Autosomal Dominant Nonsyndromic Hearing Loss 9

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Inheritance

1

Autosomal dominant HP:0000006

Heterozygous COCH variants segregate with progressive hearing loss and variable vestibular dysfunction in multigenerational pedigrees. Most are missense or in-frame variants; a terminal frameshift with experimental multimer formation has also been reported. Penetrance is age dependent and onset varies between and within alleles. A homozygous p.Pro51Ser carrier had earlier onset than most heterozygous relatives. Biallelic inactivating variants usually cause prelingual recessive DFNB110.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:9806553 SUPPORT Human Clinical

"DFNA9 is an autosomal dominant, nonsyndromic, progressive sensorineural hearing loss with vestibular pathology."

The gene-discovery paper's statement of the inheritance mode of the DFNA9 kindreds.

PMID:10400989 SUPPORT Human Clinical

"One of the patients, who had an earlier age of onset in comparison with most of the affected family members, was shown to be homozygous for the mutation."

A single homozygous carrier with earlier onset than heterozygous relatives; this is one individual and does not establish a general dosage effect.

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Pathophysiology

12

Heterozygous COCH Variant

The initiating lesion is a heterozygous germline COCH variant, usually missense or in-frame. The terminal p.Asp544Valfs*3 variant also segregated with hearing loss and produced abnormal multimers in cells despite preserved overall secretion and cell viability. Dominant DFNA9 is not explained by simple haploinsufficiency: heterozygous null mice retained hearing and a human p.Cys50Leufs*8 carrier parent had normal hearing. This auditory dosage evidence does not establish the safety of reducing cochlin for all vestibular functions. Dominant interference and toxic effects have experimental support for selected variants; a universal functional-impact category is not assigned.

COCH hgnc:2180

Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS

collagen binding (cochlin vWFA2 domain) GO:0005518

Downstream

Cochlin Domain Misfolding Selected LCCL substitutions misfold in recombinant-domain assays, while Phe527Cys destabilizes the vWFA2 domain. Trp117Arg is an experimentally observed exception.

Abnormal Cochlin Dimerization and Oligomerization Mutant cochlin promotes abnormal oligomerization and recruitment of wild-type protein in coexpression experiments.

Intracellular Retention of Mutant Cochlin Selected variants impair secretion in transfected cells; this is not universal across DFNA9 alleles.

Impaired Cochlin Proteolytic Processing Selected vWFA2 variants reduce the cleaved C-terminal product in cell culture.

Mutant Cochlin Cytotoxicity Secreted Phe230Leu reduces viability without an observed secretion or cleavage defect.

Defective Cochlin Incorporation into the Extracellular Matrix Secreted mutant proteins show abnormal matrix deposition in cell culture.

Show evidence (8 references)

PMID:22610276 SUPPORT In Vitro

"the mutant monomeric protein bound to collagen type II immobilized on the surface of the sensor chip"

Surface plasmon resonance demonstrates collagen II binding by recombinant F527C vWFA2 protein. The mutation does not eliminate binding; heterogeneous binding kinetics do not justify a uniform activity modifier.

PMID:9806553 SUPPORT Human Clinical

"Here we report three missense mutations in human COCH (previously described as Coch5b2), a novel cochlear gene, in three unrelated kindreds with DFNA9."

Identifies heterozygous COCH missense variants as the cause of DFNA9.

PMID:21073934 SUPPORT Model Organism

"Interestingly Coch(-/+) mice do not show hearing deficits, in contrast to Coch(G88E/+), which demonstrate elevated ABR thresholds similar to homozyotes."

Heterozygous Coch-null mice retain hearing at the tested ages, whereas G88E heterozygotes have elevated ABR thresholds. Late vestibular deficits in null heterozygotes limit extrapolation to all inner-ear functions.

+ 5 more references

Cochlin Domain Misfolding

Selected DFNA9 substitutions destabilize an isolated LCCL or vWFA2 domain. In the recombinant LCCL study, human p.Pro51Ser, p.Val66Gly and p.Gly88Glu equivalents misfolded, but the p.Trp117Arg equivalent folded normally. The isolated construct numbers residues 26 positions earlier than full-length cochlin. Domain misfolding is therefore an allele-dependent observation, not a demonstrated common property of every dominant variant.

protein folding GO:0006457 ⚠ ABNORMAL

Show evidence (3 references)

PMID:11574466 SUPPORT INDIRECT In Vitro

"The unexpected sensitivity of the fold with respect to mutations of solvent-accessible residues might be attributed to interference with the folding pathway of this disulfide-containing domain."

Structural explanation for why surface substitutions in the LCCL domain still misfold it; stated by the authors as a possibility.

PMID:9931344 SUPPORT INDIRECT Human Clinical

"The mutant serine at position 51 is situated between cysteines and possibly interferes with proper COCH protein folding or its interaction with extracellular matrix proteins."

An early proposal, before structural data, for the founder allele; hedged by its authors.

PMID:11574466 SUPPORT In Vitro

"Except for the Trp91Arg mutant, expression of these four LCCL mutants resulted in misfolded proteins."

Direct evidence of allele-dependent folding outcomes; construct Trp91Arg equals full-length Trp117Arg and was the normally folded exception.

Abnormal Cochlin Dimerization and Oligomerization

Selected mutant cochlins form stable dimers and subsequently oligomers in transfected cells. Coexpression experiments show recruitment of wild-type cochlin into these complexes, providing an experimentally supported route to dominant interference. Murine P53S, V68G, G90E and W119R correspond to human P51S, V66G, G88E and W117R. Dimer formation varies by allele; Phe230Leu did not form dimers in a separate assay. Biochemical oligomers are not equivalent to histologically visible patient deposits.

protein complex oligomerization GO:0051259 ⚠ ABNORMAL

Experimental models

Cochlin overexpression and conditioned-medium cell assays CELL LINE Mutant cochlin recruits wild-type protein into stable oligomers.

Show evidence (3 references)

PMID:20228067 SUPPORT In Vitro

"Furthermore, the expression of mutant cochlin eventually induces WT cochlin to form stable oligomers that are resistant to reducing agent."

Coexpression shows incorporation of wild-type cochlin into reducing-agent-resistant oligomers.

PMID:34529116 REFUTE In Vitro

"p.Phe230Leu in vWFA1 domain neither formed a dimer nor decreased C-terminal cleaved cochlin"

Phe230Leu does not share the dimerization phenotype in this assay.

PMID:38255649 SUPPORT In Vitro

"Notably, in the overexpressing study, by transient transfecting the HEK 293T cells, we found that the p.D544Vfs*3 variant increased the formation of multimeric cochlin."

