parental testing and reproductive options. When both parents carry the relevant recessive pathogenic alleles, each pregnancy has a 25% chance of an affected child. Individual variant interpretation is essential, especially when published classifications conflict.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK1434/ SUPPORT Other

"If both parents are known to be ... heterozygous ... autosomal recessive ... hearing loss-related ... pathogenic variant ... has at conception a 25% chance of having hearing loss"

The recurrence calculation is conditional on confirmed parental carrier genotypes, not merely a consanguineous pedigree.

Speech, Language and Communication Support

Action: speech and language therapy Ontology label: Speech Language Therapy NCIT:C159273

Platform: Behavioral / lifestyle

Early, individualized speech, language, educational and communication support accompanies audiological management. D/deaf and hard-of-hearing community resources should be adapted to the child and family. This is general hearing-loss care, with no DFNB93-specific intervention trial implied.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK1434/ SUPPORT Other

"A speech-language therapist as well as a neuropsychologist/psychologist for children with hearing loss provides access to resources within the community to aid in speech and language and D/deaf and hard of hearing (DHH) identity development."

General hearing-loss guidance supports communication services; no disease-specific treatment outcome is asserted.

🔬

Diagnosis

2

Genetic testing for biallelic CABP2 variants

Evaluate CABP2 in a comprehensive hearing-loss panel or genomic analysis, with interpretation of both alleles and family segregation. Homozygosity is not required. Phenotype and ancestry can inform interpretation, but variants of uncertain significance alone do not establish DFNB93.

Show evidence (2 references)

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."

CABP2 explained one case in this selected Czech cohort after GJB2 testing. This is not an unselected population diagnostic yield.

url:https://www.ncbi.nlm.nih.gov/books/NBK1434/ SUPPORT Other

"The identification of variant(s) of ... uncertain significance ... cannot be used to confirm or rule out the diagnosis."

General genetic-hearing-loss interpretation guidance applies to CABP2 testing.

Audiological testing including otoacoustic emissions

Combine age-appropriate behavioral audiometry, tympanometry, otoacoustic emissions and auditory evoked responses to characterize hearing sensitivity and possible synaptic dysfunction. Emissions can be present or absent in DFNB93; passing newborn emissions screening does not exclude later recognition of hearing impairment.

Show evidence (1 reference)

PMID:35150090 SUPPORT Human Clinical

"Physical examination, transient otoacoustic emissions (TEOAE), and pure-tone audiometry were performed at 125–8000 Hz for the affected children of FINHEAR1. TEOAE, auditory steady-state response (ASSR), and auditory brainstem response (ABR) were evaluated for the affected child of FINHEAR2."

The clinical study documents complementary assessments.

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Prevalence

1

Finland: modeled hearing loss due to homozygous CABP2 c.637+1G>T

Unknown 0.7–1.9 per 100,000 Unknown

The 2022 study estimated prevalence from population allele-frequency data. This is not an observed disease prevalence, does not cover all CABP2 alleles, and does not specify a point or birth-prevalence measure. The range crosses two numeric prevalence bands.

Show evidence (1 reference)

PMID:35150090 SUPPORT Human Clinical

"The estimated prevalence of HI in Finland due to homozygous c.637+1G>T variants ranges from 0.7 to 1.9 per 100,000 individuals."

The authors provide an allele-specific modeled prevalence estimate.

🔀

Differential Diagnoses

2

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

🔬

Clinical Trials

1

NCT06680934 NOT_APPLICABLE RECRUITING

Observational CABP2 patient registry and natural-history study collecting molecular diagnoses and clinical hearing information. The registry is not a CABP2 gene-therapy intervention.

Show evidence (1 reference)

clinicaltrials:NCT06680934 SUPPORT Other

"This registry is designed to collect comprehensive information about the molecular genetic diagnoses and clinical information of individuals with CABP2-associated hearing impairment to support a natural history study."

Registry purpose, distinct from therapeutic efficacy evidence.

🧫

Experimental Models

3

COS-7 CABP2 exon-trapping assay CELL_LINE

Wild-type and c.637+1G>T exon-6 constructs were tested in COS-7 cells because CABP2 transcript could not be detected in accessible patient blood or saliva. Mutant minigene splicing skipped exon 6.

Pathograph links

CABP2 Exon 6 Skipping recapitulates fidelity: moderate

Limitations: The minigene does not establish transcript abundance, nonsense-mediated decay or protein expression in patient cochlear hair cells.

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3484643/ SUPPORT In Vitro

"Analysis of cDNA prepared from COS-7 cells transfected with a MT ... donor site only revealed a PCR product of 177 bp, indicating that the mutation ... leads to a complete skipping of exon 6"

The mutant exon-trapping construct skipped exon 6 in COS-7 cells; this does not establish transcript stability in patient hair cells.

Heterologous CaV1.3 regulation by CABP2 CELL_LINE

HEK293T expression assays compared wild-type CaBP2 with an engineered p.Phe164Ter truncation proxy. The mutant retained some suppression of calcium-dependent inactivation. Later HEK293/hSK3-1 experiments showed that channel regulation depends on the expression system and does not fully reproduce inner-hair-cell physiology.

Pathograph links

Loss of CaBP2 Function at the Inner Hair Cell Ribbon Synapse partially recapitulates fidelity: moderate

Limitations: The engineered p.Phe164Ter construct approximates the predicted frameshift truncation and is not patient-derived protein. Initial mutant expression exceeded wild type; expression levels were adjusted for the comparison. Heterologous voltage-activation and current-density effects should not be imported directly into the hair-cell mechanism.

Show evidence (2 references)

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."

Heterologous channel measurements demonstrate residual regulatory activity.

+ 1 more reference

Purified CaBP2 calcium-binding assay OTHER

Isothermal titration calorimetry compared purified wild-type CaBP2 with the engineered C-terminal truncation proxy, demonstrating altered calcium binding.

Pathograph links

Loss of CaBP2 Function at the Inner Hair Cell Ribbon Synapse measures fidelity: moderate

Limitations: Purified-protein behavior does not determine the abundance or calcium-buffering contribution of mutant CaBP2 in patient hair cells.

Show evidence (1 reference)

PMID:22981119 SUPPORT In Vitro

"Compared with wild-type CaBP2, the truncated CaBP2 showed altered Ca(2+) binding in isothermal titration calorimetry"

Direct biochemical measurement of the engineered proteins.

