Autosomal Dominant Nonsyndromic Hearing Loss 11

Mendelian MONDO:0011032 Pathograph 13 Show in embeddings browser Autosomal Dominant Nonsyndromic Hearing Loss

DFNA11 is the autosomal dominant, hearing-only form of MYO7A disease. MYO7A encodes myosin VIIa, an unconventional motor that in hair cells forms a tripartite complex with SANS and harmonin, maintains mechanical tension across cadherin links, and transports protein components to the stereocilia tip. What makes this entry worth curating separately from Usher syndrome is that MYO7A is an allelic series in which the *type* of allele, not merely its severity, determines the disease. Biallelic MYO7A loss causes Usher syndrome type 1B - congenital profound deafness with retinitis pigmentosa and vestibular areflexia - or, in the hearing-only recessive form, DFNB2. Heterozygous DFNA11 alleles cause the mildest MYO7A phenotype: postlingual, gradually progressive moderate hearing loss with asymptomatic vestibular dysfunction and no retinal degeneration. The genetics of a 10,042-patient cohort make the allele-type distinction concrete. Every variant found in autosomal dominant cases was missense or in-frame deletion, while almost half of Usher syndrome patients carried biallelic null variants. Dominant disease therefore does not arise from haploinsufficiency - if it did, null alleles would appear among the dominant cases and they do not. The mechanistic explanation that has emerged is gain of function. Myosin VIIa is autoregulated through specific IQ motifs in its lever arm, and many reported DFNA11 mutations *activate* motor-dependent targeting of Myo7A in cultured cells, which the authors offer as the explanation for the dominant inheritance. This sits coherently alongside the earlier finding that a DFNA11 mutation in IQ5 disrupts calmodulin binding, since calmodulin occupancy of the IQ motifs is what holds the motor in check - though note that the earlier study framed its own result as impaired adaptation rather than as de-repression, so the unified reading is an interpretation of the two together and not a claim either paper makes. Nor does it cover the whole allele class: the dominant motor-domain allele p.R668H was measured as having *reduced* actin-activated ATPase activity, so at least one DFNA11 variant does not look like a simple gain of motor activity. Activation is the leading explanation here, not a settled one. The locus was defined in 1997, when a MYO7A mutation was shown to cause autosomal dominant non-syndromic deafness - the first demonstration that this gene could produce hearing loss without the Usher retinal and vestibular phenotype.

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1
Inheritance
4
Pathophys.
4
Phenotypes
3
Gaps
13
Pathograph
1
Genes
3
Variants
3
Medical Actions
1
Differentials
2
References
1
Deep Research
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Inheritance

1
Autosomal dominant HP:0000006
Heterozygous MYO7A missense or in-frame deletion variants, cosegregating with hearing loss across multigenerational pedigrees. The absence of null alleles among dominant cases is the key observation: it argues against haploinsufficiency and for a gain-of-function or dominant-negative mechanism.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:38594301 SUPPORT Human Clinical
"All variants identified in autosomal dominant cases were missense or in-frame deletion variants."
The allele-type restriction in dominant cases - no nulls - which is the genetic argument against haploinsufficiency.
PMID:29400105 SUPPORT Human Clinical
"This mutation co-segregated with hearing loss in this family. No mutation of MYO7A gene was found in the 151 controls."
Cosegregation with control-population absence in a large multigenerational pedigree.
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Discussions and Knowledge Gaps

