DFNB22 is autosomal recessive nonsyndromic sensorineural hearing loss caused by biallelic OTOA dysfunction. OTOA encodes otoancorin, a GPI-anchored protein at the interface between nonsensory inner-ear epithelia and overlying acellular gels. In knockout mice, loss of otoancorin detaches the tectorial membrane from the spiral limbus and alters its morphology. Cochlear physiology supports impaired mechanical stimulation of inner hair cells despite relatively preserved basilar-membrane amplification; direct human cochlear pathology remains unestablished. Human severity, onset and audiogram shape vary: congenital or prelingual, childhood and postlingual presentations, with mid-frequency, flat or sloping loss, have been reported. Progression occurs in some patients but its frequency and rate are not established. Pathogenic alleles include sequence variants, deletions and OTOAP1-mediated conversions. High gene-pseudogene homology complicates variant detection and requires assay-specific coverage and confirmation.
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Conditions with similar clinical presentations that must be differentiated from Autosomal Recessive Nonsyndromic Hearing Loss 22:
name: Autosomal Recessive Nonsyndromic Hearing Loss 22
creation_date: "2026-09-11T21:00:00Z"
category: Mendelian
disease_term:
preferred_term: autosomal recessive nonsyndromic hearing loss 22
term:
id: MONDO:0011762
label: autosomal recessive nonsyndromic hearing loss 22
synonyms:
- DFNB22
- deafness, autosomal recessive 22
- OTOA-related autosomal recessive nonsyndromic hearing loss
- otoancorin deficiency
description: >-
DFNB22 is autosomal recessive nonsyndromic sensorineural hearing loss caused by biallelic OTOA dysfunction.
OTOA encodes otoancorin, a GPI-anchored protein at the interface between nonsensory inner-ear epithelia and
overlying acellular gels. In knockout mice, loss of otoancorin detaches the tectorial membrane from the spiral
limbus and alters its morphology. Cochlear physiology supports impaired mechanical stimulation of inner hair
cells despite relatively preserved basilar-membrane amplification; direct human cochlear pathology remains
unestablished. Human severity, onset and audiogram shape vary: congenital or prelingual, childhood and postlingual
presentations, with mid-frequency, flat or sloping loss, have been reported. Progression occurs in some patients
but its frequency and rate are not established. Pathogenic alleles include sequence variants, deletions and
OTOAP1-mediated conversions. High gene-pseudogene homology complicates variant detection and requires assay-specific
coverage and confirmation.
parents:
- Autosomal Recessive Nonsyndromic Hearing Loss
- Hereditary Hearing Loss
prevalence:
- population: Israeli chromosomal-microarray referral cohort (19,189 consecutive CMA tests, Rabin Medical Center)
measure_type: CARRIER_FREQUENCY
notes: >-
Thirty-nine heterozygous OTOA deletions were found in 19,189 prenatal and postnatal CMA tests (reported
as 0.2%). Patients with hearing loss and duplicate relatives carrying the same deletion were excluded.
This is a deletion-carrier observation in a clinical testing cohort, not disease prevalence or total carrier
frequency. The paper estimated a 0.016-0.13% chance of a second disease-associated sequence allele in an
individual with a deletion from database frequencies and Mendelian assumptions. This was a model-based
estimate, not observed penetrance or a prospectively measured hearing-loss rate; it depends on the database,
ancestry and variant classifications.
evidence:
- reference: PMID:33753912
reference_title: "Is it time to report carrier state for recessive disorders in every microarray analysis?-A pilot model based on hearing loss genes deletions."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Of the 19,189 CMA tests were performed in our laboratory, 107 STRC microdeletions were found (0.56%),
followed in frequency by OTOA deletions (39, 0.2%), and DFNB1 locus deletions (10, 0.05%).
explanation: >-
Deletion-carrier count and testing denominator; does not estimate disease prevalence.
- reference: PMID:33753912
reference_title: "Is it time to report carrier state for recessive disorders in every microarray analysis?-A pilot model based on hearing loss genes deletions."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The estimated risk for a hearing loss in the examined individual carrying the microdeletion was estimated
as 0.11-0.67% for STRC, 0.016-0.13% for OTOA
explanation: >-
Model-based risk using sequence-variant frequencies; not measured penetrance.
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC8384849/?report=reader
reference_title: "Is it time to report carrier state for recessive disorders in every microarray analysis?—A pilot model based on hearing loss genes deletions - PMC"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: For the data analysis, we excluded patients with hearing loss.
explanation: Ascertainment excludes affected patients.
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC8384849/?report=reader
reference_title: "Is it time to report carrier state for recessive disorders in every microarray analysis?—A pilot model based on hearing loss genes deletions - PMC"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Thus, the risk for hearing loss was estimated as the prevalence of sequence variants divided by two.
explanation: The full-text methods specify the model behind the reported risk.
- population: Japanese autosomal recessive or sporadic sensorineural hearing-loss referral cohort
measure_type: UNKNOWN
notes: The study reported seven candidate OTOA-associated probands among 2262 tested (0.3%). Two had homozygous deletions and one a deletion with a likely pathogenic nonsense allele; the other four carried missense variants classified as uncertain. Family segregation was unavailable. This is a reported candidate diagnostic yield, not seven equally established molecular diagnoses or a population prevalence. Fourteen OTOA copy-number findings included single deletions and gains and must not be counted as fourteen affected cases.
evidence:
- reference: PMID:31527525
reference_title: Mid-Frequency Hearing Loss Is Characteristic Clinical Feature of OTOA-Associated Hearing Loss.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Finally, we identified seven probands with OTOA-associated HL in this study (Table 1).
explanation: Reported attribution by the study, subject to its variant-classification limits.
- reference: PMID:31527525
reference_title: Mid-Frequency Hearing Loss Is Characteristic Clinical Feature of OTOA-Associated Hearing Loss.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Three missense variants (c.235C>T, c.469C>T, and c.1705A>G) detected in trans with a pathogenic (whole gene deletion) variant (PM3) were categorized as being of “uncertain significance”.
explanation: Three deletion/missense genotypes were not definitively classified.
- reference: PMID:31527525
reference_title: Mid-Frequency Hearing Loss Is Characteristic Clinical Feature of OTOA-Associated Hearing Loss.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The remaining missense variant identified as homozygous (c.647T>C) was also categorized as of “uncertain significance”.
explanation: Fourth uncertain genotype in the reported series.
pathophysiology:
- name: Biallelic OTOA Loss-of-Function
role: trigger
biological_scale: MOLECULAR
description: >-
Biallelic OTOA loss of function is supported by homozygous deletions and splice variants and by compound
heterozygous genotypes. Reported missense alleles have varying levels of support and are not all established
pathogenic variants. The founding Palestinian family carried homozygous IVS12+2T>C (c.1320+2T>C); aberrant
splicing was predicted in that study. A later Korean proband carried c.1320+5G>C in trans with c.1765delC
(p.Gln589ArgfsX55). COS7 minigenes demonstrated abnormal splicing for c.1320+5G>C, while HEK293T assays
showed impaired surface retention of the truncated protein. Patient cochlear RNA and protein were not tested.
In two other probands, OTOAP1 sequence replaced part of OTOA and introduced p.Glu787* in trans with an
OTOA deletion. The conversion tract was at least 9 kb in one case and less than 900 bp in the other. Different
recombination or repair mechanisms for generating these tracts were proposed, not experimentally established.