🐁

Animal Models

3

Cabp2 knockout mouse

Constitutive Cabp2 disruption produces impaired auditory brainstem responses with preserved distortion-product otoacoustic emissions, enhanced inner-hair-cell calcium-current inactivation and reduced afferent firing. Inner hair cells and ribbon synapses were retained at the examined ages. These findings support presynaptic dysfunction without requiring early sensory-cell degeneration.

Species

Mouse

Genotype

Cabp2 LacZ/LacZ (constitutive knockout, homozygous)

Publication

PMID:28183797

Pathograph links

Enhanced CaV1.3 Calcium-Channel Inactivation recapitulates fidelity: moderate The defining channel defect, measured directly by patch clamp in the correct cell type.

Limitations: A constitutive knockout does not reproduce every human allele. An engineered human truncation retains some channel-regulatory activity, but residual protein in patient hair cells is unknown. Mouse single-neuron thresholds were relatively preserved and do not reproduce the full human audiometric phenotype. Assay temperature, age and cochlear position affect the observed channel phenotype.

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.

Impaired Synaptic Sound Encoding recapitulates fidelity: moderate The mouse combines preserved otoacoustic emissions with abnormal brainstem responses, supporting a presynaptic defect. This resembles an observed human pattern without implying that all patients retain emissions.

Limitations: Human emissions were documented in one Italian child but were absent in other confirmed cases. The mouse findings are age- and assay-specific.

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:28183797 SUPPORT Model Organism

"Cabp2LacZ/LacZ mice displayed intact cochlear amplification but impaired auditory brainstem responses."

Primary measurements support the observed mouse phenotype.

Reduced Temporal Precision of Auditory Nerve Firing recapitulates fidelity: moderate Single-neuron recordings show delayed and more variable first-spike timing at sound onset.

Limitations: These are mouse recordings, not direct measurements of human auditory-nerve firing.

Show evidence (1 reference)

url:https://pure.mpg.de/rest/items/item_2419839_5/component/file_2419838/content SUPPORT Model Organism

"Rate reduction and increased jitter of SGN firing at sound onset likely explain the impaired ABR wave I amplitude and threshold."

The source links temporal imprecision with the evoked-response phenotype.

Cabp1/Cabp2 double-knockout mouse with AAV CaBP2 rescue

Combined deletion of Cabp1 and Cabp2 produces much greater calcium-channel inactivation and sustained-release impairment than Cabp2 deletion alone. At depolarized holding potentials, sustained exocytosis can be abolished. Recovery after prolonged sinusoidal stimulation is delayed, whereas recovery after a shorter strong depolarization behaves differently. Ribbon-synapse abundance is retained at the examined early age, but BK-channel clusters are smaller. Neonatal Cabp2 delivery partially rescues channel function, synaptic release and hearing.

Species

Mouse

Genotype

Cabp1-/-; Cabp2-/- double knockout, with and without AAV-PHP.eB-mediated Cabp2 transgene delivery

Publication

PMID:39718549

Pathograph links

Reduced Effective Transmission at the Inner Hair Cell Ribbon Synapse recapitulates fidelity: moderate The sustained component of exocytosis fails, and afferent responses become strongly rate-dependent.

Limitations: The model removes two genes and is more severe than the Cabp2-only mouse. Its effect sizes cannot be assigned to human DFNB93. Capacitance changes depend strongly on holding potential and stimulus waveform; the single knockout does not show the same whole-cell exocytosis deficit under the published recording conditions.

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.

Impaired Synaptic Sound Encoding rescues fidelity: moderate Cabp2 delivery at postnatal day six improves channel regulation, exocytosis and auditory responses. This demonstrates rescue after neonatal treatment, not reversal of established adult human deafness.

Limitations: Rescue is partial and restores CaBP2 in an animal still lacking CaBP1. Treatment precedes mouse hearing onset; a human therapeutic window and long-term durability are not established. Contralateral transgene expression occurs, limiting the use of the opposite ear as an untreated control.

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:39718549 SUPPORT Model Organism

"Transgenic expression of CaBP2 leads to substantial recovery of IHC synaptic function and hearing sensitivity."

Primary double-knockout rescue result.

Show evidence (2 references)

PMID:39718549 SUPPORT Model Organism

"In these conditions, however, the recovery from inactivation was slowest in the DKO IHCs"

Recovery was slow after prolonged sinusoidal conditioning; this was not a uniform result across all conditioning stimuli.

PMID:39718549 SUPPORT Model Organism

"the BK channel clusters appeared smaller in the DKO IHCs as compared to controls, which could be partially reversed by virally mediated expression of CaBP2"

An additional model-specific cellular finding; direct transcriptional regulation of BK by CaBPs remains a hypothesis.

Cabp2 knockout mouse with AAV-mediated Cabp2 gene replacement

AAV2/1 or AAV-PHP.eB delivery of the Cabp2 long isoform through the round window at postnatal days 5–7 partially improved hearing in Cabp2-null mice assessed at 5–8 weeks. With AAV2/1, 16 of 24 animals improved by at least 20 dB SPL at one or more tested frequencies. PHP.eB transduced both injected and contralateral cochleae. The experiments establish preclinical feasibility, with incomplete rescue and a need to control vector spread and expression.

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: Delivery preceded hearing onset in mice, and efficacy after adult-onset treatment was not tested. PHP.eB produced contralateral transduction, so that ear is not an independent untreated control. The eGFP marker does not directly quantify CaBP2 protein. Some injected wild-type animals had impaired hearing or otoacoustic emissions; the contributions of surgery, vector, eGFP and CaBP2 expression were not resolved.

Readouts

Restored CaBP2 function, read out as inner hair cell CaV1.3 current inactivation

Direction: RESTORED

Interpretation: Restoration of the calcium-current inactivation phenotype is a functional measure of channel regulation after Cabp2 delivery; it does not directly quantify protein expression.

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.

Show evidence (3 references)

PMID:34489639 SUPPORT Model Organism

"In 67% of the AAV2/1-Cabp2-injected animals (16 out of 24 animals), the improvement reached 20 dB SPL or more at least for one of the tested frequencies"

The response criterion is improvement at at least one frequency, not complete restoration of hearing.

PMID:34489639 SUPPORT Model Organism

"Overall transduction rates were 98 ± 1% (N = 10) for injected and 56 ± 6% (N = 11) for non-injected cochleae."

PHP.eB transduction of both ears limits contralateral-control interpretation.

PMID:34489639 SUPPORT Model Organism

"DPOAEs were strongly impaired in three out of eight injected wild-type animals."

A reported safety signal in treated wild-type animals; its specific cause was not established.