3
Every in vivo model of MYO7A disease is a loss-of-function model, while DFNA11 is proposed to work by activating the motor. Does any animal reproduce the dominant activating mechanism, and until one does, what can the existing models actually be used to test?
HUMAN MODEL MISMATCH dfna11_no_in_vivo_model_of_activation
Attached to
pathophysiology#Constitutive Myosin VIIa Motor Activation pathophysiology#Progressive Stereocilia Dysfunction
This entry's central claim is that DFNA11 alleles activate myosin VIIa rather than removing it, and that this is why they are dominant while nulls are recessive. The direct evidence for activation is a cultured kidney epithelial cell assay - a heterologous system chosen because it makes motor-dependent targeting visible, not because it resembles a hair cell. The in vivo literature does not currently test that claim. The mouse models are deletions, which by construction model the recessive and Usher end of the allelic series; the tensioning study curated on the stereocilia node is an isoform deletion. A deletion model can tell you what myosin VIIa normally does, and this entry uses it for exactly that, but it cannot tell you what a constitutively activated motor does to a stereocilium over decades - which is the specific claim DFNA11 rests on. The consequence is concrete rather than academic. The proposed mechanism predicts that a therapy restoring autoinhibition would help in DFNA11 and be useless or harmful in DFNB2 and USH1B, and there is currently no in vivo system in which that prediction could be tested. A knock-in of a human activating allele is the missing experiment.
Show evidence (3 references)
PMID:39345484 SUPPORT In Vitro
"In this study, we used cultured kidney epithelial cells to screen for mutations that activate the motor-dependent targeting of Myo7A to the tips of apical microvilli on these cells."
Names the system in which the activation claim was established - cultured kidney epithelial cells, chosen for the readout rather than for fidelity to hair cells.
PMID:39345484 SUPPORT In Vitro
"Importantly, we demonstrate that many of the DFNA11 deafness mutations reported in patients activate Myo7A targeting, providing a potential explanation for the autosomal dominant genetics of this form of deafness."
The activation result and the authors' own framing of it as a potential explanation. "Potential" is theirs, and it is the epistemic level this entry's mechanism sits at.
PMID:32350269 SUPPORT INDIRECT Model Organism
"In mice with a specific deletion of the canonical isoform (Myo7a-ΔC mouse), MYO7A is severely diminished in inner hair cells (IHCs), while expression in outer hair cells is affected tonotopically."
Graded INDIRECT and quoted to establish the mismatch rather than to support the mechanism. The best available in vivo model is a deletion, so it models absence of the motor, not activation of it.
Do all DFNA11 alleles act by activating myosin VIIa, and can allele class be used prospectively to predict which of the three MYO7A diseases a newly found variant will cause?
KNOWLEDGE GAP myo7a_allele_type_determines_disease
Attached to
pathophysiology#Constitutive Myosin VIIa Motor Activation genetic#MYO7A
The correlation is unusually clean for an allelic series. Dominant cases carry only missense and in-frame deletion variants; nearly half of Usher patients carry biallelic nulls; recessive nonsyndromic cases sit between, retaining at least one missense. And a mechanism now exists that would explain it, since many DFNA11 alleles activate Myo7A targeting in cultured cells. What is not established is whether the rule runs prospectively. Only a subset of DFNA11 alleles has been tested in the activation assay, and "many" is the word used, not all - so it is unknown whether the untested dominant alleles activate, whether some act by a dominant-negative route instead, and critically whether a *recessive* missense allele would fail to activate in the same assay. That last comparison is the one that would turn a correlation into a usable predictor, and it does not appear to have been run. Until it is, a novel MYO7A missense variant in an isolated case cannot be assigned to DFNA11 rather than DFNB2 on allele class alone. The assay exists and the alleles are published, so this is tractable now. One published dominant allele already points the other way. p.R668H segregates in a family with the typical DFNA11 audiogram, and its actin-activated ATPase activity was measured as reduced rather than raised. The two results are not strictly contradictory - ATPase turnover in a recombinant enzyme assay and motor-dependent targeting in a cell are different quantities, and a variant could plausibly lower one while de-repressing the other - but nobody has run both assays on the same allele, so that reconciliation is a hypothesis rather than a finding. It is the concrete reason this entry treats activation as the leading explanation and not as the established mechanism of the allele class.
Show evidence (3 references)
PMID:39345484 SUPPORT In Vitro
"we demonstrate that many of the DFNA11 deafness mutations reported in patients activate Myo7A targeting, providing a potential explanation for the autosomal dominant genetics of this form of deafness"
Graded PARTIAL on the word "many" and on "potential explanation" - the mechanism is demonstrated for a subset and offered as an explanation, not established for the class.
PMID:38594301 SUPPORT Human Clinical
"All variants identified in autosomal dominant cases were missense or in-frame deletion variants."
The genetic correlation that the mechanism would explain.
PMID:23383098 SUPPORT In Vitro
"In the actin-activated ATPase activity assay, the rate of NADH oxidation was higher in the wild-type myosin VIIA, indicating that the ATPase activity in the p.R668H mutant myosin VIIA was significantly destroyed."
Graded PARTIAL against the activation account. A dominant DFNA11 allele with reduced motor enzymology is the untested case this discussion names, and it is why allele class is not yet a predictor.
What modifies DFNA11 severity and audiometric configuration within a single family carrying one MYO7A allele?
KNOWLEDGE GAP dfna11_audiometric_modifier
Attached to
phenotypes#High-Frequency Hearing Impairment pathophysiology#Progressive Stereocilia Dysfunction
In one large American pedigree segregating a single MYO7A allele, low- and mid-frequency hearing loss ranges from mild to severe with roughly equal numbers at each end, and severity varies between generations. Vestibular function appears to track auditory severity in at least two individuals, which points to a modifier acting inside the inner ear rather than to measurement noise or environmental exposure. Two obvious candidates were tested and excluded: SNPs in ATP2B2 and WFS1 did not segregate with the mild versus severe phenotype. The authors infer a common polymorphism not tightly linked to the MYO7A allele, which is a hypothesis about a genome-wide-mappable modifier that has not since been mapped. The unusual low- and mid-frequency configuration of this pedigree, against the high-frequency pattern typical elsewhere, may itself be the modifier's signature rather than an allele effect.
Show evidence (3 references)
PMID:18667942 SUPPORT Human Clinical
"The degree of low- and mid-frequency hearing loss in HL2 family members segregating the MYO7A mutation varies from mild to more severe, with approximately the same number of HL2 family members falling at each end of the severity spectrum."
Documents within-family variability under a single allele.
PMID:18667942 REFUTE Human Clinical
"The single-nucleotide polymorphisms examined within ATP2B2 and WFS1 did not segregate with the mild versus more severe auditory phenotype."
Graded REFUTE against the two tested candidate modifiers - a negative result that narrows the search rather than advancing it.
PMID:18667942 SUPPORT Human Clinical
"The putative MYO7A genetic modifier is likely to represent a common polymorphism that is not linked tightly to the MYO7A mutation on the MYO7A allele."
The authors' hypothesis about the modifier's nature, still unmapped.
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Pathophysiology