A South Indian family carried a homozygous 250.285-kb deletion encompassing METTL9, IGSF6, OTOA and part
of NPIPB4. Its nonsyndromic presentation does not exclude effects of neighboring genes in other deletions
or backgrounds.
genetic_context:
variant_origin: GERMLINE
functional_impact_category: LOSS_OF_FUNCTION
description: Both homozygous and compound heterozygous pathogenic genotypes occur; one zygosity does not represent the disorder.
evidence:
- reference: PMID:11972037
reference_title: "Otoancorin, an inner ear protein restricted to the interface between the apical surface of sensory epithelia and their overlying acellular gels, is defective in autosomal recessive deafness DFNB22."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The identification of the mutation (IVS12+2T>C) in the corresponding gene OTOA in one consanguineous
Palestinian family affected by nonsyndromic recessive deafness DFNB22 assigns an essential function to
otoancorin.
explanation: >-
The founding gene-disease observation and the allele it rests on.
- reference: PMID:37114731
reference_title: "[Phenotype-genotype analysis of the autosomal recessive hereditary hearing loss caused by OTOA variations]."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The pathogenic variations of OTOA gene are mainly copy number variations followed by deletion variations
and missense variations.
explanation: >-
Copy-number variants predominated among the variants classified as pathogenic in this six-pedigree series;
two additional variants remained uncertain.
- reference: PMID:33492714
reference_title: "Molecular characterization of pathogenic OTOA gene conversions in hearing loss patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Both conversions lead to loss-of-function by introducing a premature stop codon in exon 22 (p.Glu787*).
explanation: >-
Establishes gene conversion as a pathogenic allele class and names the resulting variant, which is the
same in both probands because it is pseudogene sequence rather than an independent mutation.
- reference: PMID:39916398
reference_title: "A 250-kb Microdeletion Identified in Chromosome 16 Is Associated With Non-Syndromic Sensorineural Hearing Loss in a South Indian Consanguineous Family."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A homozygous deletion of 250.285 kb was identified in the 16p12.2 region encompassing three genes, METTL9,
IGSF6, and OTOA
explanation: >-
This abstract names three genes; the full-text deletion analysis additionally includes part of NPIPB4.
The family does not establish the absence of neighboring-gene effects generally.
- reference: PMID:33492714
reference_title: Molecular characterization of pathogenic OTOA gene conversions in hearing loss patients.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: This allowed us to estimate that the size of the conversion on this second allele was less than 900bp
explanation: Upper bound for the shorter tract from the full-text sequence analysis.
- reference: PMID:30740825
reference_title: Clarification of glycosylphosphatidylinositol anchorage of OTOANCORIN and human OTOA variants associated with deafness.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Notably, no normal splicing pattern was detected in the c.1320+5G>C mutant.
explanation: 'COS7 minigene evidence: 113 mutant colonies showed alternative splicing, not patient cochlear RNA.'
downstream:
- target: Deficient Otoancorin at the Limbal Attachment Zone
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Gene deletion removes functional otoancorin, while individual splice and truncating alleles can impair
expression or surface retention. Mouse null and cell-expression assays support this route; identical
protein consequences have not been measured for all human alleles.
genes:
- preferred_term: OTOA
term:
id: hgnc:16378
label: OTOA
- name: Deficient Otoancorin at the Limbal Attachment Zone
role: mechanism
biological_scale: CELLULAR
description: >-
Mouse localization places otoancorin at the apical surface of interdental cells of the spiral limbus and
transiently at the developing greater epithelial ridge. Wild-type otoancorin expressed in HEK293T cells
was released by phosphatidylinositol-specific phospholipase C, supporting GPI anchorage. p.Gln589ArgfsX55
was constitutively released into medium and lacked detectable surface staining. This overexpression result
establishes a defect of the expressed truncated protein, but not whether sufficient mutant protein escapes
nonsense-mediated decay in patient cochlear cells. Complete protein absence has been demonstrated in the
mouse null model, not for every human genotype.
cell_types:
- preferred_term: interdental cell of the spiral limbus
term:
id: CL:0002172
label: interdental cell of cochlea
evidence:
- reference: PMID:11972037
reference_title: "Otoancorin, an inner ear protein restricted to the interface between the apical surface of sensory epithelia and their overlying acellular gels, is defective in autosomal recessive deafness DFNB22."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In the cochlea, otoancorin is detected at two attachment zones of the tectorial membrane, a permanent
one along the top of the spiral limbus and a transient one on the surface of the developing greater epithelial
ridge.
explanation: >-
Localizes the protein to the attachment zone whose failure the next node describes. The localization
is murine, hence MODEL_ORGANISM.
- reference: PMID:30740825
reference_title: "Clarification of glycosylphosphatidylinositol anchorage of OTOANCORIN and human OTOA variants associated with deafness."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The mutant OTOA with p.Gln589ArgfsX55 resulted in an uncontrolled release of OTOA into the medium in
contrast with phosphatidylinositol-specific phospholipase C-induced controlled release of WT OTOA from
the cell surface.
explanation: >-
Transfected-cell evidence of impaired surface retention of the expressed truncation; patient protein
abundance and nonsense-mediated decay remain unresolved.
- reference: PMID:30740825
reference_title: Clarification of glycosylphosphatidylinositol anchorage of OTOANCORIN and human OTOA variants associated with deafness.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: In the study, we could not properly evaluate the possibility of NMD for two mutant truncating transcripts from c.1320+5G>C and p.Gln589ArgfsX55, because OTOA transcript was not detected even from wild-type lymphoblastoid cell line (unpublished data).
explanation: Explicit limit on extrapolating the expressed truncation to endogenous patient protein.
downstream:
- target: Tectorial Membrane Detachment from the Spiral Limbus
causal_link_type: DIRECT
description: >-
Otoa knockout causes loss of limbal attachment in mice; the corresponding tissue lesion has not been
directly examined in patients.
- name: Tectorial Membrane Detachment from the Spiral Limbus
role: mechanism
biological_scale: TISSUE
description: >-
In Otoa-null mice, the tectorial membrane loses attachment to the spiral limbus while retaining its gross
form near the organ of Corti and outer hair-cell bundle imprints. It is not otherwise structurally normal:
the lateral region is thinned and fenestrated, a distinct marginal band is absent, and Hensen's stripe
is not visible. These full-text morphological observations limit interpretation of the mutant as an isolated
detachment experiment. Human temporal-bone confirmation is unavailable in the reviewed studies.
locations:
- preferred_term: tectorial membrane of the cochlea
term:
id: UBERON:0002233
label: tectorial membrane of cochlea
evidence:
- reference: PMID:23129639
reference_title: "A mouse model for human deafness DFNB22 reveals that hearing impairment is due to a loss of inner hair cell stimulation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
the tectorial membrane (TM), a ribbon-like strip of ECM that is normally anchored by one edge to the
spiral limbus and lies over the organ of Corti, retains its general form, and remains in close proximity
to the organ of Corti, but is detached from the limbal surface.
explanation: >-
The abstract establishes detachment and preserved gross form; the full-text Results and Figures 3-4 additionally
describe marginal and Hensen-stripe abnormalities.
downstream:
- target: Failure of Inner Hair Cell Stimulation
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Loss of limbal attachment and accompanying structural abnormalities are inferred to reduce hydrodynamic drive to inner hair-cell bundles. The relative contributions of detachment, altered subtectorial geometry and other membrane changes were not isolated.