The terminal frameshift also promotes multimerization in an overexpression assay.

Intracellular Retention of Mutant Cochlin

Intracellular retention is observed for a subset of variants. Val104del, Ile109Thr and Phe121Ser were retained as dimers; Cys162Tyr and Ala487Pro failed ER-to-Golgi trafficking in transfected cells. For Phe527Cys, large covalent complexes were retained while monomeric protein was secreted. Phe230Leu secretion was comparable to wild type, so its cytotoxicity is not evidence for retention. The reported association between retained protein and earlier clinical onset is a cross-variant correlation, not a prospective predictor.

protein secretion GO:0009306 ↓ DECREASED

Downstream

Cochlin Aggregate Deposition in the Ear How intracellular aggregates relate to the extracellular deposits seen in temporal bones has not been shown; the authors propose that cochlin trafficking defects underlie the characteristic pathology.

Show evidence (4 references)

PMID:22610276 SUPPORT In Vitro

"Results of immunocytochemistry analysis demonstrated localization of the cochlin mutant in the endoplasmic reticulum/Golgi complex, whereas western blot analyses of cell lysates revealed that the mutant cochlin tends to form covalent complexes that are retained in the cell."

Phe527Cys covalent complexes were retained in ER/Golgi; full-text secretion assays distinguish retained complexes from normally secreted monomer.

PMID:25230692 SUPPORT INDIRECT Human Clinical

"Mutant cochlins that were not secreted and accumulated in cells result in earlier age of onset of hearing defects."

The clinical side of the genotype-phenotype correlation, drawn from published patient data for all 21 then-known alleles against the cell findings.

PMID:12843317 REFUTE In Vitro

"We detected that mutated cochlins are not retained intracellularly, and are able to be secreted adequately by the cells, through the Golgi/ER secretory pathway, and also undergo proteolytic cleavage and glycosylation."

For the three LCCL alleles tested here, intracellular retention does not occur; this limits the node to a subset of alleles rather than refuting it for those shown to be retained.

+ 1 more reference

Impaired Cochlin Proteolytic Processing

Proteolytic processing of cochlin is impaired for selected variants. The C-terminal fragment was almost undetectable for Gly403Cys, Gly447Asp and Phe527Cys in transfected-cell media. Other variants, including Phe230Leu, retained cleavage. Occlusion of aggrecanase cleavage sites by altered protein conformation is proposed but was not directly tested. These experiments do not establish immune dysregulation as a DFNA9 mechanism.

protein processing GO:0016485 ↓ DECREASED

Show evidence (1 reference)

PMID:34529116 SUPPORT In Vitro

"Secreted and cleaved cochlin in culture medium differed among variants, with the C-terminal fragment being almost undetectable with p.Gly403Cys, p.Gly447Asp, and p.Phe527Cys (vWFA2 domain), indicating impaired cleavage of these variants by aggrecanase"

Variant-specific Western blot evidence for reduced proteolytic processing; the proposed structural explanation remains indirect.

Mutant Cochlin Cytotoxicity

Selected mutant cochlins reduce viability or induce cell death in experimental systems. Secreted Phe230Leu conditioned medium reduced NIH3T3 viability despite normal secretion and cleavage. In a separate study, mutant murine cochlin induced death and caspase-3 activation in UB/UE1 inner-ear cells, and mutant conditioned medium reduced primary cochlear fibrocyte viability. Effects depended on the cell system: HeLa and 293T cells did not show the same death response. An acute intracochlear exposure model caused spiral-ligament fibrocyte loss and transiently elevated auditory thresholds; it does not reproduce lifelong endogenous expression.

Experimental models

Cochlin overexpression and conditioned-medium cell assays CELL LINE Mutant-dependent viability effects occur in selected recipient-cell systems.

Animal models

Acute intracochlear mutant-cochlin conditioned-medium exposure Mouse partially recapitulates Acute local exposure reproduces cochlear toxicity.

Downstream

Loss of Spiral Ligament and Spiral Limbus Fibrocytes Acute intracochlear mutant conditioned-medium exposure caused spiral-ligament fibrocyte damage in mice. Spiral-limbus fibrocytes were largely spared; extension to the broader human lesion is incomplete.

Show evidence (3 references)

PMID:34529116 SUPPORT In Vitro

"As a result, only p.Phe230Leu significantly decreased cell survival"

Conditioned medium from cochlin-expressing HEK293 cells was applied to NIH3T3 cells; reduced MTT survival is distinct from retention in producer cells.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2865277/ SUPPORT In Vitro

"expression of mutant cochlin or WT and mutant cochlins together but not WT cochlin alone in differentiated UB/UE-1 cells induced cell death associated with activation of caspase-3"

The cultured inner-ear-cell result is distinct from the separately cited acute mouse cochlear exposure experiment.

PMID:38255649 REFUTE In Vitro

"As shown in Figure 4f, cell viability was not significantly lower in mutant-COCH-transfected cells compared with those in wild-type cells."

The Asp544Valfs*3 HEK293T assay did not show reduced viability, limiting generalization of cytotoxicity.

Defective Cochlin Incorporation into the Extracellular Matrix

Secreted mutant cochlins differ from wild type in how much, and in what pattern, they are deposited into cell-derived extracellular matrix; some are deposited almost normally and some not at all. The authors propose impaired self-assembly or impaired complex formation with other matrix components.

extracellular matrix organization GO:0030198 ⚠ ABNORMAL

Downstream

Cochlin Aggregate Deposition in the Ear Proposed rather than shown: secreted mutant cochlin may aggregate in vivo over a long time course, consistent with late onset.

Show evidence (1 reference)

PMID:12928864 SUPPORT INDIRECT In Vitro

"Our results suggest that DFNA9 results from gene products that fail to integrate correctly into the extracellular matrix."

The authors' conclusion from abnormal matrix deposition of secreted LCCL mutants.

Cochlin Aggregate Deposition in the Ear

The histological hallmark of DFNA9: acellular, homogeneous eosinophilic deposits in the spiral ligament, spiral limbus, distal osseous spiral lamina and the stroma beneath the vestibular neuroepithelium, which immunostain for cochlin. All examined DFNA9 temporal bones also carried deposits in the tympanic membrane and the incudomalleal and incudostapedial joints, and one patient with a vWFA2 variant had cochlin aggregates in both external auditory canals. The composition of deposits varies with site.

spiral ligament UBERON:0006725 osseous spiral lamina UBERON:0006724 crista ampullaris UBERON:0004721

Animal models

Coch G88E knock-in mouse Mouse partially recapitulates Middle ear interossicular deposits form as in humans; tympanic membrane thickening was not seen at the age examined.