4
Heterozygous MYO7A Missense Variant
DFNA11 alleles are missense changes or in-frame deletions, never nulls. They fall in two functional regions: the motor head domain, and the IQ motifs of the lever arm that bind calmodulin. Only 35 of the 882 reported MYO7A variants are causative for autosomal dominant nonsyndromic hearing loss, so the dominant alleles are a small and structurally constrained subset of the gene's variation.
MYO7A hgnc:7606 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MYO7A (hgnc:7606). hgnc:7606 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Loss of IQ-Motif Autoregulation
Show evidence (3 references)
PMID:38594301 SUPPORT Human Clinical
"Most of the reported variants were identified as genetic causes for Usher syndrome, with only 35 variants reported as causative for ADNSHL and only 49 variants reported as causative for ARNSHL11."
Quantifies how small a subset of MYO7A variation causes dominant disease.
PMID:16449806 SUPPORT Human Clinical
"Sequencing of the MYO7A gene in the linked region identified a new missense mutation resulting in an Ala230Val change in the motor domain of the myosin VIIA."
An example of the motor-domain allele class.
PMID:15300860 SUPPORT Human Clinical
"We identified a novel heterozygous missense mutation (c.2557C>T; p.R853C) in a family with autosomal dominant non-syndromic hearing loss that changes an evolutionarily invariant residue of the fifth IQ motif (IQ5), a putative calmodulin (CaM) binding domain, of MYO7A."
An example of the IQ-motif allele class, at an invariant residue.
Loss of IQ-Motif Autoregulation
Myosin VIIa's motor activity is held in check by specific IQ motifs within its lever arm, and this regulation can operate at least partly independently of the tail. A DFNA11 mutation at an invariant residue of IQ5 abolishes constitutive calmodulin binding to that motif across all physiologically relevant calcium concentrations. Reading the two lines together, the most economical account is that calmodulin occupancy of the IQ motifs is the brake, and DFNA11 alleles release it. State the caveat plainly though: the calmodulin study interpreted its own finding as impaired adaptation to environmental stimuli, not as de-repression of the motor. The reconciliation is an interpretation across two papers, not a claim either makes.
calmodulin binding GO:0005516 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased calmodulin binding (GO:0005516). GO:0005516 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Constitutive Myosin VIIa Motor Activation
Show evidence (3 references)
PMID:39345484 SUPPORT In Vitro
"Our findings reveal that Myo7A is regulated by specific IQ motifs within its lever arm, and that this regulation can function at least partially independent of its tail sequence."
Establishes the IQ motifs of the lever arm as the autoregulatory element.
PMID:15300860 SUPPORT In Vitro
"analysis of calmodulin-dependent vasoconstriction suggests constitutive binding of CaM to the wildtype, but not the p.R853C-mutated IQ5 motif at all physiologically relevant Ca2+ concentrations"
Demonstrates that a DFNA11 allele abolishes calmodulin binding to IQ5.
PMID:15300860 SUPPORT In Vitro
"this amino acid change may result in impaired adaptation to environmental stimuli and progressive deterioration of hearing transduction in heterozygotes"
Graded PARTIAL and included to keep the record honest. This is the authors' own interpretation - impaired adaptation, not motor de-repression - and it differs from the activation account this node otherwise builds.
Constitutive Myosin VIIa Motor Activation
Many reported DFNA11 mutations activate the motor-dependent targeting of Myo7A to the tips of apical microvilli in cultured epithelial cells. The authors present this as a potential explanation for the dominant inheritance of DFNA11 - an activated motor would poison the normal one in trans or mislocalise cargo, whereas simply having half the normal amount would not. The genetic evidence corroborates this independently: dominant cases carry only missense and in-frame deletion alleles, while nulls appear in the recessive and Usher populations. Two lines of evidence of different kinds converging is what raises this above a cell-culture observation.
microfilament motor activity GO:0000146 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves microfilament motor activity (GO:0000146), qualified as gain of function. GO:0000146 is a molecular function from the Gene Ontology. ⇑ GAIN OF FUNCTION
Downstream
Progressive Stereocilia Dysfunction
Show evidence (2 references)
PMID:39345484 SUPPORT In Vitro
"we demonstrate that many of the DFNA11 deafness mutations reported in patients activate Myo7A targeting, providing a potential explanation for the autosomal dominant genetics of this form of deafness"
The activation result and the authors' own link to dominant inheritance.
PMID:38594301 SUPPORT Human Clinical
"On the other hand, in patients with Usher syndrome, almost half of the patients carried biallelic null variants (nonsense, splicing, and frameshift variants)."
The contrasting allele class in the recessive disease. Nulls give Usher syndrome, not dominant hearing loss, which is the genetic corroboration of a non-haploinsufficiency mechanism.
Progressive Stereocilia Dysfunction
Myosin VIIa maintains mechanical tension across cadherin links and transports components to the stereocilia tip, and is essential for maintaining hair cell stereocilia bundles. Dysregulated motor activity degrades that maintenance function over time, giving the gradually progressive rather than congenital course. Vestibular hair cells are affected too, but subclinically - vestibular dysfunction in DFNA11 is detectable on caloric testing while remaining asymptomatic.
cochlear outer hair cell CL:0000601 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear outer hair cell (CL:0000601). CL:0000601 is a cell type from the Cell Ontology. cochlear inner hair cell CL:0000589 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear inner hair cell (CL:0000589). CL:0000589 is a cell type from the Cell Ontology.
Downstream
Postlingual Progressive Sensorineural Hearing Impairment
High-Frequency Hearing Impairment
Abnormal Vestibular Function
Show evidence (5 references)
PMID:38594301 SUPPORT Other
"In the inner ear, Myosin 7a forms a tripartite complex with SANS and Harmonin, and plays a crucial role in mechano-electro transduction in stereocilia, helps to maintain the mechanical tension across cadherin links and transports proteins components to the tip of stereocilia6,7."
Defines the normal hair-cell function whose disruption produces the phenotype.
PMID:38594301 SUPPORT Other
"It is essential to the maintenance of hair cell stereocilia bundles and loss of this function is known to cause disorganized stereocilia and HL."
Links loss of myosin VIIa function to stereocilia disorganisation and hearing loss.
PMID:32350269 SUPPORT Model Organism
"IHCs of Myo7a-ΔC mice undergo normal development, but exhibit reduced resting open probability and slowed onset of MET currents, consistent with MYO7A's proposed role in tensioning the tip link."
Direct measurement of the tensioning function, replacing an inference drawn from a cohort paper's introduction. Reduced resting open probability and slowed MET current onset are what "loss of tension across the tip link" looks like electrophysiologically.
+ 2 more references
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Autosomal Dominant Nonsyndromic Hearing Loss 11 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

4
Postlingual Progressive Sensorineural Hearing Impairment VERY_FREQUENT Auditory HP:0008596 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postlingual sensorineural hearing impairment (HP:0008596). HP:0008596 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:11889386 SUPPORT Human Clinical
"The phenotype of DFNA11 is postlingual, nonsyndromic sensorineural hearing loss with gradual progression."
The defining audiological phenotype.
PMID:38594301 SUPPORT Human Clinical
"Most of the autosomal dominant cases showed late-onset progressive hearing loss. On the other hand, cases with autosomal recessive inheritance or Usher syndrome showed congenital or early-onset hearing loss."
Confirms the onset difference between dominant and recessive MYO7A disease in a large cohort - the clinical counterpart of the allele-type split.
PMID:11889386 SUPPORT Human Clinical
"Most affected individuals had moderate cochlear hearing loss beginning in the second decade and progressing at all frequencies."
Quantifies onset decade and severity in the phenotyped family.
Abnormal Vestibular Function FREQUENT Vestibular HP:0001751 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal vestibular function (HP:0001751). HP:0001751 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:11889386 SUPPORT Human Clinical
"Variable degrees of asymptomatic vestibular dysfunction were present."
Documents vestibular involvement that is present on testing but asymptomatic.
PMID:16449806 SUPPORT Human Clinical
"We ascertained a large Italian family with an autosomal dominant form of non-syndromic sensorineural hearing loss with vestibular involvement."
Independent report of vestibular involvement in a DFNA11-linked family.
High-Frequency Hearing Impairment FREQUENT Auditory HP:0005101 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High-frequency hearing impairment (HP:0005101). HP:0005101 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32428919 SUPPORT Human Clinical
"the affected family members in this study showed delayed-onset, progressive hearing loss affecting mostly high frequencies"
High-frequency predominance in a p.R206C family.
PMID:18667942 SUPPORT Human Clinical
"a large American DFNA11 pedigree with autosomal dominant progressive sensorineural hearing loss that first impacts the low- and mid-frequency auditory range"
Graded PARTIAL because it qualifies rather than supports the high-frequency pattern - this pedigree's loss begins at low and mid frequencies instead.
Absence of Retinitis Pigmentosa Ophthalmologic
The absence is not a guarantee for every MYO7A carrier - it is a statement about the DFNA11 phenotype. The same gene causes Usher syndrome type 1B, where retinitis pigmentosa is a defining feature, so a patient carrying a MYO7A variant needs the allele type established, not the gene alone. See the diagnosis section for the ophthalmologic assessment that establishes it.
Show evidence (2 references)
PMID:11889386 REFUTE Human Clinical
"No evidence suggested retinitis pigmentosa."
Graded REFUTE because the curated claim is the *absence* of retinitis pigmentosa in DFNA11. The finding refutes retinal degeneration as a feature of this disease.
PMID:11889386 SUPPORT Human Clinical
"Showing moderate hearing loss with asymptomatic variable vestibular dysfunction and no retinal degeneration, the DFNA11 phenotype is mildest among phenotypes caused by MYO7A mutations."
Places DFNA11 as the mildest MYO7A phenotype, defined partly by this absence.
🧬