- name: Failure of Inner Hair Cell Stimulation
role: mechanism
biological_scale: CELLULAR
description: >-
In Otoa-null mice, compound action potential thresholds were elevated by 35-55 dB over 8-70 kHz while neural
masker tuning remained sharp and was sharper than wild type under the tested conditions. Basilar-membrane
sensitivity and tuning were largely preserved in the measured basal region. This dissociation supports
inefficient transmission of cochlear motion to inner hair cells. Compound action potentials measure synchronized
auditory-nerve activity and are an indirect assay of inner hair-cell stimulation, not direct recordings
of inner hair-cell mechanotransduction currents. The exact hydrodynamic intermediate and applicability
to every human allele remain unresolved.
cell_types:
- preferred_term: cochlear inner hair cell
term:
id: CL:0000589
label: cochlear inner hair cell
biological_processes:
- preferred_term: mechanical stimulation of the inner hair-cell bundle
modifier: DECREASED
evidence:
- reference: PMID:23129639
reference_title: "A mouse model for human deafness DFNB22 reveals that hearing impairment is due to a loss of inner hair cell stimulation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The compound action potential masker tuning curves, a measure of the tuning of the sensory inner hair
cells, are also sharply tuned, but the thresholds of the compound action potentials, a measure of inner
hair cell sensitivity, are significantly elevated.
explanation: >-
Auditory-nerve compound potentials support the stimulation hypothesis indirectly; sharp tuning does not
demonstrate normal inner hair-cell transduction.
downstream:
- target: Sensorineural Hearing Loss
causal_link_type: DIRECT
description: >-
Reduced sensory drive provides a mechanistic explanation for hearing impairment in the knockout, with
provisional extrapolation to humans.
- name: Relatively Preserved Cochlear Amplification in Mice
role: modifier
biological_scale: CELLULAR
description: >-
Basilar-membrane sensitivity and sharpness of tuning at the high-frequency cochlear base were not significantly
different between null and wild-type mice. This relative preservation constrains the proposed hearing-loss
mechanism. It is a parallel physiological observation, not a consequence that detachment causes normal
function. DPOAE thresholds were nevertheless elevated by 10-35 dB over 8-65 kHz; the authors proposed altered
reverse transmission as an explanation for the difference from basilar-membrane responses. Normal otoacoustic
emissions or universally intact outer hair cells cannot be inferred in human DFNB22.
cell_types:
- preferred_term: cochlear outer hair cell
term:
id: CL:0000601
label: cochlear outer hair cell
evidence:
- reference: PMID:23129639
reference_title: "A mouse model for human deafness DFNB22 reveals that hearing impairment is due to a loss of inner hair cell stimulation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Measurements of cochlear microphonic potentials, distortion product otoacoustic emissions, and basilar
membrane motion indicate that the TM remains functionally attached to the electromotile, sensorimotor
outer hair cells of the organ of Corti, and that the amplification and frequency tuning of the basilar
membrane responses to sounds are almost normal.
explanation: >-
Relative preservation of basilar-membrane amplification in mice; the full-text Results and Figure 5B
separately show elevated DPOAE thresholds.
- name: Sensorineural Hearing Loss
role: outcome
biological_scale: ORGANISM
description: >-
Bilateral sensorineural hearing loss is the clinical endpoint. Severity, onset, symmetry and audiogram
configuration vary between reported families. The Chinese series emphasized postlingual sloping loss; Japanese
cases included mid-frequency loss and progression. These cohorts do not establish a universal clinical
pattern.
evidence:
- reference: PMID:37114731
reference_title: "[Phenotype-genotype analysis of the autosomal recessive hereditary hearing loss caused by OTOA variations]."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In this study, the hearing loss caused by OTOA defects mostly presents as bilateral, symmetrical, and
postlingual, and that of a few presents as congenital.
explanation: >-
Clinical pattern in six Chinese pedigrees, not a universal description or the largest possible series.
downstream:
- target: Bilateral Sensorineural Hearing Loss
causal_link_type: DIRECT
description: Clinical manifestation of the cochlear hearing deficit.
phenotypes:
- category: Otologic
name: Bilateral Sensorineural Hearing Loss
description: >-
Bilateral sensorineural hearing loss is reported across cohorts. Symmetry is common in the Chinese and
Japanese series, but asymmetry was documented in the South Indian family. These ascertained families do
not estimate population penetrance.
phenotype_term:
preferred_term: Bilateral sensorineural hearing impairment
term:
id: HP:0008619
label: Bilateral sensorineural hearing impairment
evidence:
- reference: PMID:37114731
reference_title: "[Phenotype-genotype analysis of the autosomal recessive hereditary hearing loss caused by OTOA variations]."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In this study, the hearing loss caused by OTOA defects mostly presents as bilateral, symmetrical, and
postlingual, and that of a few presents as congenital.
explanation: >-
States bilaterality and symmetry directly.
- category: Otologic
name: Postlingual Onset
description: >-
Five of six probands in the Chinese series were described as postlingual. Other cohorts include congenital
or prelingual and childhood presentations; this fraction should not be pooled into a disorder-wide frequency
or used to infer that newborn screening usually misses DFNB22.
phenotype_term:
preferred_term: Postlingual sensorineural hearing impairment
term:
id: HP:0008596
label: Postlingual sensorineural hearing impairment
evidence:
- reference: PMID:37114731
reference_title: "[Phenotype-genotype analysis of the autosomal recessive hereditary hearing loss caused by OTOA variations]."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
which came from six sporadic pedigrees, among which a proband was diagnosed as congenital deafness and
five were diagnosed as postlingual deafness.
explanation: >-
Study-specific count, not a quantitative frequency across all DFNB22.
- category: Otologic
name: Congenital Onset
description: >-
Congenital hearing loss was described in one Chinese proband and in the second pseudogene-conversion proband.
The first conversion proband repeatedly failed neonatal OAE screening and had moderate sensorineural loss
confirmed at four months, supporting very early onset. Prelingual or childhood recognition in other reports
does not by itself establish congenital onset. No pooled frequency is assigned.
phenotype_term:
preferred_term: Congenital sensorineural hearing impairment
term:
id: HP:0008527
label: Congenital sensorineural hearing impairment
evidence:
- reference: PMID:37114731
reference_title: "[Phenotype-genotype analysis of the autosomal recessive hereditary hearing loss caused by OTOA variations]."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
among which a proband was diagnosed as congenital deafness and five were diagnosed as postlingual deafness.
explanation: >-
One explicitly congenital proband among six Chinese pedigrees.
- reference: PMID:33492714
reference_title: "Molecular characterization of pathogenic OTOA gene conversions in hearing loss patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Proband 2 is a Caucasian female child presenting with congenital mild-to-moderate sensorineural hearing
loss with no family history.
explanation: >-
Explicitly congenital onset in the second conversion proband.
- reference: PMID:33492714
reference_title: "Molecular characterization of pathogenic OTOA gene conversions in hearing loss patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
At 4 months of age, a moderate sensorineural hearing loss was highlighted by brainstem evoked response
audiometry
explanation: >-
Very early confirmed loss following failed newborn screening; not an independent estimate of congenital
frequency.
- category: Otologic
name: High-Frequency Sensorineural Hearing Loss
description: >-
Moderate-to-severe high-frequency loss was reported in the Chinese series. High-frequency configurations
also occurred in the Japanese study, alongside mid-frequency and flat patterns. No universal severity band
or frequency is established.
phenotype_term:
preferred_term: High-frequency sensorineural hearing impairment
term:
id: HP:0001757
label: High-frequency sensorineural hearing impairment
evidence:
- reference: PMID:37114731
reference_title: "[Phenotype-genotype analysis of the autosomal recessive hereditary hearing loss caused by OTOA variations]."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The hearing loss phenotype caused by OTOA variations ranged from mild to moderate in the low frequencies,
and from moderate to severe in the high frequencies in the probands
explanation: >-
States the high-frequency severity band.