Downstream

Loss of Spiral Ligament and Spiral Limbus Fibrocytes Deposits occupy the regions from which the COCH-expressing fibrocytes are lost. The temporal bones show the two together; which comes first is not established.

Degeneration of Spiral Ganglion Dendrites in the Osseous Spiral Lamina Deposits extend into the distal osseous spiral lamina, where the afferent dendrites degenerate; a direct mechanical or toxic effect on the dendrites has not been shown.

Vestibular End-Organ Dysfunction Deposits in the stroma beneath the vestibular neuroepithelium accompany the vestibular failure; the intervening steps are not known.

Middle ear ossicular joint deposits The same deposition process extends to the incudomalleal and incudostapedial joints.

Tympanic membrane deposits Deposits are also found in the pars tensa of the tympanic membrane.

External auditory canal stenosis from cochlin aggregates In one reported patient, cochlin aggregates with amyloid-like foci thickened the subcutaneous tissue of both external auditory canals.

Semicircular canal sclerosis and narrowing The radiological canal lesions appear late and are proposed to be the end stage of protein deposition or low-grade inflammation; this is a hypothesis.

Vestibular Neural Degeneration Vestibular deposits and dendritic degeneration co-occurred; a toxic or mechanical causal step has not been demonstrated.

Show evidence (2 references)

PMID:16481359 SUPPORT Human Clinical

"DFNA9 is an inner ear disorder with a unique histopathology showing loss of cellularity and aggregation of abundant homogeneous acellular eosinophilic deposits in the cochlear and vestibular labyrinths, similar to protein aggregation in well-known neurodegenerative disorders."

Describes the characteristic deposits in a p.Pro51Ser temporal bone.

PMID:9806553 SUPPORT Human Clinical

"These areas correspond to human inner ear structures which show histopathological findings of acidophilic ground substance in DFNA9 patients."

Links the sites of COCH expression to the sites of the deposits.

Loss of Spiral Ligament and Spiral Limbus Fibrocytes

The fibrocytes of the spiral ligament and spiral limbus, and the stromal cells of the crista ampullaris, are where COCH is expressed. In affected temporal bones these cells are absent or markedly reduced. Cochlin remains abundant in the tissue even where the fibrocytes that made it have atrophied. The functional consequence of fibrocyte loss for cochlear homeostasis in DFNA9 has not been measured, so no edge is drawn from this node to the hearing phenotype.

spiral ligament fibrocyte CL:0020005

spiral ligament UBERON:0006725

Show evidence (2 references)

PMID:11709536 SUPPORT Human Clinical

"By in situ hybridization of mouse and human inner ear sections, we find high-level expression of COCH mRNA in the fibrocytes of the spiral limbus and of the spiral ligament in the cochlea, and in the fibrocytes of the connective tissue stroma underlying the sensory epithelium of the crista..."

Identifies the COCH-expressing cell populations.

PMID:16481359 SUPPORT Human Clinical

"The high-level expression and stability of cochlin in the inner ear, even in the absence and severe atrophy of the fibrocytes that normally express COCH, are shown through these studies"

Records fibrocyte atrophy in a p.Pro51Ser temporal bone together with persistent cochlin.

Degeneration of Spiral Ganglion Dendrites in the Osseous Spiral Lamina

Bilateral temporal bones from one 42-year-old p.Leu114Pro carrier with residual hearing showed marked degeneration of spiral-ganglion dendrites in the osseous spiral lamina. The left spiral-ganglion cell count was 53% of age-matched normal values, but distal dendritic loss was more extensive than loss of neuronal somata or sensory hair cells. This single-patient histological correlation supports a peripheral neural contribution to hearing loss. Postmortem artifact and previous lymphoma treatment limit attribution of every finding to DFNA9.

spiral ganglion neuron CL:0011113

osseous spiral lamina UBERON:0006724

Downstream

Adult-onset progressive sensorineural hearing loss Dendrite degeneration is the histological correlate of the measured hearing loss in the examined bone.

Show evidence (2 references)

PMID:27023102 SUPPORT Human Clinical

"In addition, it is the only case with otopathology characterization in an individual with any COCH mutation and residual hearing, thus allowing assessment of primary histopathological events in DFNA9, before progression to more profound hearing loss."

Residual hearing in one patient made these bilateral specimens informative about degeneration before end-stage deafness.

PMID:27023102 SUPPORT Human Clinical

"The total spiral ganglion cell count was 14,279, which represented 53% of normal age-matched controls."

Quantified neuronal soma loss in the left temporal bone; distal dendritic loss was more extensive.

Vestibular Neural Degeneration

The p.Leu114Pro temporal-bone study demonstrated degeneration of distal vestibular dendrites and reduced vestibular ganglion cells. The left Scarpa ganglion cell count was 56% of age-matched controls. Mild-to-moderate atrophy also affected canal and otolith neuroepithelium. The patient reported no vestibular symptoms, showing that tissue degeneration and perceived imbalance need not coincide.

vestibular ganglion UBERON:0002824

Downstream

Vestibular End-Organ Dysfunction Neural and sensory epithelial degeneration provide an anatomical basis for vestibular dysfunction, but this patient had no reported vestibular symptoms.

Show evidence (2 references)

PMID:27023102 SUPPORT Human Clinical

"Degeneration of distal vestibular dendritic fibers at the base of the neuroepithelium was demonstrated using anti-neurofilament immunostaining"

Human histological evidence for distal vestibular neuronal degeneration.

PMID:27023102 SUPPORT Human Clinical

"The total Scarpa’s ganglion cell count was 11,288, which represented 56% of normal age-match controls."

Quantification in the left temporal bone from one carrier.

Vestibular End-Organ Dysfunction

Vestibular canal and otolith responses decline variably with age. In the p.Pro51Ser cross-sectional study, cervical VEMP abnormalities generally appeared before caloric and head-impulse abnormalities, but estimated timing depended on test, canal and analytic approach. Water and air caloric amplitudes are not interchangeable. Auditory versus vestibular onset order differs between cohorts and reference methods. LCCL variants commonly involve vestibular function, but domain location does not reliably predict an individual course.

crista ampullaris UBERON:0004721 macula of utricle of membranous labyrinth UBERON:0002214

Animal models

Coch G88E knock-in mouse Mouse recapitulates Vestibular dysfunction precedes auditory dysfunction in this model; human sequence varies by cohort and test.