Genetic Associations

1
MYO7A
Gene: MYO7A hgnc:7606 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MYO7A (hgnc:7606). hgnc:7606 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (6 references)
PMID:38594301 SUPPORT Human Clinical
"The MYO7A gene is known to be responsible for both syndromic hearing loss (Usher syndrome type1B:USH1B) and non-syndromic hearing loss including autosomal dominant and autosomal recessive inheritance (DFNA11, DFNB2)."
Establishes the three-disease allelic series at this locus.
PMID:35453549 SUPPORT Human Clinical
"Fourteen variants causing autosomal dominant deafness were clustered in motor and MyTH4 domains of MYO7A protein."
Locates the dominant alleles in two specific domains.
PMID:35453549 SUPPORT Human Clinical
"Missense variants in the motor domain caused late onset of hearing loss with ascending tendency."
The prognostic half of the correlation - motor-domain missense variants give later onset with an ascending audiogram.
+ 3 more references
Variants (3)
p.R206C
A recurrent dominant allele reported in unrelated Taiwanese and mainland Chinese families, likely a mutation hot spot or founder allele. Its pathogenicity was initially ambiguous and was resolved by the second, clearly dominant family.
Show evidence (1 reference)
PMID:32428919 SUPPORT Human Clinical
"The recurrent p.R206C variant in MYO7A is pathogenic and is likely in a mutation hot spot or due to a founder effect."
Establishes recurrence and resolves the earlier ambiguity about pathogenicity.
p.R853C
An IQ5 allele at an evolutionarily invariant residue that abolishes calmodulin binding to the fifth IQ motif.
Show evidence (1 reference)
PMID:15300860 SUPPORT Human Clinical
"A defect in CaM/MYO7A interaction represents a novel pathomechanism for genetic hearing loss."
The mechanistic significance the authors attach to this allele class.
p.R668H
A motor-domain allele that segregates dominantly in a family with the typical ascending DFNA11 audiogram, at a residue conserved across species and modelled as linking the lobes of the motor domain. Its measured effect is the one that does not fit the activation account: actin-activated ATPase activity is reduced, not raised. Curated because a dominant allele with diminished motor enzymology is the counterexample the allele-class discussion identifies as untested.
Show evidence (2 references)
PMID:23383098 SUPPORT Human Clinical
"A c.2003G→A (p.R668H) mutation of the MYO7A, is heterozygous in all affected family members and absent in 100 healthy individuals."
Establishes dominant segregation of this allele in the reported family.
PMID:23383098 SUPPORT In Vitro
"In the actin-activated ATPase activity assay, the rate of NADH oxidation was higher in the wild-type myosin VIIA, indicating that the ATPase activity in the p.R668H mutant myosin VIIA was significantly destroyed."
The functional measurement. Graded IN_VITRO because it is an enzyme assay on recombinant protein, separate from the family segregation graded above.
💊

Medical Actions

3
Hearing Amplification
Hearing aids, the first-line intervention. There is no disease-modifying therapy. What is specific to this disorder is the timing question rather than the modality: the loss is postlingual and progressive, so the clinically useful commitment is long-term audiological follow-up that catches deterioration early rather than a single fitting decision.
Target Phenotypes: Postlingual sensorineural hearing impairment HP:0008596 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Postlingual sensorineural hearing impairment (HP:0008596). HP:0008596 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37371710 SUPPORT Other
"A long audiological follow-up is of paramount importance to identify hearing threshold deteriorations early and ensure prompt treatment with hearing aids or cochlear implants."
Graded PARTIAL and cited at the group level deliberately. It is a narrative review of autosomal dominant nonsyndromic hearing loss as a class, not of DFNA11, so it supports the management approach for the class this disorder belongs to. No DFNA11-specific treatment study exists in the cache.
Cochlear Implantation
Action: cochlear implantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cochlear implantation, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Cochlear implantation as thresholds deteriorate beyond what amplification can address. Curated separately from amplification because the two differ in what can be said about them: implantation is a surgical procedure with a bindable action term, and no DFNA11-specific outcome series exists, so the entry records the intervention without claiming an outcome for this genotype.
Target Phenotypes: Postlingual sensorineural hearing impairment HP:0008596 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Postlingual sensorineural hearing impairment (HP:0008596). HP:0008596 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37371710 SUPPORT Other
"A long audiological follow-up is of paramount importance to identify hearing threshold deteriorations early and ensure prompt treatment with hearing aids or cochlear implants."
Graded PARTIAL and cited at the group level deliberately. This is a narrative review of autosomal dominant nonsyndromic hearing loss as a class, not of DFNA11, so it supports implantation as the management approach for the class this disorder belongs to. No DFNA11-specific implantation outcome is reported anywhere in the cache.
Genetic Counselling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Dominant counselling with a 50% transmission risk, and - more consequentially here - counselling about what the MYO7A finding does and does not predict. The same gene causes Usher syndrome type 1B, so a family told they carry a MYO7A variant needs the allele type and the ophthalmologic result explained together, or the reasonable inference is that blindness is coming.
Show evidence (1 reference)
PMID:38594301 SUPPORT Human Clinical
"The MYO7A gene is known to be responsible for both syndromic hearing loss (Usher syndrome type1B:USH1B) and non-syndromic hearing loss including autosomal dominant and autosomal recessive inheritance (DFNA11, DFNB2)."
The allelic series that makes counselling at this locus a substantive task rather than a recurrence-risk figure.
🔬