{ }

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: >-
Autosomal recessive nonsyndromic hearing loss caused by biallelic pathogenic CABP2 variants. Hearing
loss is usually bilateral and prelingual, often moderate to severe with greatest involvement of
middle frequencies; onset, severity and audiogram configuration vary. CaBP2 normally limits CaV1.3
channel inactivation in cochlear inner hair cells. Mouse and heterologous-cell studies support
impaired presynaptic sound encoding, with reduced auditory-nerve firing and temporal precision.
Preserved otoacoustic emissions in some patients support auditory synaptopathy, but absent emissions
in other affected individuals show that preserved cochlear amplification is not a universal clinical
feature. Hearing aids and communication support are used clinically; cochlear CABP2 gene replacement
remains preclinical.

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 classified the autosomal recessive CABP2–nonsyndromic
hearing loss relationship as Definitive in its February 2020 evaluation.
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: 'Finland: modeled hearing loss due to homozygous CABP2 c.637+1G>T'
measure_type: UNKNOWN
prevalence_class: UNKNOWN
rate_low: 0.7
rate_high: 1.9
rate_denominator: POPULATION
notes: >-
The 2022 study estimated prevalence from population allele-frequency data. This is not an observed
disease prevalence, does not cover all CABP2 alleles, and does not specify a point or birth-prevalence
measure. The range crosses two numeric prevalence bands.
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 estimated prevalence of HI in Finland due to homozygous c.637+1G>T variants ranges from
0.7 to 1.9 per 100,000 individuals.
explanation: >-
The authors provide an allele-specific modeled prevalence estimate.
pathophysiology:
- name: Biallelic CABP2 Loss-of-Function Variant
role: trigger
biological_scale: MOLECULAR
description: >-
Biallelic pathogenic CABP2 variants impair CaBP2 function. Reported alleles include splice-site,
nonsense and missense variants. For the recurrent c.637+1G>T allele, exon skipping was demonstrated
in a minigene assay and truncation is predicted if the abnormal transcript escapes nonsense-mediated
decay; endogenous mutant protein abundance in patient hair cells was not measured.
genetic_context:
gene:
preferred_term: CABP2
term:
id: hgnc:1385
label: CABP2
variant_origin: GERMLINE
functional_impact_category: LOSS_OF_FUNCTION
description: >-
Both homozygous and compound-heterozygous CABP2 genotypes have been reported. Functional loss
may be partial or complete depending on the allele; biochemical tests of an engineered truncation
do not establish the amount of residual protein in patients.
downstream:
- target: CABP2 Exon 6 Skipping
causal_link_type: DIRECT
description: >-
The c.637+1G>T splice-donor allele causes exon 6 skipping in a COS-7 minigene assay.
- target: Loss of CaBP2 Function at the Inner Hair Cell Ribbon Synapse
causal_link_type: DIRECT
description: >-
Other pathogenic alleles can impair CaBP2 function through mechanisms that need not involve
exon 6 skipping.
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.
- name: CABP2 Exon 6 Skipping
role: central_effector
biological_scale: MOLECULAR
description: >-
The recurrent c.637+1G>T allele disrupts splicing in a COS-7 exon-trapping assay. Skipping exon
6 predicts a frameshift, p.Phe164Serfs*4, and loss of the last two EF hands if the RNA escapes
degradation. This assay establishes a splice defect, not the abundance or stability of the transcript
in human inner hair cells.
downstream:
- target: Loss of CaBP2 Function at the Inner Hair Cell Ribbon Synapse
causal_link_type: DIRECT
description: >-
The predicted truncation removes C-terminal EF hands. An engineered p.Phe164Ter proxy has altered
calcium binding and weakened, residual CaV1.3 regulation.
evidence:
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3484643/
reference_title: A Mutation in CABP2, Expressed in Cochlear Hair Cells, Causes Autosomal-Recessive Hearing Impairment - PMC
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Skipping of exon 6, if RNA is not degraded by nonsense-mediated mRNA decay, is predicted to
lead to a shifted reading frame, a premature truncation of the protein
explanation: >-
Exon trapping and the predicted translation consequence; patient RNA and protein were not measured.
- name: Loss of CaBP2 Function at the Inner Hair Cell Ribbon Synapse
role: central_effector
biological_scale: MOLECULAR
description: >-
CaBP2 regulates presynaptic calcium channels in cochlear inner hair cells. The founding truncation
proxy showed altered calcium binding and weaker, but retained, inhibition of CaV1.3 inactivation.
In mice, a genetic expression reporter localized Cabp2 to inner and outer hair cells but not
spiral ganglion neurons, supporting a presynaptic site of the principal sound-encoding defect.
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.

- 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: >-
An engineered truncation models loss of the C-terminal EF hands; its residual activity must
not be equated with the amount of mutant protein in patient hair cells.
- name: Enhanced CaV1.3 Calcium-Channel Inactivation
role: central_effector
biological_scale: MOLECULAR
description: >-
Cabp2-deficient mouse inner hair cells show increased CaV1.3 inactivation despite preserved peak
calcium-current amplitude and voltage dependence of activation under the tested conditions. At
room temperature, the single knockout primarily increases voltage-dependent inactivation; its
increase in calcium-dependent inactivation did not reach significance. Removing both CaBP1 and
CaBP2 markedly enhances both components. Normal peak current does not directly measure channel
number, and double-knockout effects do not establish the magnitude of a CABP2-only human defect.
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: Reduced Effective Transmission at the Inner Hair Cell Ribbon Synapse
causal_link_type: UNKNOWN
description: >-
Greater steady-state inactivation is proposed to reduce the calcium-channel pool available
to support presynaptic transmission in vivo.
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.

- reference: url:https://pure.mpg.de/rest/items/item_2419839_5/component/file_2419838/content
reference_title: https://pure.mpg.de/rest/items/item_2419839_5/component/file_2419838/content
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
we found significantly increased VDI and a nonsignificant trend toward increased CDI in IHCs
of 2- to 3-wk-old
explanation: >-
The single-knockout room-temperature measurements distinguish the two components of inactivation.
- name: Reduced Effective Transmission at the Inner Hair Cell Ribbon Synapse
role: central_effector
biological_scale: CELLULAR
description: >-
Reduced availability of presynaptic CaV1.3 channels is proposed to decrease effective transmitter
delivery to auditory afferents. Whole-cell capacitance assays did not show reduced exocytosis
in Cabp2-only knockout hair cells; some sustained responses were increased, possibly through
extrasynaptic release. In contrast, combined Cabp1/Cabp2 deletion directly reduces sustained
exocytosis, especially at depolarized holding potentials. The double-knockout result supports
the mechanism but cannot be assigned unchanged to human DFNB93.
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: UNKNOWN
description: >-
Reduced effective presynaptic drive is proposed to account for lower afferent firing rates.
- target: Reduced Temporal Precision of Auditory Nerve Firing
causal_link_type: UNKNOWN
description: >-
Impaired presynaptic encoding is proposed to delay and desynchronize afferent responses.
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.