Downstream

Progressive bilateral vestibular hypofunction The end-organ failure is measured clinically as bilaterally reduced vestibular responses.

Vestibular areflexia Continued decline ends in absent responses.

Oscillopsia Loss of the vestibulo-ocular reflex removes gaze stabilization during head movement; oscillopsia is head-movement dependent in the reported patient.

Postural instability in the dark Without vestibular input, balance depends on vision and proprioception and fails when vision is removed.

Episodic vertigo Attacks of vertigo arise from the diseased labyrinth, but why some carriers have Menière-like attacks and others a silent decline is not explained.

Show evidence (4 references)

PMID:18697796 SUPPORT Model Organism

"These results suggest that vestibular function is affected beginning as early as 11 months when cochlear function appears to be normal, and dysfunction increases with age."

Vestibular dysfunction precedes cochlear dysfunction in the G88E knock-in mouse.

PMID:16151338 SUPPORT Human Clinical

"Vestibular impairment starts earlier, progresses more rapidly, and, eventually, is more complete than hearing impairment in P51S COCH mutation carriers."

The human counterpart in 74 p.Pro51Ser carriers.

PMID:34369417 REFUTE Human Clinical

"Hearing deterioration started earlier than vestibular deterioration in female carriers, which is different from earlier reports."

Qualifies the "vestibular first" sequence: in the larger 2021 series it did not hold for female carriers. The node itself (vestibular failure) is not in doubt; the timing relative to hearing is.

+ 1 more reference

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Histopathology

2

Cochlin-positive acellular eosinophilic inner-ear deposits

Homogeneous acellular deposits in cochlear and vestibular connective tissues stain for cochlin and occur with loss of the resident fibrocytes. Eosinophilic or amyloid-like morphology does not by itself establish conventional amyloid composition.

Show evidence (2 references)

PMID:16481359 SUPPORT Human Clinical

"DFNA9 is an inner ear disorder with a unique histopathology showing loss of cellularity and aggregation of abundant homogeneous acellular eosinophilic deposits in the cochlear and vestibular labyrinths, similar to protein aggregation in well-known neurodegenerative disorders."

Describes the characteristic deposits in a p.Pro51Ser temporal bone.

PMID:16481359 SUPPORT Human Clinical

"The high-level expression and stability of cochlin in the inner ear, even in the absence and severe atrophy of the fibrocytes that normally express COCH, are shown through these studies"

Records fibrocyte atrophy in a p.Pro51Ser temporal bone together with persistent cochlin.

Peripheral cochlear and vestibular neuronal degeneration

The bilateral temporal bones from one p.Leu114Pro carrier with residual hearing showed prominent distal cochlear and vestibular dendritic degeneration with reduced spiral and vestibular ganglion cells. This single-patient observation is not a universal quantitative estimate.

Show evidence (2 references)

PMID:27023102 SUPPORT INDIRECT Human Clinical

"A quantitative cytologic analysis of atrophy in this specimen and immunostaining using anti-neurofilament and anti-myelin protein zero antibodies confirmed that the principal histopathologic correlate of hearing loss was degeneration of the dendritic fibers of spiral ganglion cells in the..."

Histological correlation in bilateral temporal bones from one patient, not an experimental demonstration of causality.

PMID:27023102 SUPPORT Human Clinical

"Degeneration of distal vestibular dendritic fibers at the base of the neuroepithelium was demonstrated using anti-neurofilament immunostaining"

Human histological evidence for distal vestibular neuronal degeneration.

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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

15

Ear 13

Adult-onset progressive sensorineural hearing loss Adult onset sensorineural hearing impairment HP:0008615

Course: PROGRESSIVE

Show evidence (6 references)

PMID:9806553 SUPPORT Human Clinical

"DFNA9 is an autosomal dominant, nonsyndromic, progressive sensorineural hearing loss with vestibular pathology."

Defining clinical feature.

PMID:34369416 SUPPORT Human Clinical

"Hearing dysfunction in p.P51S carriers begins at about 38 years of age (ranging from 28 to 43 years) on average in female and 46 years (ranging from 42 to 49 years) in male carriers"

Onset ages from 111 Belgian and Dutch p.Pro51Ser carriers.

PMID:11843927 SUPPORT Human Clinical

"Pure-tone thresholds deteriorated by about 2-7 dB per year (mean 3.8 dB per year) in a variable, often asymmetrical, fashion."

Rate of progression in a longitudinally followed Dutch family (14 genotyped).

+ 3 more references

Childhood or prelingual sensorineural hearing loss Sensorineural hearing impairment HP:0000407

Onset: CHILDHOOD

Show evidence (1 reference)

PMID:42195045 SUPPORT Human Clinical

"In addition, one family carrying the p.Phe121Ser variant exhibits clearly early-onset hearing loss, beginning between 8 and 22 years of age, and even prelingual in two individuals."

Observed early onset within a specific Phe121Ser family; not a frequency estimate for all DFNA9.

High-frequency predominant hearing loss High-frequency sensorineural hearing impairment HP:0001757

Show evidence (2 references)

PMID:10891988 SUPPORT Human Clinical

"Hearing impairment started unilaterally, predominantly in the high frequencies."

Single-patient follow-up.

PMID:10891988 SUPPORT Human Clinical

"Disease progressed to severe bilateral high-frequency hearing impairment and vestibular areflexia."

The same patient later.

Profound hearing loss in late disease Profound sensorineural hearing impairment HP:0011476

Show evidence (2 references)

PMID:30806805 SUPPORT REVIEW SYNTHESIS Human Clinical

"Profound SNHL was observed at 76 years on average (60-84 years)."

Pooled estimate from eleven p.Pro51Ser genotype-phenotype studies.

PMID:14501450 SUPPORT Human Clinical

"All patients developed late-onset progressive sensorineural hearing loss eventually leading to severe deafness and vestibular failure."

Outcome in a multigeneration Belgian p.Pro51Ser family.

Impaired speech discrimination Abnormal speech discrimination HP:0001963

Show evidence (1 reference)

PMID:39864432 SUPPORT Human Clinical

"Differences between carriers and control participants seem evident in the third decade of life and become more pronounced in the decades that follow."

Longitudinally assessed p.Pro51Ser cohort; the age curves also combine cross-sectional observations.

Progressive bilateral vestibular hypofunction Vestibular hyporeflexia HP:0001756

Course: PROGRESSIVE

Show evidence (3 references)

PMID:34369417 SUPPORT Human Clinical

"BVP was predicted at about 53 years of age on average with VNG caloric gain (water irrigation) and between 47 and 57 years of age for the three SCCs."