- category: Otologic
name: Low-Frequency Sensorineural Hearing Loss
description: >-
Mild-to-moderate low-frequency loss was reported in the Chinese series. This describes that cohort and
does not exclude other audiogram shapes.
phenotype_term:
preferred_term: Low-frequency sensorineural hearing impairment
term:
id: HP:0008573
label: Low-frequency sensorineural hearing impairment
evidence:
- reference: PMID:37114731
reference_title: "[Phenotype-genotype analysis of the autosomal recessive hereditary hearing loss caused by OTOA variations]."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The hearing loss phenotype caused by OTOA variations ranged from mild to moderate in the low frequencies,
and from moderate to severe in the high frequencies in the probands
explanation: >-
States the low-frequency severity band.
- name: Mid-Frequency Hearing Loss
category: Otologic
description: The Japanese series reported mid-frequency configurations in nine of fourteen ears. This includes cases carrying uncertain missense variants, but mid-frequency loss also occurred with homozygous deletions. It is a recurrent presentation rather than a diagnostic requirement.
phenotype_term:
preferred_term: Mid-frequency hearing loss
term:
id: HP:0012781
label: Mid-frequency hearing loss
evidence:
- reference: PMID:31527525
reference_title: Mid-Frequency Hearing Loss Is Characteristic Clinical Feature of OTOA-Associated Hearing Loss.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: mid-frequency HL was observed in nine ears, flat type in three ears, and high-frequency HL in two ears.
explanation: Ear-level distribution in the seven reported probands; four genotypes included uncertain missense variants.
- name: Progressive Sensorineural Hearing Loss
category: Otologic
description: Three adult participants in the Japanese series reported progression. Serial audiometry in one deletion/missense proband showed a pure-tone average increasing from 41.25 dB at age four to 55 dB at nineteen; that missense allele was classified as uncertain. A homozygous-deletion participant also reported progression. These observations support possible progression, without establishing its frequency or a general rate.
phenotype_term:
preferred_term: Progressive sensorineural hearing impairment
term:
id: HP:0000408
label: Progressive sensorineural hearing impairment
evidence:
- reference: PMID:31527525
reference_title: Mid-Frequency Hearing Loss Is Characteristic Clinical Feature of OTOA-Associated Hearing Loss.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'Progression of HL was noticed, based on the medical charts, for three (all adults: HL5890, HL0511, and HL5367) of the seven individuals.'
explanation: Study-specific progression reports, with genotype uncertainty in two of these three participants.
- reference: PMID:31527525
reference_title: Mid-Frequency Hearing Loss Is Characteristic Clinical Feature of OTOA-Associated Hearing Loss.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Serial audiograms could be obtained from one individual (HL5367), and the averaged hearing threshold (PTA) was observed to have slowly deteriorated from 41.25 dB at 4 years old to 55 dB at 19 years old.
explanation: Longitudinal measurement in a deletion/missense candidate case; the study classified p.Arg157Cys as uncertain.
genetic:
- name: OTOA
gene_term:
preferred_term: OTOA
term:
id: hgnc:16378
label: OTOA
relationship_type: CAUSATIVE
notes: >-
OTOA encodes otoancorin, localized to nonsensory epithelial surfaces at acellular-gel attachment zones
in the mouse inner ear. The founding paper's 1088-residue abstract refers to murine sequence and must not
be treated as a human protein length. OTOA and OTOAP1 share greater than 99% identity in the paralogous
region, complicating mapping, copy-number calls and primer/probe placement. Alleles include whole or partial
deletions, splice and truncating variants, selected missense variants and pseudogene-mediated conversions.
A conversion can resemble an exon deletion in read-depth output; locus-specific amplification and sequencing
are required to distinguish the physical alterations. Proposed recombination mechanisms generating a conversion
are distinct from the observed converted sequence. Neither isolated heterozygosity nor a pair of uncertain
variants alone establishes recessive OTOA disease.
evidence:
- reference: PMID:11972037
reference_title: "Otoancorin, an inner ear protein restricted to the interface between the apical surface of sensory epithelia and their overlying acellular gels, is defective in autosomal recessive deafness DFNB22."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
A 3,673-bp murine cDNA predicted to encode a glycosylphosphatidylinositol-anchored protein of 1,088 amino
acids was isolated during a study aimed at identifying transcripts specifically expressed in the inner
ear.
explanation: >-
Murine cDNA characterization, not a human protein length or proof that extra-auditory findings are impossible.
- reference: PMID:25528277
reference_title: "Exome sequencing and genome-wide copy number variant mapping reveal novel associations with sensorineural hereditary hearing loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
High-resolution genome-wide CNV analysis of 150 cases and 157 controls revealed deletions in genes known
to be involved in hearing (e.g. GJB6, OTOA, and STRC, encoding connexin 30, otoancorin, and stereocilin,
respectively), supporting CNV contributions to hearing loss phenotypes.
explanation: >-
Case-control CNV analysis found OTOA-overlapping calls in cases and controls; this is not confirmation
of biallelic causation for every overlapping call.
- reference: PMID:32681043
reference_title: Spectrum of genetic variants in moderate to severe sporadic hearing loss in Pakistan.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: A large homozygous deletion including OTOA was identified in individual SPK7.
explanation: Additional deletion case in a Pakistani sporadic hearing-loss cohort.
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Reported causative genotypes are homozygous or compound heterozygous, consistent with autosomal recessive
inheritance. When both parents carry established pathogenic alleles, each pregnancy has a 25% chance of
an affected child. Apply recurrence counseling after verifying familial variants, phase and diagnostic
attribution.
evidence:
- reference: PMID:11972037
reference_title: "Otoancorin, an inner ear protein restricted to the interface between the apical surface of sensory epithelia and their overlying acellular gels, is defective in autosomal recessive deafness DFNB22."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The identification of the mutation (IVS12+2T>C) in the corresponding gene OTOA in one consanguineous
Palestinian family affected by nonsyndromic recessive deafness DFNB22 assigns an essential function to
otoancorin.
explanation: >-
Names the inheritance mode and the consanguineous pedigree it was established in.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
reference_title: "Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf"
supports: SUPPORT
evidence_source: OTHER
snippet: If both parents are known to be heterozygous for an autosomal recessive hearing loss-related pathogenic variant, each sib of the proband has at conception a 25% chance of having hearing loss, a 50% chance of having no hearing loss and being a carrier, and a 25% chance of having no hearing loss and not being a carrier.
explanation: General recessive recurrence risk, conditional on established parental pathogenic variants.
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC122933/?report=xml
reference_title: "Otoancorin, an inner ear protein restricted to the interface between the apical surface of sensory epithelia and their overlying acellular gels, is defective in autosomal recessive deafness DFNB22 - PMC"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: was not detected in a total of 417 Jordanian, Lebanese, Palestinian, and Jewish (mainly from Sephardi and Yemenite ethnic groups) individuals with normal hearing.
explanation: Founding-family segregation and control data from the full text; not a penetrance estimate.
animal_models:
- name: Otoa-EGFP knock-in null mouse
species: Mouse
genotype: Otoa(EGFP/EGFP)
publication: PMID:23129639
description: >-
EGFP replaces the first coding exon of Otoa. Absent full-length transcript and undetectable otoancorin
immunoreactivity support a null model. Physiological experiments used littermates younger than three months.