- 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: >-
Previously, patch-clamp recordings surprisingly revealed normal whole-cell exocytosis in CaBP2-deficient
IHCs despite enhanced inactivation of calcium channels
explanation: >-
The paper explicitly contrasts preserved single-knockout capacitance responses with the double-knockout
release deficit.
- name: Reduced Spiral Ganglion Neuron Firing
role: consequence
biological_scale: CELLULAR
description: >-
Single-unit recordings in Cabp2-null mice show reduced spontaneous and sound-evoked spiral ganglion
neuron firing. In the single knockout, neural frequency tuning and spike-rate thresholds can
remain normal despite reduced maximal firing. The more severe rate dependence in Cabp1/Cabp2
double-knockout mice provides additional mechanistic evidence, with the limitation that some
recorded units could be cochlear-nucleus neurons.
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: Impaired Synaptic Sound Encoding
causal_link_type: DIRECT
description: >-
Reduced auditory-nerve activity degrades the neural representation of sound.
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: Reduced Temporal Precision of Auditory Nerve Firing
role: consequence
biological_scale: CELLULAR
description: >-
In Cabp2-null mice, first spikes after sound onset occur later and with greater trial-to-trial
variability. Reduced timing precision, together with lower firing rates, provides a physiological
explanation for reduced auditory brainstem response amplitudes and elevated response thresholds.
cell_types:
- preferred_term: spiral ganglion neuron
term:
id: CL:0011113
label: spiral ganglion neuron
downstream:
- target: Impaired Synaptic Sound Encoding
causal_link_type: DIRECT
description: >-
Delayed and less synchronized auditory-nerve responses impair population sound encoding.
evidence:
- reference: url:https://pure.mpg.de/rest/items/item_2419839_5/component/file_2419838/content
reference_title: https://pure.mpg.de/rest/items/item_2419839_5/component/file_2419838/content
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Rate reduction and increased jitter of SGN firing at sound onset likely explain the impaired
ABR wave I amplitude and threshold.
explanation: >-
The authors link reduced firing and temporal precision to the brainstem response phenotype.
- name: Impaired Synaptic Sound Encoding
role: consequence
biological_scale: ORGANISM
description: >-
Impaired presynaptic encoding produces abnormal auditory brainstem responses and hearing impairment.
Cabp2-null mice retain cochlear amplification under the reported conditions. Transient otoacoustic
emissions were present in an Italian child, but were absent in founding Iranian cases and in
two Finnish children. Preserved emissions support synaptopathy when present; their absence does
not exclude genetically confirmed DFNB93.
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: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: >-
At 4 months of age, TEOAE showed no responses, and ASSR (Figure 1d) and ABR results revealed
responses on average at 40–55 dB levels which led to a diagnosis of moderate sensorineural
HI.
explanation: >-
A genetically confirmed Finnish infant had absent emissions and elevated evoked-response thresholds,
limiting any universal preserved-emissions claim.
downstream:
- target: Bilateral Sensorineural Hearing Loss
causal_link_type: UNKNOWN
description: >-
The synaptic defect is the principal model-supported mechanism for human hearing impairment.
- target: Abnormal Auditory Brainstem Response
causal_link_type: DIRECT
description: >-
Reduced and desynchronized afferent activity alters evoked population responses.
phenotypes:
- category: Otologic
name: Bilateral Sensorineural Hearing Loss
description: >-
Bilateral hearing loss is commonly moderate to severe and symmetric, although severity varies
between families. Mid-frequency loss is frequent in the published descriptions. Serial audiograms
in two Finnish children showed nonprogressive loss over the observed childhood intervals; these
observations do not establish lifelong stability for all genotypes.
phenotype_term:
preferred_term: Bilateral sensorineural hearing impairment
term:
id: HP:0008619
label: Bilateral 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.

- 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: >-
Audiograms taken at the ages of 6.0 and 13.7 years for II:1 and at 2.4, 3.0, and 3.5 years
for II:4 (Figure 1c) feature symmetrical, moderate-to-severe non-progressive HI that is more
conspicuous in the mid-frequencies forming a U-shaped audiogram
explanation: >-
Serial childhood audiograms establish stability in these two siblings, not across all patients.
- category: Otologic
name: Prelingual Onset
description: >-
Congenital or prelingual onset is documented in several families, including the Danish child
detected by newborn screening. Onset is not established in every patient: an older Finnish sibling
passed newborn emissions screening and was diagnosed at six years.
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: >-
Bilateral hearing loss was detected when the patient was 3 days old by the national standardized
hearing screening.
explanation: >-
The Danish case had neonatal detection.
- 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: >-
Although FINHEAR1 II:4 presented with congenital HI, we cannot confirm her brother II:1 has
congenital HI since he was not diagnosed until 6 years of age.
explanation: >-
Onset uncertainty prevents an obligatory prelingual classification.
- category: Otologic
name: Severe Hearing Loss in a Subset of Families
severity: SEVERE
description: >-
Severe hearing loss was reported in a consanguineous Iranian family with the c.311G>A missense
variant. The report extends the severity spectrum without establishing a frequency or deterministic
genotype–severity relationship.
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
description: >-
Elevated auditory evoked-response thresholds were documented in a Finnish infant with biallelic
CABP2 variants. Responses should be interpreted together with behavioral audiometry, middle-ear
assessment and otoacoustic emissions; a preserved-emissions pattern is not required for the molecular
diagnosis.
phenotype_term:
preferred_term: Abnormal auditory evoked potentials
term:
id: HP:0006958
label: Abnormal auditory evoked potentials
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: >-
At 4 months of age, TEOAE showed no responses, and ASSR (Figure 1d) and ABR results revealed
responses on average at 40–55 dB levels which led to a diagnosis of moderate sensorineural
HI.
explanation: >-
Direct human evoked-response measurements rather than an inference from the synaptopathy label.
- category: Otologic
name: Preserved Otoacoustic Emissions
description: >-
Transient evoked otoacoustic emissions were observed at age four in the affected Italian boy.
His affected sister was not tested. Preserved emissions support functioning cochlear amplification
in that individual at that age; other genetically confirmed patients have absent emissions.
phenotype_term:
preferred_term: Preserved otoacoustic emissions
evidence:
- reference: url:https://pure.mpg.de/rest/items/item_2419839_5/component/file_2419838/content
reference_title: https://pure.mpg.de/rest/items/item_2419839_5/component/file_2419838/content
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
a transitory evoked otoacoustic emission (TEOAE) was observed in subject III:1 in the course
of clinical examination at the age of 4 y (subject III:3 was not tested for TEOAE).
explanation: >-
The primary report specifies the individual, age and untested sibling.
- category: Otologic
name: U-Shaped (Mid-Frequency) Audiometric Configuration
description: >-
A U-shaped audiogram with greatest loss in middle frequencies is documented in the founding families
and in the Finnish children. It is a useful clinical clue but does not uniquely identify CABP2-related
disease.
phenotype_term:
preferred_term: Mid-frequency hearing loss
term:
id: HP:0012781
label: Mid-frequency hearing loss
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: >-
symmetrical, moderate-to-severe non-progressive HI that is more conspicuous in the mid-frequencies
forming a U-shaped audiogram
explanation: >-
Direct longitudinal audiometry in the Finnish family.
- category: Otologic
name: Reverse-Slope Audiometric Configuration
description: >-
A reverse-slope pattern, with lower frequencies more affected, was reported in the 2026 North
American case. Audiometric configuration alone should not exclude CABP2 from molecular evaluation.
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.