Cross-sectional modeled ages for reaching test-specific bilateral vestibulopathy thresholds; water caloric values cannot be generalized to air stimulation.

PMID:38093757 SUPPORT Human Clinical

"COCH mutation is the most common non-idiopathic cause of BV in our population."

Three tertiary centres in Belgium, the Netherlands and Switzerland, where the p.Pro51Ser founder allele is common; not a general population estimate.

PMID:25230692 SUPPORT Human Clinical

"In addition, individuals with LCCL domain mutations show accompanying vestibular dysfunction, whereas those with vWFA domain mutations exhibit predominantly hearing loss."

Historical domain-associated tendency, with variability between alleles and limited individual predictive value.

Vestibular areflexia HP:0008568

Show evidence (2 references)

PMID:11843927 SUPPORT Human Clinical

"More advanced stages of vestibular impairment, i.e. vestibular hyporeflexia and complete vestibular areflexia, were eventually found in a number of cases."

Progression to areflexia in a Dutch p.Pro51Ser family.

PMID:16151339 SUPPORT Human Clinical

"Remarkably, the proportion of patients who developed complete vestibular areflexia within the age range of 40 to 56 years was significantly lower for the G88E mutation carriers than for the P51S mutation carriers."

Allele-dependent frequency of areflexia in mid-life.

Episodic vertigo Paroxysmal vertigo HP:0010532

Temporal: RECURRENT

Show evidence (2 references)

PMID:10400989 SUPPORT Human Clinical

"In all three families with hearing loss and imbalance problems, >25% of the patients showed additional symptoms, including episodes of vertigo, tinnitus, aural fullness and hearing loss."

One Belgian and two Dutch families.

PMID:11843927 SUPPORT Human Clinical

"One mutation carrier developed recurrent episodes of vertigo accompanied by nausea and vomiting, resembling Ménière's disease."

A single carrier in a family of 14 genotyped members.

Tinnitus HP:0000360

Show evidence (1 reference)

PMID:10400989 SUPPORT Human Clinical

"In all three families with hearing loss and imbalance problems, >25% of the patients showed additional symptoms, including episodes of vertigo, tinnitus, aural fullness and hearing loss."

Tinnitus among the episodic symptoms in the three families.

Semicircular canal sclerosis and narrowing Abnormal semicircular canal morphology HP:0011380

Show evidence (3 references)

PMID:24662630 SUPPORT Human Clinical

"In 8 of them similar sclerotic lesions and/or narrowing were demonstrated in one or more semicircular canals on computed tomography CT scan, with a signal loss at corresponding areas on T2-weighted magnetic resonance (MR) images."

First description, nine p.Pro51Ser patients.

PMID:31998212 SUPPORT Human Clinical

"In our population, 91% of tested ears had sclerotic lesions and/or narrowing in one or more SCCs on CT scan."

The 45-patient cohort included 90 potential ears, but only 23 had CT; the quoted 91% is 21 of 23 tested ears.

PMID:39271588 SUPPORT Human Clinical

"Signal loss in at least one SCCs was detected in 97.7% of subjects"

43 of 44 imaged recipients. The cohort included 29 confirmed p.Pro51Ser carriers, one p.Gly88Glu carrier and 15 without an available specific genotype.

Middle ear ossicular joint deposits Abnormality of the middle ear ossicles HP:0004452

Show evidence (1 reference)

PMID:21052762 SUPPORT Human Clinical

"All temporal bones with DFNA9 had abnormal deposits within the tympanic membrane, incudomalleal joint, and incudostapedial joint."

Twelve temporal bones from seven affected individuals.

Tympanic membrane deposits Abnormal tympanic membrane morphology HP:0040090

Show evidence (1 reference)

PMID:21052762 SUPPORT Human Clinical

"The deposits within the tympanic membrane resembled cartilage morphologically and stained positively for aggrecan, an extracellular matrix protein found in cartilage."

Characterizes the tympanic membrane deposits.

External auditory canal stenosis from cochlin aggregates Stenosis of the external auditory canal HP:0000402

Show evidence (1 reference)

PMID:31493294 SUPPORT Human Clinical

"A 54-year-old woman presented with progressive sensorineural hearing loss and bilateral EAC narrowing by subcutaneous thickening."

Single case report.

Eye 1

Oscillopsia HP:0034773

Show evidence (1 reference)

PMID:10891988 SUPPORT Human Clinical

"He suffered from instability in the dark, head movement-dependent oscillopsia, paroxysmal positional vertigo, and vertigo with and without nausea."

Single-patient report.

Nervous System 1

Postural instability in the dark HP:0002172

Show evidence (1 reference)

PMID:10891988 SUPPORT Human Clinical

"He suffered from instability in the dark, head movement-dependent oscillopsia, paroxysmal positional vertigo, and vertigo with and without nausea."

Single-patient report.

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Genetic Associations

1

COCH (Causal)

Gene: COCH hgnc:2180

Show evidence (3 references)

PMID:9806553 SUPPORT Human Clinical

"Here we report three missense mutations in human COCH (previously described as Coch5b2), a novel cochlear gene, in three unrelated kindreds with DFNA9."

Gene discovery.

PMID:9931344 SUPPORT Human Clinical

"Sequence analysis revealed a 208C-->T mutation in the COCH gene, resulting in a Pro51Ser substitution in the predicted protein in all affected individuals of the family but not in unaffected family members and 200 control individuals."

Segregation and control absence for the p.Pro51Ser allele.

PMID:33815940 SUPPORT BACKGROUND Human Clinical

"The c.151C>T founder mutation in COCH is a frequent cause of late-onset, dominantly inherited hearing impairment and vestibular dysfunction (DFNA9) in the Dutch/Belgian population."

Founder status of p.Pro51Ser; background sentence in an in vitro therapy paper. The cDNA numbering (c.151C>T) and the older 208C>T refer to the same variant.

Variants (6)

COCH p.Pro51Ser

Gene: COCH hgnc:2180

Dutch/Belgian founder allele, currently described as c.151C>T; the original report used older nucleotide numbering. It is associated with age-dependent hearing and vestibular impairment. Sequence-specific antisense experiments use this allele.

Show evidence (2 references)

PMID:9931344 SUPPORT Human Clinical

"Sequence analysis revealed a 208C-->T mutation in the COCH gene, resulting in a Pro51Ser substitution in the predicted protein in all affected individuals of the family but not in unaffected family members and 200 control individuals."

Segregation and control absence for the p.Pro51Ser allele.