The model links tectorial-membrane attachment and morphology to reduced auditory-nerve sensitivity, but
does not establish the human tissue lesion or the effects of every allele.
modeled_mechanisms:
- target: Tectorial Membrane Detachment from the Spiral Limbus
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
description: >-
Limbal detachment occurs with thinning and fenestration of the lateral membrane and loss of Hensen's
stripe; this is not an otherwise intact membrane.
limitations: >-
Human cochlear pathology has not been directly examined in the cited studies. Multiple membrane abnormalities
prevent attribution of every physiological effect solely to detachment.
readouts:
- name: Position of the tectorial membrane relative to the limbal surface
target: Tectorial Membrane Detachment from the Spiral Limbus
direction: ALTERED
interpretation: >-
Structural readout of the attachment failure.
evidence:
- reference: PMID:23129639
reference_title: "A mouse model for human deafness DFNB22 reveals that hearing impairment is due to a loss of inner hair cell stimulation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
the tectorial membrane (TM), a ribbon-like strip of ECM that is normally anchored by one edge to
the spiral limbus and lies over the organ of Corti, retains its general form, and remains in close
proximity to the organ of Corti, but is detached from the limbal surface.
explanation: >-
The observation behind this readout.
- target: Failure of Inner Hair Cell Stimulation
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: CELLULAR
description: >-
Elevated auditory-nerve compound action potential thresholds, despite relatively preserved basilar-membrane
responses, support impaired transmission of mechanical drive to inner hair cells.
limitations: >-
CAP is an indirect measure of inner hair-cell stimulation. Direct inner hair-cell currents, adult human
natural history and allele-specific residual function are not established by this null model.
readouts:
- name: Compound action potential threshold
target: Failure of Inner Hair Cell Stimulation
direction: INCREASED
interpretation: >-
Elevated auditory-nerve response thresholds support reduced sensory drive; they do not directly measure
inner hair-cell transduction.
evidence:
- reference: PMID:23129639
reference_title: "A mouse model for human deafness DFNB22 reveals that hearing impairment is due to a loss of inner hair cell stimulation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
the thresholds of the compound action potentials, a measure of inner hair cell sensitivity, are significantly
elevated.
explanation: >-
The measurement itself.
- name: Compound action potential masker tuning curve sharpness
target: Failure of Inner Hair Cell Stimulation
interpretation: >-
Full-text Figure 5F and Results show sharper masker tuning than wild type under the tested stimulus
conditions, not unchanged tuning or proof of normal transduction.
evidence:
- reference: PMID:23129639
reference_title: "A mouse model for human deafness DFNB22 reveals that hearing impairment is due to a loss of inner hair cell stimulation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The compound action potential masker tuning curves, a measure of the tuning of the sensory inner
hair cells, are also sharply tuned
explanation: >-
The abstract states sharp tuning; the full-text comparison reports increased sharpness relative to
wild type.
- target: Relatively Preserved Cochlear Amplification in Mice
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: CELLULAR
description: >-
Basilar-membrane sensitivity and tuning in the measured high-frequency basal region were not significantly
altered. This relative preservation differs from elevated DPOAE thresholds.
limitations: >-
Measurements were restricted to the high-frequency cochlear base. DPOAE thresholds increased by 10-35
dB over 8-65 kHz; therefore neither normal emissions nor absence of all outer hair-cell effects is established.
Human correspondence remains unresolved.
readouts:
- name: Basilar-membrane sensitivity and tuning at the high-frequency cochlear base
target: Relatively Preserved Cochlear Amplification in Mice
direction: UNCHANGED
interpretation: >-
No significant group difference in the measured basal responses; this does not describe DPOAE thresholds,
which increased.
evidence:
- reference: PMID:23129639
reference_title: "A mouse model for human deafness DFNB22 reveals that hearing impairment is due to a loss of inner hair cell stimulation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
the amplification and frequency tuning of the basilar membrane responses to sounds are almost normal.
explanation: >-
The measurement establishing preservation.
evidence:
- reference: PMID:23129639
reference_title: "A mouse model for human deafness DFNB22 reveals that hearing impairment is due to a loss of inner hair cell stimulation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Gene targeting in ES cells was used to create an EGFP knock-in, otoancorin KO (Otoa(EGFP/EGFP)) mouse.
explanation: >-
Establishes the model's construction, which is what licenses treating it as an otoancorin-null model
of this disease.
diagnosis:
- name: Copy-Number-Aware Genetic Testing
description: >-
Use genetic testing that evaluates OTOA sequence variants and deletions/duplications and has appropriate
coverage of the homologous OTOA/OTOAP1 region. Short-read panel or exome data can detect CNVs when analyzed
appropriately, but assay-specific limitations matter. In the conversion study, exome CNV analysis flagged
an apparent exon-22 deletion; MLPA confirmed a larger deletion but lacked probes in the paralogous region.
Long-range PCR with Sanger and nanopore sequencing resolved the converted allele. Thus conversion may be
flagged or misclassified rather than uniformly invisible. Confirm candidate variants, phase and familial
segregation and assess current pathogenicity; a single heterozygous deletion or an uncertain missense genotype
is not a complete recessive diagnosis.
evidence:
- reference: PMID:28000701
reference_title: "The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Eight of these patients have a large homozygous deletion involving STRC, OTOA or USH2A, which could only
be identified by copy number variation detection.
explanation: >-
Eight deletion diagnoses collectively involved STRC, OTOA or USH2A; the number is not eight OTOA cases.
- reference: PMID:37114731
reference_title: "[Phenotype-genotype analysis of the autosomal recessive hereditary hearing loss caused by OTOA variations]."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the copy number variations were validated by multiplex ligation-dependent probe amplification (MLPA)
in the family members.
explanation: >-
Names the confirmatory assay used in the case series.
- reference: PMID:33492714
reference_title: "Molecular characterization of pathogenic OTOA gene conversions in hearing loss patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The conversions were initially detected through sequencing depths anomalies at the OTOA locus after exome
sequencing, then confirmed with long range polymerase chain reactions.
explanation: >-
Read-depth anomalies triggered further analysis; the full text identifies the initial signal as CNV calls,
subsequently resolved by locus-specific amplification and sequencing.
- reference: PMID:33492714
reference_title: Molecular characterization of pathogenic OTOA gene conversions in hearing loss patients.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The resolution of the paternal allele was hindered by the fact that the region spanning intron 20 to exon 29 of OTOA displays very high sequence identity with exons 1 to 9 of the OTOAP1 pseudogene (NR_003676.3) and therefore lacks MLPA probes.
explanation: Probe coverage and homology explain this assay-specific limitation.
- name: Audiologic assessment and serial follow-up
description: Use age-appropriate diagnostic audiometry or ABR, with tympanometry, otoacoustic emissions and speech assessment as appropriate. Repeated audiometry documents progression and guides hearing support. Failed or preserved emissions alone do not confirm or exclude OTOA disease. Surveillance follows general genetic-hearing-loss care; a DFNB22-specific interval is not established.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
reference_title: "Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf"
supports: SUPPORT
evidence_source: OTHER
snippet: 'Regular follow up is recommended for all individuals with genetic hearing loss in order to:'
explanation: General surveillance recommendation, not a disease-specific interval.
treatments:
- name: Hearing Amplification and Auditory Rehabilitation
therapeutic_modality: DEVICE
treatment_term:
preferred_term: auditory rehabilitation with amplification
term:
id: NCIT:C15315
label: Rehabilitation
description: >-
Individualized hearing aids and auditory rehabilitation follow general guidance for mild-to-severe hearing
loss. They address the hearing phenotype; the mouse mechanism does not guarantee an intact human afferent
pathway or a particular aided outcome. Genotype-specific efficacy is not established by the reviewed studies.
target_phenotypes:
- preferred_term: Bilateral sensorineural hearing impairment
term:
id: HP:0008619
label: Bilateral sensorineural hearing impairment
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
reference_title: "Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf"
supports: SUPPORT
evidence_source: OTHER
snippet: customized by an audiologist to the degree and frequency of hearing loss, can be used in individuals with mild-to-severe hearing loss.
explanation: General guidance on hearing aids, not an OTOA-specific outcome study.