Diagnosis

2
Ophthalmologic assessment to exclude Usher syndrome type 1B
The step that makes the DFNA11 diagnosis rather than the MYO7A diagnosis. Finding a MYO7A variant does not distinguish DFNA11 from USH1B, and USH1B is the far commoner outcome at this locus, so retinal assessment - electroretinography plus ophthalmoscopy, with visual acuity, tonometry and slit-lamp examination - is what establishes the nonsyndromic label. It is the procedural basis of the entry's "Absence of Retinitis Pigmentosa" claim, and it is a longitudinal commitment rather than a one-off test in a child, since retinitis pigmentosa in Usher syndrome declares itself over years.
Show evidence (1 reference)
PMID:11889386 SUPPORT Human Clinical
"Selected subjects underwent additional examinations including speech discrimination scoring, acoustic reflex measurements, Békésy audiometry, evoked and distortion-product otoacoustic emissions, auditory brainstem responses, and bithermal caloric testing; visual acuity, ocular tonometry,..."
The examination battery in the family from which the absence of retinopathy is curated, naming electroretinography and ophthalmoscopy specifically.
Distortion-product otoacoustic emissions as an early marker
Outer hair cell function measured by distortion-product otoacoustic emissions can be abnormal before pure-tone thresholds move. This matters for a progressive disorder in which the mechanism is a maintenance failure at the stereocilia: the cellular lesion precedes the audiometric one, so a normal audiogram in an at-risk family member does not establish that the cochlea is unaffected.
Show evidence (1 reference)
PMID:32097363 SUPPORT Human Clinical
"Some subjects showed partly abnormal results in the distortion products of otoacoustic emissions before the elevation of hearing thresholds."
The observation itself, in a large linkage-confirmed family. Graded SUPPORT rather than as a validated screening test - it is reported in "some subjects", not quantified as a sensitivity.
📈

Progression

2
Childhood to third decade
Gently sloping audiogram in childhood, flattening after about age 30. High frequencies are affected first and deteriorate slowly.
Show evidence (1 reference)
PMID:32097363 SUPPORT Human Clinical
"Audiograms tended to show gently sloping configuration in childhood and flat configuration after the age of 30 years."
The audiogram configuration and the age at which it changes.
Later adult life
Low frequencies begin to deteriorate later than high frequencies but then progress more rapidly, which is what converts the sloping childhood audiogram into the flat adult one. Vestibular function was normal throughout in this family, although caloric abnormalities are reported in others - see the vestibular phenotype.
Show evidence (2 references)
PMID:32097363 SUPPORT Human Clinical
"Hearing loss at high frequencies progressed slowly, while hearing at low frequencies started to deteriorate later but progressed more rapidly."
The differing rates by frequency, which is the mechanism of the configuration change.
PMID:32097363 SUPPORT Human Clinical
"Vestibular function was within the normal range in all the subjects tested."
Graded PARTIAL because it conflicts with the caloric abnormalities curated in the vestibular phenotype from another family. Quoted rather than omitted: vestibular involvement in DFNA11 is not uniform, and an entry that only carried the positive finding would overstate it.
📊

Prevalence

2
Japanese hearing loss patients
Point Prevalence 1360.0 per 100,000 >1 in 1,000
1.36% of a 10,042-patient Japanese hearing loss cohort had MYO7A-associated hearing loss (137 patients). Note carefully what this figure is and is not: it is the proportion among people who already have hearing loss, covering all three MYO7A phenotypes together - DFNA11, DFNB2 and USH1B - not the population prevalence of DFNA11. A dominant-specific figure is curated as the second record below.
Show evidence (1 reference)
PMID:38594301 SUPPORT Human Clinical
"As a result, 137 patients were identified with MYO7A-associated hearing loss so that the prevalence among Japanese hearing loss patients was 1.36%."
Graded PARTIAL because the figure covers all MYO7A-associated hearing loss, not DFNA11 alone, and is a proportion within an ascertained hearing loss cohort rather than a population rate.
Korean postlingual autosomal dominant nonsyndromic hearing loss families
Point Prevalence 4700.0 per 100,000 >1 in 1,000
MYO7A variants in 4.7% of post-lingual families. This is the dominant-specific figure the first record lacks, but read it the same way: it is a proportion among families already ascertained for postlingual dominant hearing loss, not a population rate. The same sentence notes 12 of 14 families were multiplex, which is what an ascertainment scheme biased toward large segregating pedigrees would produce.
Show evidence (1 reference)
PMID:35453549 SUPPORT Human Clinical
"MYO7A variants were detected in 4.7% of post-lingual families, and 12 of 14 families were multiplex."
Graded PARTIAL. It gives a dominant-specific yield but within an ascertained family cohort, so it bounds how often MYO7A explains dominant postlingual hearing loss rather than how common DFNA11 is.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Autosomal Dominant Nonsyndromic Hearing Loss 11:

Usher syndrome type 1B
Overlapping Features The differential that matters at this locus, because it is the same gene. USH1B is caused by biallelic MYO7A variants and presents with congenital profound sensorineural hearing loss, vestibular areflexia, and retinitis pigmentosa. DFNA11 is heterozygous, postlingual and progressive, has at most subclinical vestibular involvement, and no retinopathy. The timing is what makes this a real diagnostic problem rather than a textbook distinction. Retinitis pigmentosa in USH1 develops in early adolescence, so a normal retinal examination in a young child does not distinguish the two - which is why the ophthalmologic assessment in this entry's diagnosis section is a longitudinal commitment and not a one-off test.
Distinguishing Features
  • Zygosity and allele class: heterozygous missense or in-frame deletion in DFNA11, against biallelic variants often including nulls in USH1B.
  • Onset and course: postlingual and progressive in DFNA11, against congenital and profound in USH1B.
  • Vestibular function: normal to subclinically abnormal on caloric testing in DFNA11, against areflexia in USH1B.
  • Retinal status on longitudinal electroretinography and ophthalmoscopy - longitudinal because a normal childhood examination does not distinguish the two.
Show evidence (3 references)
PMID:20301442 SUPPORT Human Clinical
"Usher syndrome type I (USH1) is characterized by congenital bilateral profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa (RP)."
The full USH1 triad against which DFNA11 is defined - profound congenital hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa. DFNA11 has none of the three in that form.
PMID:20301442 SUPPORT Human Clinical
"RP, a progressive bilateral symmetric degeneration of photoreceptors in the retina, develops in early adolescence, resulting in progressively constricted visual fields first, due to rod photoreceptor cell loss, followed by impaired visual acuity due to cone photoreceptor cell loss."
The timing that makes a childhood retinal examination non-exclusionary, and therefore the basis for recommending longitudinal rather than single assessment. Quoted in full so the subject of "develops in early adolescence" travels with it.
PMID:20301442 SUPPORT Human Clinical
"five genes – MYO7A, USH1C, CDH23, PCDH15, and USH1G – confirms the diagnosis."
Names MYO7A among the USH1 genes, which is what makes this differential gene-identical rather than merely phenotypically similar.
{ }

Source YAML

click to show 
name: Autosomal Dominant Nonsyndromic Hearing Loss 11
category: Mendelian
creation_date: "2026-08-27T00:00:00Z"
synonyms:
- DFNA11
- MYO7A-related autosomal dominant nonsyndromic hearing loss
- Deafness, autosomal dominant 11
- Nonsyndromic hearing loss, autosomal dominant 11
description: >-
  DFNA11 is the autosomal dominant, hearing-only form of MYO7A disease. MYO7A encodes
  myosin VIIa, an unconventional motor that in hair cells forms a tripartite complex with
  SANS and harmonin, maintains mechanical tension across cadherin links, and transports
  protein components to the stereocilia tip.

  What makes this entry worth curating separately from Usher syndrome is that MYO7A is an
  allelic series in which the *type* of allele, not merely its severity, determines the
  disease. Biallelic MYO7A loss causes Usher syndrome type 1B - congenital profound
  deafness with retinitis pigmentosa and vestibular areflexia - or, in the hearing-only
  recessive form, DFNB2. Heterozygous DFNA11 alleles cause the mildest MYO7A phenotype:
  postlingual, gradually progressive moderate hearing loss with asymptomatic vestibular
  dysfunction and no retinal degeneration.

  The genetics of a 10,042-patient cohort make the allele-type distinction concrete. Every
  variant found in autosomal dominant cases was missense or in-frame deletion, while
  almost half of Usher syndrome patients carried biallelic null variants. Dominant disease
  therefore does not arise from haploinsufficiency - if it did, null alleles would appear
  among the dominant cases and they do not.

  The mechanistic explanation that has emerged is gain of function. Myosin VIIa is
  autoregulated through specific IQ motifs in its lever arm, and many reported DFNA11
  mutations *activate* motor-dependent targeting of Myo7A in cultured cells, which the
  authors offer as the explanation for the dominant inheritance. This sits coherently
  alongside the earlier finding that a DFNA11 mutation in IQ5 disrupts calmodulin binding,
  since calmodulin occupancy of the IQ motifs is what holds the motor in check - though
  note that the earlier study framed its own result as impaired adaptation rather than as
  de-repression, so the unified reading is an interpretation of the two together and not a
  claim either paper makes. Nor does it cover the whole allele class: the dominant
  motor-domain allele p.R668H was measured as having *reduced* actin-activated ATPase
  activity, so at least one DFNA11 variant does not look like a simple gain of motor
  activity. Activation is the leading explanation here, not a settled one.

  The locus was defined in 1997, when a MYO7A mutation was shown to cause autosomal
  dominant non-syndromic deafness - the first demonstration that this gene could produce
  hearing loss without the Usher retinal and vestibular phenotype.
references:
- reference: PMID:20301442
  title: "Usher Syndrome Type I."
  tags:
  - GeneReviews
- reference: PMID:9354784
  title: "Autosomal dominant non-syndromic deafness caused by a mutation in the myosin VIIA gene."
disease_term:
  preferred_term: autosomal dominant nonsyndromic hearing loss 11
  term:
    id: MONDO:0011032
    label: autosomal dominant nonsyndromic hearing loss 11
parents:
- Autosomal Dominant Nonsyndromic Hearing Loss
inheritance:
- name: Autosomal dominant
  description: >-
    Heterozygous MYO7A missense or in-frame deletion variants, cosegregating with hearing
    loss across multigenerational pedigrees. The absence of null alleles among dominant
    cases is the key observation: it argues against haploinsufficiency and for a
    gain-of-function or dominant-negative mechanism.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:38594301
    reference_title: "The prevalence and clinical features of MYO7A-related hearing loss including DFNA11, DFNB2 and USH1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All variants identified in autosomal dominant cases were missense or in-frame deletion variants."
    explanation: >-
      The allele-type restriction in dominant cases - no nulls - which is the genetic
      argument against haploinsufficiency.
  - reference: PMID:29400105
    reference_title: "Identification of a MYO7A mutation in a large Chinese DFNA11 family and genotype-phenotype review for DFNA11."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This mutation co-segregated with hearing loss in this family. No mutation of MYO7A gene was found in the 151 controls."
    explanation: Cosegregation with control-population absence in a large multigenerational pedigree.
pathophysiology:
- name: Heterozygous MYO7A Missense Variant
  description: >-
    DFNA11 alleles are missense changes or in-frame deletions, never nulls. They fall in
    two functional regions: the motor head domain, and the IQ motifs of the lever arm that
    bind calmodulin. Only 35 of the 882 reported MYO7A variants are causative for autosomal
    dominant nonsyndromic hearing loss, so the dominant alleles are a small and
    structurally constrained subset of the gene's variation.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: MYO7A
    term:
      id: hgnc:7606
      label: MYO7A
  downstream:
  - target: Loss of IQ-Motif Autoregulation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:38594301
    reference_title: "The prevalence and clinical features of MYO7A-related hearing loss including DFNA11, DFNB2 and USH1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most of the reported variants were identified as genetic causes for Usher syndrome, with only 35 variants reported as causative for ADNSHL and only 49 variants reported as causative for ARNSHL11."
    explanation: Quantifies how small a subset of MYO7A variation causes dominant disease.
  - reference: PMID:16449806
    reference_title: "Identification of a novel mutation in the myosin VIIA motor domain in a family with autosomal dominant hearing loss (DFNA11)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequencing of the MYO7A gene in the linked region identified a new missense mutation resulting in an Ala230Val change in the motor domain of the myosin VIIA."
    explanation: An example of the motor-domain allele class.
  - reference: PMID:15300860
    reference_title: "Impaired calmodulin binding of myosin-7A causes autosomal dominant hearing loss (DFNA11)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a novel heterozygous missense mutation (c.2557C>T; p.R853C) in a family with autosomal dominant non-syndromic hearing loss that changes an evolutionarily invariant residue of the fifth IQ motif (IQ5), a putative calmodulin (CaM) binding domain, of MYO7A."
    explanation: An example of the IQ-motif allele class, at an invariant residue.
- name: Loss of IQ-Motif Autoregulation
  description: >-
    Myosin VIIa's motor activity is held in check by specific IQ motifs within its lever
    arm, and this regulation can operate at least partly independently of the tail. A
    DFNA11 mutation at an invariant residue of IQ5 abolishes constitutive calmodulin
    binding to that motif across all physiologically relevant calcium concentrations.