PMID:33815940 SUPPORT BACKGROUND Human Clinical

"The c.151C>T founder mutation in COCH is a frequent cause of late-onset, dominantly inherited hearing impairment and vestibular dysfunction (DFNA9) in the Dutch/Belgian population."

Founder status of p.Pro51Ser; background sentence in an in vitro therapy paper. The cDNA numbering (c.151C>T) and the older 208C>T refer to the same variant.

COCH p.Gly88Glu

Gene: COCH hgnc:2180

LCCL variant associated with progressive hearing and vestibular impairment. Complete vestibular areflexia in midlife was less frequent than in the compared p.Pro51Ser group. G88E knock-in mice reproduce late functional deficits incompletely.

Show evidence (1 reference)

PMID:16151339 SUPPORT Human Clinical

"Remarkably, the proportion of patients who developed complete vestibular areflexia within the age range of 40 to 56 years was significantly lower for the G88E mutation carriers than for the P51S mutation carriers."

Allele-dependent frequency of areflexia in mid-life.

COCH p.Phe121Ser

Gene: COCH hgnc:2180

An LCCL variant retained intracellularly in overexpression assays. Onset varies between families: second or third decade in an American pedigree, with childhood and two prelingual cases in a French pedigree.

Show evidence (2 references)

PMID:21046548 SUPPORT Human Clinical

"The onset of the hearing loss, in the 2nd or 3rd decade of life, is earlier than in most DFNA9 families."

An earlier-onset LCCL allele (p.Phe121Ser) in an American family.

PMID:42195045 SUPPORT Human Clinical

"In addition, one family carrying the p.Phe121Ser variant exhibits clearly early-onset hearing loss, beginning between 8 and 22 years of age, and even prelingual in two individuals."

Observed early onset within a specific Phe121Ser family; not a frequency estimate for all DFNA9.

COCH p.Phe230Leu

Gene: COCH hgnc:2180

A vWFA1 variant whose secretion and cleavage were comparable to wild type. Secreted conditioned medium reduced NIH3T3 viability; retention and dimerization were not observed in this study.

Show evidence (1 reference)

PMID:34529116 SUPPORT In Vitro

"While its secretion and cleavage are comparable to wild-type cochlin, p.Phe230Leu is cytotoxic."

Mechanistic distinction from retained or poorly cleaved mutants.

COCH p.Phe527Cys

Gene: COCH hgnc:2180

A vWFA2 variant destabilizing the domain and promoting covalent complexes. Large complexes were retained while monomeric protein was secreted. Collagen II binding persisted; another assay found reduced C-terminal cleavage.

Show evidence (3 references)

PMID:22610276 SUPPORT In Vitro

"Results of immunocytochemistry analysis demonstrated localization of the cochlin mutant in the endoplasmic reticulum/Golgi complex, whereas western blot analyses of cell lysates revealed that the mutant cochlin tends to form covalent complexes that are retained in the cell."

Phe527Cys covalent complexes were retained in ER/Golgi; full-text secretion assays distinguish retained complexes from normally secreted monomer.

PMID:22610276 SUPPORT In Vitro

"the mutant monomeric protein bound to collagen type II immobilized on the surface of the sensor chip"

Surface plasmon resonance demonstrates collagen II binding by recombinant F527C vWFA2 protein. The mutation does not eliminate binding; heterogeneous binding kinetics do not justify a uniform activity modifier.

PMID:34529116 SUPPORT In Vitro

"Secreted and cleaved cochlin in culture medium differed among variants, with the C-terminal fragment being almost undetectable with p.Gly403Cys, p.Gly447Asp, and p.Phe527Cys (vWFA2 domain), indicating impaired cleavage of these variants by aggrecanase"

Variant-specific Western blot evidence for reduced proteolytic processing; the proposed structural explanation remains indirect.

COCH p.Asp544Valfs*3

Gene: COCH hgnc:2180

A terminal frameshift reported in a Chinese family with hearing loss and limited vestibular findings. The mutant protein formed multimers in HEK293T cells without significant loss of overall secretion or cell viability. Predicted effects on cleavage were not measured; a general loss-of-function mechanism is not established.

Show evidence (2 references)

PMID:38255649 SUPPORT Human Clinical

"The proband presented mild vestibular symptoms and normal functional assessment results in almost every test, while the variant co-segregated with hearing impairment in the pedigree."

Family segregation and clinical observations.

PMID:38255649 SUPPORT In Vitro

"Notably, in the overexpressing study, by transient transfecting the HEK 293T cells, we found that the p.D544Vfs*3 variant increased the formation of multimeric cochlin."

Cell experiments demonstrate multimer formation; no nonsense-mediated decay mechanism is assumed.

💊

Medical Actions

8

Hearing aids

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

Platform: Device

Conventional amplification provides auditory rehabilitation. Cross-sectional p.Pro51Ser audiograms predict when threshold-based candidacy may arise, but decisions also depend on aided speech performance and individual needs; a modeled age is not a treatment rule.

Target Phenotypes: Adult onset sensorineural hearing impairment HP:0008615

Show evidence (1 reference)

PMID:34369416 SUPPORT Human Clinical

"At about 48 to 50 years of age on average, the majority of DFNA9 patients may need conventional hearing aids (PTA ≥ 40 dB HL), whereas this is about 56 to 59 years for cochlear implants (PTA ≥ 70 dB HL)."

Predicted timing of amplification and implant candidacy from audiometric thresholds.

Cochlear implantation

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

Platform: Device

For severe to profound loss. In a retrospective comparison of 56 p.Pro51Ser recipients with matched postlingually deafened controls, speech perception and quality of life improved similarly and remained stable to five years; better preoperative aided speech perception predicted better outcome, which the authors read as favouring earlier implantation. The association with preoperative performance does not prove that earlier implantation causes better outcomes.

Target Phenotypes: Profound sensorineural hearing impairment HP:0011476

Show evidence (2 references)

PMID:42259506 SUPPORT Human Clinical

"CI provides durable, noninferior outcomes in DFNA9 patients compared with controls."

Retrospective cohort, 56 DFNA9 recipients versus matched controls.

PMID:39271588 SUPPORT Human Clinical

"The phoneme scores significantly improved from 35% (IQR 11-50) pre-implantation to 84% (IQR 76-90) one year post-implantation."