- name: Cochlear Implantation
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
description: >-
Consider specialist cochlear-implant assessment for severe-to-profound hearing loss according to hearing
ability and clinical candidacy. A Filipino implant cohort included a homozygous OTOA c.2301+1G>T candidate
case, but that patient also had substantial perinatal and acquired risk factors. Implant outcomes were
reported collectively across heterogeneous genotypes, not as an OTOA-specific efficacy estimate. The proposed
mouse lesion does not establish intact neural targets or guarantee benefit in every patient.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
reference_title: "Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf"
supports: SUPPORT
evidence_source: OTHER
snippet: Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months.
explanation: General candidacy guidance.
- reference: PMID:30828794
reference_title: Exome sequencing reveals novel variants and unique allelic spectrum for hearing impairment in Filipino cochlear implantees.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: However there was no significant difference in post-surgical thresholds, suggesting that carriage of the genetic variants reported here does not determine the outcome of cochlear implantation, with average implant-aided hearing at 38dB across frequencies.
explanation: Cohort-level comparison across heterogeneous genotypes; not an OTOA-specific treatment effect.
- reference: PMID:30828794
reference_title: Exome sequencing reveals novel variants and unique allelic spectrum for hearing impairment in Filipino cochlear implantees.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'Patient #14 has global developmental delay and a history of maternal rubella, low birth weight, exchange transfusion for jaundice, antibiotic treatment and mechanical ventilation for neonatal pneumonia, and intraventricular hemorrhage.'
explanation: Table 1 footnote documents competing contributors in the OTOA candidate case; these are not curated as DFNB22 manifestations.
- name: Genetic Counselling
treatment_term:
preferred_term: genetic counseling
term:
id: NCIT:C15240
label: Genetic Counseling
description: >-
Provide nondirective counseling after molecular confirmation. Recurrence risk is conditional on the established
parental pathogenic genotypes. Testing relatives must be designed to detect the actual familial allele
class, including deletions or resolved conversions.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
reference_title: "Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf"
supports: SUPPORT
evidence_source: OTHER
snippet: If both parents are known to be heterozygous for an autosomal recessive hearing loss-related pathogenic variant, each sib of the proband has at conception a 25% chance of having hearing loss, a 50% chance of having no hearing loss and being a carrier, and a 25% chance of having no hearing loss and not being a carrier.
explanation: General recessive recurrence risk, conditional on established parental pathogenic variants.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
reference_title: "Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf"
supports: SUPPORT
evidence_source: OTHER
snippet: Carrier testing for relatives who may have a hearing loss-related pathogenic variant requires prior identification of the pathogenic variants in the family.
explanation: Prerequisite for informative family testing.
- name: Communication and language support
description: Establish communication goals and provide appropriate language access, speech-language services and educational support. These are general measures for hearing loss, not evidence of a primary neurodevelopmental syndrome caused by OTOA.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
reference_title: "Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf"
supports: SUPPORT
evidence_source: OTHER
snippet: On initial evaluation of individuals with hearing loss, the goals for communication must be established with a focus on equipping individuals with language and appropriate access to language.
explanation: General hearing-loss management.
- name: Hearing-conservation counseling
description: Avoid repeated hazardous noise exposure as part of general care for documented hearing loss. Increased OTOA-specific noise vulnerability and a genotype-specific preventive effect have not been demonstrated here.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
reference_title: "Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf"
supports: SUPPORT
evidence_source: OTHER
snippet: Since this risk can be minimized by avoidance, persons with documented hearing loss should be counseled appropriately and repeated overexposure to loud noises should be avoided.
explanation: General hearing-conservation guidance.
differential_diagnoses:
- name: STRC-related hearing loss (DFNB16)
description: >-
STRC-related recessive hearing loss overlaps clinically and also requires attention to deletions and gene-pseudogene
homology. Audiogram shape alone does not distinguish it from OTOA disease; molecular testing can evaluate
both loci.
evidence:
- reference: PMID:28000701
reference_title: "The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Eight of these patients have a large homozygous deletion involving STRC, OTOA or USH2A, which could only
be identified by copy number variation detection.
explanation: >-
Puts the two genes in the same deletion-detected diagnostic class in one cohort.
- name: TECTA-related hearing loss
description: TECTA disease can also produce mid-frequency hearing loss and involves the tectorial membrane. Molecular testing distinguishes it from OTOA-related disease. DFNB22 mouse membranes have structural abnormalities as well as detachment, so normal membrane structure is not a valid differentiator.
evidence:
- reference: PMID:31527525
reference_title: Mid-Frequency Hearing Loss Is Characteristic Clinical Feature of OTOA-Associated Hearing Loss.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: is also known as a genetic cause of mid-frequency HL
explanation: The full source sentence identifies TECTA as another cause of mid-frequency hearing loss; the quoted clause follows its gene name and reference markers.
- name: Additional genetic diagnoses in a complex phenotype
description: Extra-auditory findings warrant evaluation for additional causes. Two siblings with OTOA deletion and mid-frequency hearing loss also had a homozygous ERCC4 missense variant and an NER-disorder-like phenotype. The ERCC4 allele was classified as uncertain and lacked functional confirmation; this report supports considering blended diagnoses, not assigning photosensitivity or intellectual disability to DFNB22.
evidence:
- reference: PMID:39769235
reference_title: "Unveiling Secondary Mutations in Blended Phenotypes: Dual ERCC4 and OTOA Pathogenic Variants Through WES Analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: While the homozygous deletion in OTOA is a well-established cause of deafness, the pathogenicity of the ERCC4 variant identified in our patients is currently supported only by allele frequency data, in silico predictions, and clinical concordance.
explanation: The full-text limitation prevents upgrading the proposed second diagnosis to a functionally confirmed mechanism.
discussions:
- discussion_id: otoa_mouse_to_human_correspondence
kind: KNOWLEDGE_GAP
prompt: How closely does the Otoa-null mouse physiology represent human OTOA hearing loss?
rationale: The mouse has limbal detachment, additional membrane abnormalities, elevated CAP and DPOAE thresholds, and relatively preserved basal basilar-membrane responses. It does not predict universally normal human emissions. One conversion proband repeatedly failed neonatal OAE screening, but screening results do not localize the lesion or directly test the proposed hydrodynamic mechanism. Human physiological characterization across confirmed genotypes remains limited.
attaches_to:
- pathophysiology#Failure of Inner Hair Cell Stimulation
- pathophysiology#Relatively Preserved Cochlear Amplification in Mice
evidence:
- reference: PMID:33492714
reference_title: Molecular characterization of pathogenic OTOA gene conversions in hearing loss patients.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The proband’s neonatal auditory screening (otoacoustic emissions) failed for both ears. After four repeated failures she was referred for a full hearing evaluation.
explanation: Human screening result; insufficient to establish outer hair-cell dysfunction or refute the mouse mechanism.