    Reading the two lines together, the most economical account is that calmodulin
    occupancy of the IQ motifs is the brake, and DFNA11 alleles release it. State the
    caveat plainly though: the calmodulin study interpreted its own finding as impaired
    adaptation to environmental stimuli, not as de-repression of the motor. The
    reconciliation is an interpretation across two papers, not a claim either makes.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: calmodulin binding
    modifier: DECREASED
    term:
      id: GO:0005516
      label: calmodulin binding
  downstream:
  - target: Constitutive Myosin VIIa Motor Activation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:39345484
    reference_title: "Select autosomal dominant DFNA11 deafness mutations activate Myo7A in epithelial cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our findings reveal that Myo7A is regulated by specific IQ motifs within its lever arm, and that this regulation can function at least partially independent of its tail sequence."
    explanation: Establishes the IQ motifs of the lever arm as the autoregulatory element.
  - reference: PMID:15300860
    reference_title: "Impaired calmodulin binding of myosin-7A causes autosomal dominant hearing loss (DFNA11)."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "analysis of calmodulin-dependent vasoconstriction suggests constitutive binding of CaM to the wildtype, but not the p.R853C-mutated IQ5 motif at all physiologically relevant Ca2+ concentrations"
    explanation: Demonstrates that a DFNA11 allele abolishes calmodulin binding to IQ5.
  - reference: PMID:15300860
    reference_title: "Impaired calmodulin binding of myosin-7A causes autosomal dominant hearing loss (DFNA11)."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "this amino acid change may result in impaired adaptation to environmental stimuli and progressive deterioration of hearing transduction in heterozygotes"
    explanation: >-
      Graded PARTIAL and included to keep the record honest. This is the authors' own
      interpretation - impaired adaptation, not motor de-repression - and it differs from
      the activation account this node otherwise builds.
- name: Constitutive Myosin VIIa Motor Activation
  description: >-
    Many reported DFNA11 mutations activate the motor-dependent targeting of Myo7A to the
    tips of apical microvilli in cultured epithelial cells. The authors present this as a
    potential explanation for the dominant inheritance of DFNA11 - an activated motor
    would poison the normal one in trans or mislocalise cargo, whereas simply having half
    the normal amount would not.

    The genetic evidence corroborates this independently: dominant cases carry only
    missense and in-frame deletion alleles, while nulls appear in the recessive and Usher
    populations. Two lines of evidence of different kinds converging is what raises this
    above a cell-culture observation.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: microfilament motor activity
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0000146
      label: microfilament motor activity
  downstream:
  - target: Progressive Stereocilia Dysfunction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:39345484
    reference_title: "Select autosomal dominant DFNA11 deafness mutations activate Myo7A in epithelial cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we demonstrate that many of the DFNA11 deafness mutations reported in patients activate Myo7A targeting, providing a potential explanation for the autosomal dominant genetics of this form of deafness"
    explanation: The activation result and the authors' own link to dominant inheritance.
  - reference: PMID:38594301
    reference_title: "The prevalence and clinical features of MYO7A-related hearing loss including DFNA11, DFNB2 and USH1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On the other hand, in patients with Usher syndrome, almost half of the patients carried biallelic null variants (nonsense, splicing, and frameshift variants)."
    explanation: >-
      The contrasting allele class in the recessive disease. Nulls give Usher syndrome, not
      dominant hearing loss, which is the genetic corroboration of a non-haploinsufficiency
      mechanism.
  notes: >-
    The GO binding is `microfilament motor activity` (GO:0000146) with modifier
    GAIN_OF_FUNCTION. The claim is qualitative - the motor escapes its normal regulatory
    constraint - not that motor activity is merely quantitatively higher, which is why
    GAIN_OF_FUNCTION rather than INCREASED.