45 DFNA9 recipients (49 ears).

Allele-specific antisense oligonucleotide knockdown of p.Pro51Ser COCH

Action: Pharmacotherapy NCIT:C15986

Platform: Antisense oligonucleotide RNase H knockdown

RNA target: COCH hgnc:2180 mutant COCH mRNA carrying c.151C>T (p.Pro51Ser)

Experimental RNase H1 gapmer antisense oligonucleotides reduced mutant COCH transcripts in inducible Flp-In T-REx293 minigene cell lines. At 25 nM the lead mutation-targeting AON reduced mutant transcript by 60% without a significant wild-type reduction; specificity decreased at higher doses. Intronic haplotype markers were alternative allele-selective targets, not pathogenic regulatory variants. No hearing rescue was measured. Inner-ear delivery, durability and safety remain unresolved; preserved hearing in heterozygous null animals does not guarantee preserved vestibular function after knockdown.

Mechanism Target:

Heterozygous COCH Variant — Allele-selective transcript degradation aims to reduce production of mutant cochlin. This is a preclinical intervention on the initiating genetic mechanism, not a demonstrated human treatment.

Show evidence (4 references)

PMID:33815940 SUPPORT In Vitro

"The most potent AON, directed against the c.151C>T mutation, was able to induce a 60% decrease in mutant COCH transcripts without affecting wild-type COCH transcript levels."

Minigene-expressing cells only.

PMID:33815940 SUPPORT In Vitro

"Allele specificity decreased when increasing concentrations of AON were delivered to the cells."

Dose-dependent loss of selectivity, a limitation of the approach.

PMID:38218018 SUPPORT INDIRECT Model Organism

"We established a genomically humanized mouse model for the Dutch/Belgian c.151C>T founder mutation in COCH."

A genomically humanized p.Pro51Ser model intended for sequence-specific therapy testing; the cited study describes model construction and normal hearing through nine months, not treatment efficacy.

+ 1 more reference

Meclizine for episodic vertigo

Action: Pharmacotherapy NCIT:C15986

Agent: Meclizine CHEBI:6709

Platform: Small molecule

Reported symptomatic treatment in the p.Phe121Ser family. Vertigo treatment with these agents and dietary salt restriction had minimal success; this report does not establish efficacy or support chronic prophylactic use.

Target Phenotypes: Paroxysmal vertigo HP:0010532

Show evidence (1 reference)

PMID:21046548 REFUTE Human Clinical

"The vertiginous symptoms are in the form of frequent but intermittent attacks that have been treated with antivert, diuretics, hydrochlorothiazide, valium or dietary salt restriction with minimal success."

Direct family report of attempted treatment with minimal benefit; not a controlled treatment comparison.

Hydrochlorothiazide for episodic vertigo

Action: Pharmacotherapy NCIT:C15986

Agent: hydrochlorothiazide CHEBI:5778

Platform: Small molecule

Reported symptomatic treatment in the p.Phe121Ser family. Vertigo treatment with these agents and dietary salt restriction had minimal success; this report does not establish efficacy or support chronic prophylactic use.

Target Phenotypes: Paroxysmal vertigo HP:0010532

Show evidence (1 reference)

PMID:21046548 REFUTE Human Clinical

"The vertiginous symptoms are in the form of frequent but intermittent attacks that have been treated with antivert, diuretics, hydrochlorothiazide, valium or dietary salt restriction with minimal success."

Direct family report of attempted treatment with minimal benefit; not a controlled treatment comparison.

Diazepam for episodic vertigo

Action: Pharmacotherapy NCIT:C15986

Agent: diazepam CHEBI:49575

Platform: Small molecule

Reported symptomatic treatment in the p.Phe121Ser family. Vertigo treatment with these agents and dietary salt restriction had minimal success; this report does not establish efficacy or support chronic prophylactic use.

Target Phenotypes: Paroxysmal vertigo HP:0010532

Show evidence (1 reference)

PMID:21046548 REFUTE Human Clinical

"The vertiginous symptoms are in the form of frequent but intermittent attacks that have been treated with antivert, diuretics, hydrochlorothiazide, valium or dietary salt restriction with minimal success."

Direct family report of attempted treatment with minimal benefit; not a controlled treatment comparison.

Balance rehabilitation and environmental adaptations

Action: Rehabilitation NCIT:C15315

Platform: Behavioral / lifestyle

Supportive care addresses mobility, visual compensation and fall hazards. A mixed vestibular-hypofunction survey, including 56 respondents reporting DFNA9 among 122 who specified an etiology, described assistive devices, improved lighting and activity adaptations. These patient-reported strategies and physiotherapy context support individualized rehabilitation planning, not a demonstrated DFNA9-specific treatment effect.

Target Phenotypes: Postural instability HP:0002172

Show evidence (2 references)

PMID:38234975 SUPPORT Human Clinical

"The participants coped with their daily struggles by investing in assistive products and technology, like adapted bikes, special footwear, walking frames."

Mixed-etiology, self-reported survey including DFNA9; no controlled efficacy estimate.

PMID:38234975 SUPPORT Human Clinical

"They described the importance of ensuring minimal light intensity for visibility (i.e., installing light sources in dark places)."

Environmental adaptation reported by patients with chronic vestibular hypofunction.

Investigational combined vestibular and cochlear implantation

Action: Vestibular and cochlear electrode implantation Ontology label: Surgical Procedure NCIT:C15329

Platform: Device

Combined implantation is being studied for severe peripheral bilateral vestibulopathy with implant-eligible hearing loss. In three DFNA9 participants, surgical probing, removal or bypass of canal obstruction enabled electrode placement. Two patients had electrically evoked vertical vestibulo-ocular responses and perception; one had perception without measurable vestibulo-ocular reflex responses. This supports feasibility in selected patients, not established benefit for all DFNA9.

Mechanism Target:

Vestibular End-Organ Dysfunction — Electrical stimulation aims to bypass deficient vestibular sensory transduction; clinical efficacy remains under investigation.

Show evidence (1 reference)

PMID:39743754 SUPPORT Human Clinical

"In all patients, the electrodes could be implanted in the semicircular canal ampullae."

Three selected DFNA9 patients with semicircular-canal obstruction; the full text distinguishes electrode placement from variable evoked responses.

🔬

Diagnosis

4

Pure-tone and speech audiometry

Serial pure-tone and speech audiometry documents hearing and communication function. Age-referenced pure-tone models estimate population trajectories but do not by themselves establish hearing-aid or implant eligibility. Speech-in-noise testing can reveal functional difficulty while conventional thresholds remain relatively preserved.

audiometric test NCIT:C38036

Show evidence (2 references)

PMID:34369416 SUPPORT Human Clinical

"Their hearing thresholds were compared with p50th, p95th, and p97.5th percentile values of presbyacusis (ISO 7029 standards)."