- discussion_id: otoa_allele_class_and_onset
kind: KNOWLEDGE_GAP
prompt: Which confirmed genotypes explain variation in onset, configuration and progression?
rationale: Congenital, prelingual, childhood and postlingual presentations occur across reports. Small differently ascertained cohorts, uncertain missense variants, incomplete segregation and sparse serial audiometry prevent reliable allele-class correlations. Diagnosis or recognition age must be distinguished from true onset, and reported candidate cases must be separated from firmly established molecular diagnoses.
attaches_to:
- pathophysiology#Biallelic OTOA Loss-of-Function
- phenotypes#Postlingual Onset
- phenotypes#Congenital Onset
- phenotypes#Progressive Sensorineural Hearing Loss
notes: >-
The disease scope is recessive OTOA-related hearing loss. An isolated heterozygous deletion is carrier evidence
unless a second pathogenic allele is established. Additional findings in multigene deletions or proposed
blended diagnoses should not automatically be attributed to OTOA. The causal cochlear tissue mechanism is
supported primarily by mouse experiments, supplemented by human genetics and transfected-cell assays; human
membrane pathology and genotype-specific treatment outcomes remain incompletely characterized.
references:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
title: "Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf"
tags:
- GeneReviews
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
OTOA (chromosome 16p12.2; OMIM 607038; disease OMIM #607039) encodes otoancorin, a ~120 kDa GPI-anchored protein. Otoancorin localizes to the interface between the apical surface of the inner-ear sensory epithelia and their overlying acellular gels. In the cochlea it marks the two attachment zones of the tectorial membrane: the permanent zone along the spiral limbus and the transient zone on the greater epithelial ridge. In the vestibular system it localizes to nonsensory cells in contact with the otoconial membranes and cupulae. The founding mutation, a splice variant IVS12+2T>C, was identified in a consanguineous Palestinian DFNB22 family (PMID 11972037).
The GPI anchorage was later validated experimentally. A frameshift allele, p.Gln589ArgfsX55, abolishes controlled release of otoancorin, causing uncontrolled release into the culture medium rather than the expected phosphatidylinositol-specific phospholipase C (PI-PLC)-dependent release — confirming that the pathogenic mechanism is loss of proper membrane anchorage of the protein (PMID 30740825).
"Otoancorin is located at the interface between the apical surface of the inner ear sensory epithelia and their overlying acellular gels." — PMID: 11972037
"Otoancorin (OTOA), encoded by OTOA, is required for the development of the tectorial membrane in the inner ear. Mutations in this gene cause nonsyndromic hearing loss (DFNB22)." — PMID: 30740825
Ontology annotations: Gene HGNC:16378 (OTOA); GO:0031225 (anchored component of membrane); GO:0098590 (plasma membrane region); biological process GO:0042491 / GO:0060119 (inner ear receptor cell development); CHEBI: glycosylphosphatidylinositol anchor.
The Otoa(EGFP/EGFP) knockout mouse resolves precisely how loss of otoancorin causes deafness. In these animals the TM retains its general form and remains close to the organ of Corti, but is detached from the limbal (spiral limbus) surface. Physiological measurements show that the TM stays functionally attached to the electromotile OHCs: cochlear microphonics, distortion-product otoacoustic emissions (DPOAEs), and basilar-membrane motion are almost normal, indicating preserved amplification and frequency tuning. However, compound action potential (CAP) thresholds — a read-out of IHC sensitivity — are significantly elevated, while CAP masker tuning curves remain sharply tuned. The conclusion is that DFNB22 hearing loss arises from a defect in inner hair cell stimulation, not from a failure of OHC-driven amplification (PMID 23129639).
"These results indicate that the hearing loss in patients with Otoa mutations is caused by a defect in inner hair cell stimulation, and reveal the limbal attachment of the TM plays a critical role in this process." — PMID: 23129639
This is mechanistically distinctive: many deafness genes act through OHC dysfunction or hair-bundle/mechanotransduction defects, whereas OTOA loss selectively disrupts the mechanical coupling that drives the IHCs, the afferent sensory cells.
Ontology annotations: CL:0000601 (cochlear inner hair cell), CL:0000599 (cochlear outer hair cell); UBERON:0002518 (tectorial membrane), UBERON:0002227 (organ of Corti), UBERON:0004681 (spiral limbus); GO:0007605 (sensory perception of sound).
OTOA lies in a low-copy-repeat region on 16p12.2 that shares high sequence homology with the pseudogene OTOAP1, predisposing the locus to non-allelic homologous recombination (NAHR). Recurrent deletions of OTOA are a well-recognized cause of moderate-to-severe hearing loss. In a chromosomal-microarray (CMA) cohort of 19,189 tests at Rabin Medical Center, heterozygous OTOA microdeletions were detected in 39 individuals (0.2% carrier frequency) (PMID 33753912).
A second, subtler mechanism is pathogenic gene conversion, in which OTOAP1 pseudogene sequence is copied into OTOA, introducing a premature stop codon p.Glu787* in exon 22. Two compound-heterozygous patients (one converted allele plus one deletion) had moderate hearing loss, with converted tracts ranging from ~900 bp to >9 kbp (PMID 33492714). Contiguous-gene deletions also occur: a 250.285 kb homozygous 16p12.2 deletion encompassing METTL9, IGSF6, and OTOA segregated with nonsyndromic SNHL in a South Indian consanguineous family (PMID 39916398).
Because these events are structural and occur in a repeat-rich region, short-read whole-exome sequencing and standard panels often miss them, and confirmation requires qPCR, MLPA, CMA, or long-read sequencing (PMID 35640668).
"Bi-allelic loss-of-function variants of OTOA are a well-known cause of moderate-to-severe hearing loss. Whereas non-allelic homologous recombination-mediated deletions of the gene are well known, gene conversions to pseudogene OTOAP1 have been reported" — PMID: 33492714
"OTOA deletions (39, 0.2%)" — PMID: 33753912
"A homozygous deletion of 250.285 kb was identified in the 16p12.2 region encompassing three genes, METTL9, IGSF6, and OTOA" — PMID: 39916398
Across reported families, DFNB22 presents as congenital/prelingual, bilateral, generally stable, nonsyndromic sensorineural hearing loss in the moderate-to-severe range (PMIDs 33492714, 32681043). Although OTOA is one of the more common CNV-driven recessive deafness loci, the absolute risk to any given microdeletion carrier is low. In the general CMA cohort, the OTOA microdeletion carrier frequency of 0.2% (39/19,189) placed it second to STRC (0.56%) and above the DFNB1/GJB6 locus (0.05%). The estimated probability that a given OTOA-microdeletion carrier is themselves affected (i.e., carries a second pathogenic allele) was only 0.016–0.13% — lower than for STRC (0.11–0.67%) and DFNB1 (1.9–7.5%) — with higher risk in specific (e.g., consanguineous or founder) populations (PMID 33753912).
"Of the 19,189 CMA tests were performed in our laboratory, 107 STRC microdeletions were found (0.56%), followed in frequency by OTOA deletions (39, 0.2%), and DFNB1 locus deletions (10, 0.05%). The estimated risk for a hearing loss in the examined individual carrying the microdeletion was estimated as 0.11-0.67% for STRC, 0.016-0.13% for OTOA" — PMID: 33753912
Ontology annotations: HP:0000407 (Sensorineural hearing impairment), HP:0008527 (Congenital sensorineural hearing impairment), HP:0000365 (Hearing impairment), HP:0000006 (Autosomal recessive inheritance).
DFNB22 is a monogenic form of nonsyndromic sensorineural hearing loss — that is, hearing loss without accompanying malformations or dysfunction of other organ systems. It is one of the numbered "DFNB" (autosomal recessive) deafness loci.
| Phenotype | Type | Onset | Severity | Progression | Frequency | HPO |
|---|---|---|---|---|---|---|
| Bilateral sensorineural hearing loss | Audiometric abnormality / physical | Congenital / prelingual | Moderate to severe | Generally stable | ~100% of affected | HP:0000407 |
| Congenital SNHL | Clinical sign | Neonatal/congenital | Moderate–severe | Stable | Predominant presentation | HP:0008527 |
| Speech/language delay (if unaided) | Developmental consequence | Childhood | Variable | Improves with habilitation | Secondary to HL | HP:0000750 |
Not applicable as a cause. DFNB22 is a monogenic disorder with no established environmental, lifestyle, or infectious contributors. (General ototoxin/noise avoidance is prudent to preserve residual hearing but is not disease-specific.)