- category: Otologic
name: Absent Otoacoustic Emissions
description: >-
Absent emissions were documented in a Finnish infant on newborn screening and again at four months.
A second Finnish child failed neonatal emissions screening. This clinical variability limits
the use of preserved emissions as a mandatory diagnostic feature.
phenotype_term:
preferred_term: Absent otoacoustic emissions
term:
id: HP:6000182
label: Absent otoacoustic emissions
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: >-
FINHEAR2 has one affected member, II:3 (Figure 1a), who failed newborn screening as otoacoustic
emissions were not elicited. At 4 months of age, TEOAE showed no responses
explanation: >-
Repeated absent emissions in an affected child.
genetic:
- name: CABP2
gene_term:
preferred_term: CABP2
term:
id: hgnc:1385
label: CABP2
relationship_type: CAUSATIVE
notes: >-
Reported CABP2 alleles include splice-site, nonsense, missense and frameshift variants. The recurrent
splice allele NM_016366.3:c.637+1G>T is enriched in Finland; the 2022 study reports allele frequencies
of 3.3 × 10−3 in Finnish gnomAD participants and 4.2 × 10−3 in FinnGen. These are allele frequencies,
not carrier or disease frequencies. A shared haplotype was demonstrated in the founding Iranian
families, whereas the Danish case had a run of homozygosity suggesting shared ancestry. These
observations do not establish one shared founder haplotype across all populations. CABP1 compensation
is supported in mice but is not an established human genetic modifier.
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.

- 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 AF of the CABP2 c.637+1G>T variant within the Finnish population is 3.3 × 10−3
explanation: >-
Allele frequency is distinguished from carrier frequency.
- 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 imputed c.637+1G>T variant has an AF of 4.2 × 10−3
explanation: >-
The FinnGen estimate derives from imputed genotypes.
variants:
- name: NM_016366.3:c.637+1G>T
gene:
preferred_term: CABP2
term:
id: hgnc:1385
label: CABP2
type: splice donor variant
description: >-
Recurrent splice-donor allele found homozygously in multiple families. Exon skipping predicts
p.Phe164Serfs*4 if the transcript escapes decay; patient protein abundance is unresolved.
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: >-
we identified a homozygous pathogenic splice site variant c.637+1G>T in CAPB2
explanation: >-
The recurrent allele was classified as pathogenic in the Finnish study; CAPB2 is a source
typographical error.
clinical_significance: PATHOGENIC
- name: CABP2 c.466G>T (p.Glu156Ter)
gene:
preferred_term: CABP2
term:
id: hgnc:1385
label: CABP2
type: nonsense variant
description: >-
Homozygous nonsense allele in two Italian siblings. Nonsense-mediated decay was predicted,
not measured in patient hair cells.
evidence:
- reference: url:https://pure.mpg.de/rest/items/item_2419839_5/component/file_2419838/content
reference_title: https://pure.mpg.de/rest/items/item_2419839_5/component/file_2419838/content
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The same CABP2 c.466G > T mutation was found in the homozygous state in the proband’s sister
explanation: >-
Independent affected sibling with the same nonsense allele.
- name: CABP2 c.311G>A (p.Gly104Asp)
gene:
preferred_term: CABP2
term:
id: hgnc:1385
label: CABP2
type: missense variant
description: >-
The Iranian severe-hearing-loss report classified this missense allele as pathogenic. No allele-specific
CaV1.3 assay is reported in the cached abstract.
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: >-
WES results showed a novel rare variant (c.311G>A) in the CABP2gene.This missense variant
in the exon 4 of the CABP2gene meets the criteria of being pathogenic
explanation: >-
Published clinical classification; not a direct functional measurement.
clinical_significance: PATHOGENIC
- name: NM_001318496.1:c.250G>A (p.Glu84Lys)
gene:
preferred_term: CABP2
term:
id: hgnc:1385
label: CABP2
type: missense variant
description: >-
Reported as pathogenic in Israeli family DF326. The 2025 synthesis lists the family as compound
heterozygous with a splice-site allele. Numbering of this missense allele differs on the shorter
transcript, where the protein change is p.Glu78Lys.
evidence:
- reference: PMID:33111345
reference_title: Spectrum of genes for inherited hearing loss in the Israeli Jewish population, including the novel human deafness gene ATOH1.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CABP2 NM_001318496.1 | DF326 | AR | Mixed | chr11:67289435 | c.250G>A | Missense | Glu84Lys
| 0 | 0 | 1337669 | P (PM2, PM3_S, PP1_M, PP3, PP4)
explanation: >-
Table 1 provides transcript, variant, family and pathogenic classification.
clinical_significance: PATHOGENIC
- name: NM_016366.3:c.590T>C (p.Ile197Thr)
gene:
preferred_term: CABP2
term:
id: hgnc:1385
label: CABP2
type: missense variant
description: >-
Reported with hearing loss in several populations. The Egyptian study attributes hearing impairment
to this allele while describing it as presumably benign under its ACMG analysis, creating an
unresolved interpretation conflict. Its skeletal and dental findings were attributed separately
to LTBP3. This report is not sufficient to assign an unqualified pathogenic classification
or a CABP2 skeletal syndrome.
evidence:
- reference: PMID:38192829
reference_title: 'Brachyolmia, dental anomalies and short stature (DASS): Phenotype and genotype analyses of Egyptian and Pakistani patients.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The CABP2 variant (c.590T > C; p.Ile197Thr) was declared presumably benign following the
ACMG guidelines.
explanation: >-
The paper itself reports an interpretation inconsistent with its causal narrative.
- reference: PMID:38192829
reference_title: 'Brachyolmia, dental anomalies and short stature (DASS): Phenotype and genotype analyses of Egyptian and Pakistani patients.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we believe that the CABP2 variant (NM_016366.3: c.590T > C; p.Ile197Thr) in exon-6 is causing
hearing impairment in family A.
explanation: >-
The authors nevertheless favor this allele as causal; both statements are retained as the
source conflict.
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Autosomal recessive inheritance is supported by segregation of biallelic CABP2 variants. Homozygous
and compound-heterozygous genotypes are reported. Consanguinity is common in the initial families
but is not required. Hearing impairment in ungenotyped relatives should not be attributed to
a single CABP2 allele: the Danish mother and other maternal relatives remained genetically unresolved.
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.