Onset is judged by comparing pure-tone thresholds against age-referenced presbyacusis norms.

PMID:39864432 SUPPORT Human Clinical

"Differences between carriers and control participants seem evident in the third decade of life and become more pronounced in the decades that follow."

Longitudinally assessed p.Pro51Ser cohort; the age curves also combine cross-sectional observations.

Vestibular function testing

Caloric testing, video head impulse testing and cervical or ocular VEMPs assess complementary canal and otolith functions. Test-dependent onset estimates in p.Pro51Ser carriers should not be treated as an invariant sequence. Air-caloric responses cannot be interpreted using the same amplitude threshold as water calorics.

Show evidence (1 reference)

PMID:34369417 SUPPORT Human Clinical

"With the categorical approach, otolith function was declining first (3rd decade), followed by caloric response (5th decade) and vHIT VOR-gains (5th-6th decade)."

Which vestibular test becomes abnormal first.

Temporal bone MRI

T2-weighted MRI can identify semicircular-canal narrowing or fluid-signal loss in advanced DFNA9. In the selected p.Pro51Ser cohort, all 38 MRI-tested ears were abnormal. CT detects a partly overlapping sclerotic or narrowed component. Imaging is useful for implant planning; prediction of future vestibular decline remains unvalidated. Delayed contrast enhancement without hydrops was observed in a four-patient series; a later single case had unilateral utricular hydrops during sudden hearing deterioration, so hydrops is neither established as universal nor excluded in DFNA9.

magnetic resonance imaging NCIT:C16809

Show evidence (4 references)

PMID:31998212 SUPPORT Human Clinical

"All tested ears had narrowing or signal loss in at least one SCC on T2-weighted MRI."

38 MRI-tested ears within a 45-person cohort, not all 90 potential ears.

PMID:31998212 SUPPORT Human Clinical

"CT abnormalities correlated with hypofunction of caloric responses."

CT correlation in the tested subset; later MRI work did not establish a consistent association with vHIT function.

PMID:31390618 SUPPORT Human Clinical

"None of the patients showed a significant vestibular and cochlear endolymphatic hydrops at MRI, while high bilateral contrast enhancement on 4-h delayed postcontrast 3D FLAIR sequence was observed in all ears."

Four patients (three related), eight ears; delayed enhancement suggests altered barrier permeability but does not directly measure it.

+ 1 more reference

COCH sequencing

A heterozygous pathogenic COCH variant supports DFNA9 in a compatible phenotype. Usually adult onset and cochleovestibular involvement are useful clues, but childhood cases and hearing-predominant alleles occur. Interpret variant consequence rather than class alone: biallelic inactivation causes DFNB110, whereas a terminal frameshift can retain protein production and form abnormal multimers.

genetic testing NCIT:C15709

Show evidence (2 references)

PMID:11843927 SUPPORT Human Clinical

"DFNA9/COCH should be considered as a possible cause in patients developing combined progressive cochlear and vestibular impairment, or suspected hereditary Ménière-like disease, from around middle age."

The clinical presentation that should prompt COCH testing.

PMID:32939038 SUPPORT INDIRECT Human Clinical

"This data have a dramatic impact on the accuracy of genetic counseling for both heterozygote and homozygote carriers of LOF variants in COCH."

Counselling implication of the recessive loss-of-function mechanism.

📊

Prevalence

1

Worldwide

Unknown Not yet documented

Population prevalence remains uncertain. Published cohorts are enriched for Belgian and Dutch p.Pro51Ser families; proportions from hearing-loss referral clinics or vestibular clinics are not population estimates.

Show evidence (1 reference)

PMID:16481359 SUPPORT Human Clinical

"Prevalence of COCH mutations worldwide is unknown, as there is no systematic screening effort for late-onset hearing disorders"

States that no prevalence estimate exists.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Autosomal Dominant Nonsyndromic Hearing Loss 9:

Menière disease

Overlapping Features Episodic vertigo, tinnitus and aural fullness in DFNA9 can satisfy Menière criteria, but DFNA9 is familial and progresses to bilateral vestibular loss, and no COCH exon 4 or 5 variants were found in 30 patients with sporadic definite Menière disease.

Distinguishing Features

Autosomal dominant family history and a heterozygous COCH variant.
Progression to bilateral vestibular hypofunction or areflexia.
Semicircular canal sclerosis or signal loss on imaging in advanced DFNA9.

Show evidence (1 reference)

PMID:14704763 SUPPORT Human Clinical

"Patients with definite MD have a low prevalence of mutations in exons 4 and 5 of the COCH gene."

Thirty patients with definite sporadic Menière disease; only exons 4 and 5 sequenced.

Autosomal recessive nonsyndromic hearing loss 110 (DFNB110)

Overlapping Features Biallelic inactivating COCH variants usually cause prelingual DFNB110; vestibular involvement is variable. Some coding variants alter splicing. Heterozygous loss-of-function carriers may hear normally, whereas dominant DFNA9 often involves an abnormal protein product. Early onset can occur in either disorder, and a terminal frameshift associated with DFNA9 should not be equated with simple loss of function.

Distinguishing Features

Biallelic loss-of-function or splice-altering COCH variants versus a heterozygous disease-associated abnormal-protein allele.
Usually congenital or prelingual onset in DFNB110, but age of onset alone is insufficient.

Show evidence (2 references)

PMID:29449721 SUPPORT Human Clinical

"Here, we describe two brothers with congenital prelingual deafness and a homozygous nonsense c.292C>T(p.Arg98*) COCH variant, suggesting a loss-of-function effect."

First recessive COCH family.

PMID:32562050 SUPPORT Human Clinical

"This study confirms the involvement of loss-of-function mutations in COCH in autosomal recessive nonsyndromic hearing loss, expands the mutational landscape of DFNB110 to include coding variants that alter RNA splicing, and highlights the need to investigate the effect of coding variants on RNA splicing."

Independent confirmation in a multi-ethnic cohort.

🔬

Clinical Trials

6

NCT03716908 NOT_APPLICABLE RECRUITING

Observational p.Pro51Ser natural-history study of hearing and vestibular function in symptomatic and presymptomatic carriers.

Show evidence (1 reference)

clinicaltrials:NCT03716908 SUPPORT Human Clinical

"The aim of this study is to carry out a prospective cross-sectional study on symptomatic and presymptomatic affected carriers of the Pro51Ser (P51S) Coagulation Factor C Homology (COCH) mutation in order to correlate vestibular data using the complete vestibular test battery with the known data..."