Upstream vs downstream: The mutation and protein loss are upstream; TM detachment is the central lesion; IHC understimulation is the proximate downstream cause of the clinical deafness. The disorder is mechanical/structural, not driven by apoptosis, inflammation, metabolic, or immune processes.
OTOA biallelic LoF (deletion / gene conversion / splice / frameshift)
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▼
Absent / non-functional otoancorin (GPI-anchored tether)
│
▼
Tectorial membrane not anchored at spiral-limbus (limbal) attachment
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┌────────┴───────────────┐
▼ ▼
TM stays coupled to TM detached from limbus →
OUTER hair cells mechanical drive to INNER
→ amplification & hair cell stereocilia lost
tuning ~NORMAL │
(normal CM, DPOAE, ▼
BM motion) IHC receptor potentials ↓
│
▼
CAP thresholds ↑ (IHC sensitivity ↓)
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▼
Congenital bilateral moderate-to-severe SNHL (stable)
The unifying interpretation is that DFNB22 is a "connectivity" / mechanical-coupling deafness: the cochlea's amplifier (OHCs) works, but the sensory receiver (IHCs) is under-driven because the TM has lost its anchor to the spiral limbus. This explains both the clinical severity (moderate-to-severe rather than profound) and a predicted audiologic signature of comparatively preserved otoacoustic emissions with elevated behavioral/ABR thresholds — a pattern shared with other TM-anchoring/structural deafness genes (e.g., TECTA, OTOG, STRC). The human genomics layer — a segmental duplication with the OTOAP1 pseudogene — superimposes a diagnostic challenge: the disease is under-ascertained by short-read exome sequencing and requires copy-number/gene-conversion-aware testing.
| Feature | DFNB22 (OTOA) |
|---|---|
| Gene / locus | OTOA, 16p12.2 |
| Protein | Otoancorin (~120 kDa, GPI-anchored) |
| Core lesion | TM detachment from spiral limbus |
| OHC amplification | Spared (near-normal DPOAE/CM) |
| IHC stimulation | Impaired (↑ CAP thresholds) |
| Phenotype | Congenital bilateral moderate–severe SNHL, stable |
| Inheritance | Autosomal recessive, fully penetrant |
| Carrier freq (microdeletion) | ~0.2% (39/19,189, CMA cohort) |
| Per-carrier affected risk | 0.016–0.13% |
| Key mutational mechanisms | NAHR deletions; OTOAP1 gene conversion (p.Glu787*) |
| Diagnostic caveat | Missed by short-read WES; needs CMA/MLPA/qPCR/long-read |
| Treatment | Hearing aids, cochlear implant, speech therapy |
| PMID | Title (abbrev.) | Evidence type | Supports |
|---|---|---|---|
| 11972037 | Otoancorin defective in DFNB22 | Human clinical + molecular | Gene–disease link; protein localization; founding IVS12+2T>C (F1) |
| 30740825 | GPI anchorage of otoancorin; human OTOA variants | In vitro / molecular | GPI anchorage; LoF via loss of anchorage (F1) |
| 23129639 | Mouse model of DFNB22 | Model organism (mouse) | Mechanism: TM detachment → IHC-stimulation defect (F2) |
| 33492714 | OTOA gene conversions | Human molecular | Gene conversion (p.Glu787*); moderate-severe phenotype (F3, F4) |
| 33753912 | Carrier reporting from CMA / HL deletions | Population/epidemiologic | Carrier frequency 0.2%; per-carrier risk (F3, F4) |
| 39916398 | 250-kb 16p12.2 microdeletion | Human clinical | Contiguous-gene deletion causing DFNB22 (F3) |
| 35640668 | WES of 113 Chinese HL families | Human clinical | Need for qPCR to detect OTOA/STRC CNVs (F3) |
| 32681043 | Sporadic HL spectrum, Pakistan | Human clinical | Multi-exon OTOA deletion; moderate-severe HL (F4) |
| 33095980 | NGS in Chinese HL cohort | Human clinical | OTOA among identified deafness genes |
| 33105617 | Italian HL genetics | Human clinical | Context: NSHL diagnostic strategy |
| 39769235 | Dual ERCC4 + OTOA diagnoses | Human clinical | Blended-phenotype/dual-diagnosis caution |
| 37114731 | Phenotype-genotype of AR HL | Human clinical | Phenotype-genotype context |
| 42527583 | PALM3 and hearing loss | Human + mouse | Dual-diagnosis/candidate-gene caution alongside OTOA |
All four core findings are convergently supported: the gene–disease link and protein function (PMIDs 11972037, 30740825), the mechanism (PMID 23129639), the diagnostic genomics (PMIDs 33492714, 33753912, 39916398, 35640668), and the clinical/epidemiologic profile (PMIDs 33753912, 33492714, 32681043). No paper reviewed contradicts these conclusions.
Evidence source key: Human clinical = patient/family reports and cohorts; Model organism = mouse; In vitro = cell-based functional assays; Population/epidemiologic = cohort frequency analyses. All mechanistic and clinical claims are cited to primary literature by PMID.
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 13 |
| Resolved | 13 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 7 |
| Quoted claims found in source | 7 |
| Quoted claims not found in source | 0 |
| References weighed for topical relevance | 13 |
| On topic | 13 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 19 |
| Resolved | 17 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 1 |
| Unverifiable | 1 |
| Terms whose name was checked | 16 |
| Terms named correctly | 6 |
| Terms named as a different term | 6 |
| Terms whose name is worth a second look | 4 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
CL:0000599 (3 mentions) - the report calls it "cochlear outer hair cell"; CL calls it conidiumUBERON:0002518 (2 mentions) - the report calls it "tectorial membrane"; UBERON calls it otolith organUBERON:0004681 (2 mentions) - the report calls it "spiral limbus"; UBERON calls it vestibular systemHP:0000407 (2 mentions) - the report calls it "Sensorineural hearing impairment", "~100% of affected"; HP calls it Sensorineural hearing impairmentHP:0008527 (2 mentions) - the report calls it "Congenital sensorineural hearing impairment", "Predominant presentation"; HP calls it Congenital sensorineural hearing impairmentHP:0000750 (1 mention) - the report calls it "Secondary to HL"; HP calls it Delayed speech and language developmentThese terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:
GO:0031225 (obsolete anchored component of membrane) (2 mentions) - replaced by GO:0016020The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
GO:0031225 (2 mentions) - the report calls it "anchored component of membrane"; GO calls it obsolete anchored component of membraneCL:0000601 (3 mentions) - the report calls it "cochlear inner hair cell", "Cell types / processes: Inner hair cells"; CL calls it cochlear outer hair cell**UBERON:0002227 (2 mentions) - the report calls it "organ of Corti"; UBERON calls it spiral organ of cochlea, and lists "organ of Corti" among its other namesHP:0000006 (2 mentions) - the report calls it "Autosomal recessive inheritance", "Inheritance: Autosomal recessive"; HP calls it Autosomal dominant inheritance**The report gives these identifiers more than one name of its own:
HGNC:16378 - called "OTOA", "Causal gene:* OTOA"CL:0000601 - called "cochlear inner hair cell", "Cell types / processes:** Inner hair cells"HP:0000407 - called "Sensorineural hearing impairment", "~100% of affected"HP:0008527 - called "Congenital sensorineural hearing impairment", "Predominant presentation"HP:0000006 - called "Autosomal recessive inheritance", "Inheritance:** Autosomal recessive"