- reference: PMID:40927552
reference_title: Is CABP2-Associated Hearing Loss (DFNB93) a Gene Therapy Target? Preclinical Progress and Patient Registry.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
p.(Glu78Lys) and p.?/ p.(Glu84Lys) and p.? | Comp het | Congenital | Moderate to profound
explanation: >-
Table 2 reports compound heterozygosity in DF326; the review is secondary 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 patient’s mother and the remaining family members suffering from hearing loss on her side
of the family remain genetically unresolved.
explanation: >-
The family history does not establish dominant CABP2 disease.
animal_models:
- name: Cabp2 knockout mouse
species: Mouse
genotype: Cabp2 LacZ/LacZ (constitutive knockout, homozygous)
publication: PMID:28183797
description: >-
Constitutive Cabp2 disruption produces impaired auditory brainstem responses with preserved distortion-product
otoacoustic emissions, enhanced inner-hair-cell calcium-current inactivation and reduced afferent
firing. Inner hair cells and ribbon synapses were retained at the examined ages. These findings
support presynaptic dysfunction without requiring early sensory-cell degeneration.
modeled_mechanisms:
- target: Enhanced CaV1.3 Calcium-Channel Inactivation
relationship: RECAPITULATES
fidelity: MODERATE
description: >-
The defining channel defect, measured directly by patch clamp in the correct cell type.
limitations: >-
A constitutive knockout does not reproduce every human allele. An engineered human truncation
retains some channel-regulatory activity, but residual protein in patient hair cells is unknown.
Mouse single-neuron thresholds were relatively preserved and do not reproduce the full human
audiometric phenotype. Assay temperature, age and cochlear position affect the observed channel
phenotype.
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: Impaired Synaptic Sound Encoding
relationship: RECAPITULATES
fidelity: MODERATE
description: >-
The mouse combines preserved otoacoustic emissions with abnormal brainstem responses, supporting
a presynaptic defect. This resembles an observed human pattern without implying that all patients
retain emissions.
limitations: >-
Human emissions were documented in one Italian child but were absent in other confirmed cases.
The mouse findings are age- and assay-specific.
readouts:
- name: Cochlear amplification (otoacoustic emissions)
target: Impaired Synaptic Sound Encoding
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: Impaired Synaptic Sound Encoding
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: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: >-
Primary measurements support the observed mouse phenotype.
- target: Reduced Temporal Precision of Auditory Nerve Firing
relationship: RECAPITULATES
fidelity: MODERATE
description: >-
Single-neuron recordings show delayed and more variable first-spike timing at sound onset.
limitations: >-
These are mouse recordings, not direct measurements of human auditory-nerve firing.
evidence:
- reference: url:https://pure.mpg.de/rest/items/item_2419839_5/component/file_2419838/content
reference_title: https://pure.mpg.de/rest/items/item_2419839_5/component/file_2419838/content
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Rate reduction and increased jitter of SGN firing at sound onset likely explain the impaired
ABR wave I amplitude and threshold.
explanation: >-
The source links temporal imprecision with the evoked-response phenotype.
- 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: >-
Combined deletion of Cabp1 and Cabp2 produces much greater calcium-channel inactivation and sustained-release
impairment than Cabp2 deletion alone. At depolarized holding potentials, sustained exocytosis
can be abolished. Recovery after prolonged sinusoidal stimulation is delayed, whereas recovery
after a shorter strong depolarization behaves differently. Ribbon-synapse abundance is retained
at the examined early age, but BK-channel clusters are smaller. Neonatal Cabp2 delivery partially
rescues channel function, synaptic release and hearing.
modeled_mechanisms:
- target: Reduced Effective Transmission 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: >-
The model removes two genes and is more severe than the Cabp2-only mouse. Its effect sizes
cannot be assigned to human DFNB93. Capacitance changes depend strongly on holding potential
and stimulus waveform; the single knockout does not show the same whole-cell exocytosis deficit
under the published recording conditions.
readouts:
- name: Sustained exocytosis in inner hair cells
target: Reduced Effective Transmission 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: Impaired Synaptic Sound Encoding
relationship: RESCUES
fidelity: MODERATE
description: >-
Cabp2 delivery at postnatal day six improves channel regulation, exocytosis and auditory responses.
This demonstrates rescue after neonatal treatment, not reversal of established adult human
deafness.
limitations: >-
Rescue is partial and restores CaBP2 in an animal still lacking CaBP1. Treatment precedes mouse
hearing onset; a human therapeutic window and long-term durability are not established. Contralateral
transgene expression occurs, limiting the use of the opposite ear as an untreated control.
readouts:
- name: Hearing sensitivity and inner hair cell synaptic function after Cabp2 delivery
target: Impaired Synaptic Sound Encoding
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: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: >-
Primary double-knockout rescue result.
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 these conditions, however, the recovery from inactivation was slowest in the DKO IHCs
explanation: >-
Recovery was slow after prolonged sinusoidal conditioning; this was not a uniform result across
all conditioning stimuli.
- 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: >-
the BK channel clusters appeared smaller in the DKO IHCs as compared to controls, which could
be partially reversed by virally mediated expression of CaBP2
explanation: >-
An additional model-specific cellular finding; direct transcriptional regulation of BK by CaBPs
remains a hypothesis.
- 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: >-
AAV2/1 or AAV-PHP.eB delivery of the Cabp2 long isoform through the round window at postnatal
days 5–7 partially improved hearing in Cabp2-null mice assessed at 5–8 weeks. With AAV2/1, 16
of 24 animals improved by at least 20 dB SPL at one or more tested frequencies. PHP.eB transduced
both injected and contralateral cochleae. The experiments establish preclinical feasibility,
with incomplete rescue and a need to control vector spread and expression.
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: >-
Delivery preceded hearing onset in mice, and efficacy after adult-onset treatment was not tested.
PHP.eB produced contralateral transduction, so that ear is not an independent untreated control.
The eGFP marker does not directly quantify CaBP2 protein. Some injected wild-type animals had
impaired hearing or otoacoustic emissions; the contributions of surgery, vector, eGFP and CaBP2
expression were not resolved.
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: >-
Restoration of the calcium-current inactivation phenotype is a functional measure of channel
regulation after Cabp2 delivery; it does not directly quantify protein expression.
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.

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: >-
In 67% of the AAV2/1-Cabp2-injected animals (16 out of 24 animals), the improvement reached
20 dB SPL or more at least for one of the tested frequencies
explanation: >-
The response criterion is improvement at at least one frequency, not complete restoration of
hearing.
- 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: >-
Overall transduction rates were 98 ± 1% (N = 10) for injected and 56 ± 6% (N = 11) for non-injected
cochleae.
explanation: >-
PHP.eB transduction of both ears limits contralateral-control interpretation.
- 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: >-
DPOAEs were strongly impaired in three out of eight injected wild-type animals.
explanation: >-
A reported safety signal in treated wild-type animals; its specific cause was not established.
diagnosis:
- name: Genetic testing for biallelic CABP2 variants
description: >-
Evaluate CABP2 in a comprehensive hearing-loss panel or genomic analysis, with interpretation
of both alleles and family segregation. Homozygosity is not required. Phenotype and ancestry
can inform interpretation, but variants of uncertain significance alone do not establish DFNB93.
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: >-
CABP2 explained one case in this selected Czech cohort after GJB2 testing. This is not an unselected
population diagnostic yield.

- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The identification of variant(s) of ... uncertain significance ... cannot be used to confirm
or rule out the diagnosis.
explanation: >-
General genetic-hearing-loss interpretation guidance applies to CABP2 testing.
- name: Audiological testing including otoacoustic emissions
description: >-
Combine age-appropriate behavioral audiometry, tympanometry, otoacoustic emissions and auditory
evoked responses to characterize hearing sensitivity and possible synaptic dysfunction. Emissions
can be present or absent in DFNB93; passing newborn emissions screening does not exclude later
recognition of hearing impairment.
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: >-
Physical examination, transient otoacoustic emissions (TEOAE), and pure-tone audiometry were
performed at 125–8000 Hz for the affected children of FINHEAR1. TEOAE, auditory steady-state
response (ASSR), and auditory brainstem response (ABR) were evaluated for the affected child
of FINHEAR2.
explanation: >-
The clinical study documents complementary assessments.
treatments:
- name: Hearing Aids
therapeutic_modality: DEVICE
description: >-
Fit and assess hearing aids according to the individual hearing profile and communication needs.
A genetically confirmed North American case had a positive reported prognosis with hearing aids
and multidisciplinary follow-up. This single report does not establish a response rate, and synaptic
dysfunction may limit speech perception despite improved aided thresholds.
treatment_term:
preferred_term: hearing aid amplification
term:
id: NCIT:C15315
label: Rehabilitation
qualifiers:
- predicate:
preferred_term: medical device
term:
id: NCIT:C16830
label: Medical Device
value:
preferred_term: hearing aid
term:
id: NCIT:C183182
label: Hearing Aid
target_mechanisms:
- target: Impaired Synaptic Sound Encoding
description: >-
Amplification can improve audibility while leaving the molecular channel-regulation defect
unchanged; benefit requires individual assessment.
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: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.
- name: Cochlear Gene Replacement (investigational)
therapeutic_modality: GENE_THERAPY
description: >-
AAV-mediated Cabp2 delivery improved inner-hair-cell calcium currents and hearing in neonatal
Cabp2-null mice, and partially restored synaptic function in Cabp1/Cabp2 double-knockout mice.
These are preclinical experiments. Early treatment, incomplete rescue, contralateral vector spread
and adverse auditory findings in some treated wild-type mice limit extrapolation to human efficacy,
durability and safety.
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: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.
- name: Cochlear Implantation
description: >-
Consider cochlear implant assessment for severe-to-profound hearing loss when appropriate after
individualized audiological evaluation. This follows general genetic-hearing-loss guidance; CABP2-specific
implant outcome rates are not established by the cited evidence.
therapeutic_modality: DEVICE
treatment_term:
preferred_term: cochlear device implantation
term:
id: NCIT:C15329
label: Surgical Procedure
qualifiers:
- predicate:
preferred_term: medical device
term:
id: NCIT:C16830
label: Medical Device
value:
preferred_term: cochlear implant
term:
id: NCIT:C157820
label: Cochlear Implant
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: OTHER
snippet: Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months.
explanation: General guidance supports considering implantation after clinical assessment; this is not a DFNB93-specific efficacy claim.
directness: INDIRECT
- name: Genetic Counseling
description: >-
Counseling addresses recessive inheritance, variant interpretation, parental testing and reproductive
options. When both parents carry the relevant recessive pathogenic alleles, each pregnancy has
a 25% chance of an affected child. Individual variant interpretation is essential, especially
when published classifications conflict.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: OTHER
snippet: If both parents are known to be ... heterozygous ... autosomal recessive ... hearing loss-related ... pathogenic variant ... has at conception a 25% chance of having hearing loss
explanation: The recurrence calculation is conditional on confirmed parental carrier genotypes, not merely a consanguineous pedigree.
- name: Speech, Language and Communication Support
description: Early, individualized speech, language, educational and communication support accompanies audiological management. D/deaf and hard-of-hearing community resources should be adapted to the child and family. This is general hearing-loss care, with no DFNB93-specific intervention trial implied.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: speech and language therapy
term:
id: NCIT:C159273
label: Speech Language Therapy
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: OTHER
snippet: A speech-language therapist as well as a neuropsychologist/psychologist for children with hearing loss provides access to resources within the community to aid in speech and language and D/deaf and hard of hearing (DHH) identity development.
explanation: General hearing-loss guidance supports communication services; no disease-specific treatment outcome is asserted.
differential_diagnoses:
- name: OTOF-related auditory neuropathy (DFNB9)
description: >-
OTOF-related disease is another presynaptic auditory synaptopathy. Audiometric severity and emissions
can overlap, and molecular testing distinguishes the causal gene. Results from OTOF gene-therapy
trials do not establish efficacy for CABP2.
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: OTHER
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: >-
GJB2-related hearing loss is a common alternative molecular diagnosis. The Iranian severe-CABP2
family underwent GJB2 and other-gene testing before exome sequencing. This family-specific diagnostic
sequence is not a requirement that every patient undergo isolated GJB2 testing first.
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#Impaired Synaptic Sound Encoding
prompt: >-
Do DFNB93 patients benefit from amplification, given that auditory synaptopathy as a class is
described as responding poorly to it?
rationale: >-
Clinical reports describe benefit from hearing aids, whereas mechanistic work predicts that pronounced
channel inactivation could limit benefit from amplification alone. Comparative aided speech-perception
measurements would clarify the range of benefit and the value of signal-to-noise improvement
in DFNB93.
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#Bilateral Sensorineural Hearing Loss
prompt: >-
How does hearing change from childhood into adulthood across CABP2 genotypes?
rationale: >-
Serial audiograms in two Finnish children demonstrate stable hearing over the reported childhood
intervals. Longer-term, genotype-stratified natural-history data are needed to establish whether
this stability persists across adulthood and across other alleles. Progressive mouse hearing
impairment should not be treated as proof of human progression.
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#Bilateral 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.

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)
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3484643/
title: A Mutation in CABP2, Expressed in Cochlear Hair Cells, Causes Autosomal-Recessive Hearing Impairment - PMC
- reference: url:https://pure.mpg.de/rest/items/item_2419839_5/component/file_2419838/content
title: https://pure.mpg.de/rest/items/item_2419839_5/component/file_2419838/content
- reference: PMID:33111345
title: Spectrum of genes for inherited hearing loss in the Israeli Jewish population, including the novel human deafness gene ATOH1.
- reference: PMID:38192829
title: 'Brachyolmia, dental anomalies and short stature (DASS): Phenotype and genotype analyses of Egyptian and Pakistani patients.'
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
tags:
- GeneReviews
- reference: clinicaltrials:NCT06680934
title: Patient Registry for Individuals With CABP2-Associated Hearing Loss
clinical_trials:
- name: NCT06680934
phase: NOT_APPLICABLE
status: RECRUITING
description: >-
Observational CABP2 patient registry and natural-history study collecting molecular diagnoses
and clinical hearing information. The registry is not a CABP2 gene-therapy intervention.
evidence:
- reference: clinicaltrials:NCT06680934
reference_title: Patient Registry for Individuals With CABP2-Associated Hearing Loss
supports: SUPPORT
evidence_source: OTHER
snippet: >-
This registry is designed to collect comprehensive information about the molecular genetic
diagnoses and clinical information of individuals with CABP2-associated hearing impairment
to support a natural history study.
explanation: >-
Registry purpose, distinct from therapeutic efficacy evidence.
notes: >-
ClinicalTrials.gov listed RECRUITING on 2026-09-27; the record was last updated on 2026-01-27.
experimental_models:
- name: COS-7 CABP2 exon-trapping assay
experimental_model_type: CELL_LINE
description: >-
Wild-type and c.637+1G>T exon-6 constructs were tested in COS-7 cells because CABP2 transcript
could not be detected in accessible patient blood or saliva. Mutant minigene splicing skipped
exon 6.
modeled_mechanisms:
- target: CABP2 Exon 6 Skipping
relationship: RECAPITULATES
fidelity: MODERATE
limitations: >-
The minigene does not establish transcript abundance, nonsense-mediated decay or protein expression
in patient cochlear hair cells.
evidence:
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3484643/
reference_title: A Mutation in CABP2, Expressed in Cochlear Hair Cells, Causes Autosomal-Recessive Hearing Impairment - PMC
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Analysis of cDNA prepared from COS-7 cells transfected with a MT ... donor site only revealed
a PCR product of 177 bp, indicating that the mutation ... leads to a complete skipping of
exon 6
explanation: >-
The mutant exon-trapping construct skipped exon 6 in COS-7 cells; this does not establish
transcript stability in patient hair cells.
- name: Heterologous CaV1.3 regulation by CABP2
experimental_model_type: CELL_LINE
description: >-
HEK293T expression assays compared wild-type CaBP2 with an engineered p.Phe164Ter truncation
proxy. The mutant retained some suppression of calcium-dependent inactivation. Later HEK293/hSK3-1
experiments showed that channel regulation depends on the expression system and does not fully
reproduce inner-hair-cell physiology.
modeled_mechanisms:
- target: Loss of CaBP2 Function at the Inner Hair Cell Ribbon Synapse
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
limitations: >-
The engineered p.Phe164Ter construct approximates the predicted frameshift truncation and is
not patient-derived protein. Initial mutant expression exceeded wild type; expression levels
were adjusted for the comparison. Heterologous voltage-activation and current-density effects
should not be imported directly into the hair-cell mechanism.
evidence:
- 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: >-
Heterologous channel measurements demonstrate residual regulatory activity.
- reference: url:https://pure.mpg.de/rest/items/item_2419839_5/component/file_2419838/content
reference_title: https://pure.mpg.de/rest/items/item_2419839_5/component/file_2419838/content
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
we did not observe the previously reported decrease of Ca 2+-current density upon CABP2 coexpression
explanation: >-
The later expression system did not reproduce the earlier current-density effect.
- name: Purified CaBP2 calcium-binding assay
experimental_model_type: OTHER
description: >-
Isothermal titration calorimetry compared purified wild-type CaBP2 with the engineered C-terminal
truncation proxy, demonstrating altered calcium binding.
modeled_mechanisms:
- target: Loss of CaBP2 Function at the Inner Hair Cell Ribbon Synapse
relationship: MEASURES
fidelity: MODERATE
limitations: >-
Purified-protein behavior does not determine the abundance or calcium-buffering contribution
of mutant CaBP2 in patient hair cells.
evidence:
- 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
explanation: >-
Direct biochemical measurement of the engineered proteins.

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References & Deep Research

References

17

PMID:22981119

A mutation in CABP2, expressed in cochlear hair cells, causes autosomal-recessive hearing impairment.