    The term names activity rather than binding on purpose. A binding term would describe
    where the motor sits; the claim here is about what it does once autoinhibition is lost.
- name: Progressive Stereocilia Dysfunction
  description: >-
    Myosin VIIa maintains mechanical tension across cadherin links and transports
    components to the stereocilia tip, and is essential for maintaining hair cell
    stereocilia bundles. Dysregulated motor activity degrades that maintenance function
    over time, giving the gradually progressive rather than congenital course. Vestibular
    hair cells are affected too, but subclinically - vestibular dysfunction in DFNA11 is
    detectable on caloric testing while remaining asymptomatic.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  evidence:
  - reference: PMID:38594301
    reference_title: "The prevalence and clinical features of MYO7A-related hearing loss including DFNA11, DFNB2 and USH1B."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In the inner ear, Myosin 7a forms a tripartite complex with SANS and Harmonin, and plays a crucial role in mechano-electro transduction in stereocilia, helps to maintain the mechanical tension across cadherin links and transports proteins components to the tip of stereocilia6,7."
    explanation: Defines the normal hair-cell function whose disruption produces the phenotype.
  - reference: PMID:38594301
    reference_title: "The prevalence and clinical features of MYO7A-related hearing loss including DFNA11, DFNB2 and USH1B."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It is essential to the maintenance of hair cell stereocilia bundles and loss of this function is known to cause disorganized stereocilia and HL."
    explanation: Links loss of myosin VIIa function to stereocilia disorganisation and hearing loss.
  - reference: PMID:32350269
    reference_title: "Myosin-VIIa is expressed in multiple isoforms and essential for tensioning the hair cell mechanotransduction complex."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "IHCs of Myo7a-ΔC mice undergo normal development, but exhibit reduced resting open probability and slowed onset of MET currents, consistent with MYO7A's proposed role in tensioning the tip link."
    explanation: >-
      Direct measurement of the tensioning function, replacing an inference drawn from a
      cohort paper's introduction. Reduced resting open probability and slowed MET current
      onset are what "loss of tension across the tip link" looks like electrophysiologically.
  - reference: PMID:32350269
    reference_title: "Myosin-VIIa is expressed in multiple isoforms and essential for tensioning the hair cell mechanotransduction complex."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mature IHCs of Myo7a-ΔC mice degenerate over time, giving rise to progressive hearing loss."
    explanation: >-
      The temporal claim this node makes, measured rather than assumed: hair cells develop
      normally and then degenerate, which is why the human course is progressive rather
      than congenital.
  - reference: PMID:32350269
    reference_title: "Myosin-VIIa is expressed in multiple isoforms and essential for tensioning the hair cell mechanotransduction complex."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "MYO7A is proposed to function as a motor that tensions the hair cell mechanotransduction (MET) complex, but conclusive evidence is lacking."
    explanation: >-
      Graded PARTIAL and quoted as the state of the field before this study. It is the
      honest reading of the two OTHER-graded review sentences also cited on this node -
      they assert the tensioning role, and until this paper the evidence for it was not
      conclusive.
  downstream:
  - target: Postlingual Progressive Sensorineural Hearing Impairment
    causal_link_type: DIRECT
  - target: High-Frequency Hearing Impairment
    causal_link_type: DIRECT
  - target: Abnormal Vestibular Function
    causal_link_type: DIRECT
phenotypes:
- name: Postlingual Progressive Sensorineural Hearing Impairment
  category: Auditory
  description: >-
    Postlingual, gradually progressive sensorineural hearing loss, typically beginning in
    the second decade and progressing across frequencies. This late-onset progressive
    course is the consistent distinguishing feature from the congenital or early-onset
    hearing loss of DFNB2 and USH1B.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Postlingual sensorineural hearing impairment
    term:
      id: HP:0008596
      label: Postlingual sensorineural hearing impairment
  evidence:
  - reference: PMID:11889386
    reference_title: "Phenotype of DFNA11: a nonsyndromic hearing loss caused by a myosin VIIA mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The phenotype of DFNA11 is postlingual, nonsyndromic sensorineural hearing loss with gradual progression."
    explanation: The defining audiological phenotype.
  - reference: PMID:38594301
    reference_title: "The prevalence and clinical features of MYO7A-related hearing loss including DFNA11, DFNB2 and USH1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most of the autosomal dominant cases showed late-onset progressive hearing loss. On the other hand, cases with autosomal recessive inheritance or Usher syndrome showed congenital or early-onset hearing loss."
    explanation: >-
      Confirms the onset difference between dominant and recessive MYO7A disease in a large
      cohort - the clinical counterpart of the allele-type split.
  - reference: PMID:11889386
    reference_title: "Phenotype of DFNA11: a nonsyndromic hearing loss caused by a myosin VIIA mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most affected individuals had moderate cochlear hearing loss beginning in the second decade and progressing at all frequencies."
    explanation: Quantifies onset decade and severity in the phenotyped family.
- name: Abnormal Vestibular Function
  category: Vestibular
  description: >-
    Vestibular dysfunction that is detectable on testing but asymptomatic - a distinctive
    combination. In Usher syndrome type 1B the vestibular involvement is clinically
    obvious; in DFNA11 it is subclinical and found only by caloric testing.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormal vestibular function
    term:
      id: HP:0001751
      label: Abnormal vestibular function
  evidence:
  - reference: PMID:11889386
    reference_title: "Phenotype of DFNA11: a nonsyndromic hearing loss caused by a myosin VIIA mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variable degrees of asymptomatic vestibular dysfunction were present."
    explanation: Documents vestibular involvement that is present on testing but asymptomatic.
  - reference: PMID:16449806
    reference_title: "Identification of a novel mutation in the myosin VIIA motor domain in a family with autosomal dominant hearing loss (DFNA11)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We ascertained a large Italian family with an autosomal dominant form of non-syndromic sensorineural hearing loss with vestibular involvement."
    explanation: Independent report of vestibular involvement in a DFNA11-linked family.
- name: High-Frequency Hearing Impairment
  category: Auditory
  description: >-
    High frequencies are commonly worst affected, though the audiometric configuration is
    not uniform - one large pedigree has loss beginning in the low and mid frequencies
    instead.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: High-frequency hearing impairment
    term:
      id: HP:0005101
      label: High-frequency hearing impairment
  evidence:
  - reference: PMID:32428919
    reference_title: "The p.R206C Mutation in MYO7A Leads to Autosomal Dominant Nonsyndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the affected family members in this study showed delayed-onset, progressive hearing loss affecting mostly high frequencies"
    explanation: High-frequency predominance in a p.R206C family.
  - reference: PMID:18667942
    reference_title: "In search of the DFNA11 myosin VIIA low- and mid-frequency auditory genetic modifier."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a large American DFNA11 pedigree with autosomal dominant progressive sensorineural hearing loss that first impacts the low- and mid-frequency auditory range"
    explanation: >-
      Graded PARTIAL because it qualifies rather than supports the high-frequency pattern -
      this pedigree's loss begins at low and mid frequencies instead.
- name: Absence of Retinitis Pigmentosa
  category: Ophthalmologic
  diagnostic: true
  description: >-
    No retinal degeneration, established by electroretinography and ophthalmoscopy in a
    phenotyped DFNA11 family. This is a defining negative: MYO7A is the commonest Usher
    type 1 gene, so the absence of retinopathy is what makes DFNA11 nonsyndromic and is
    the single most consequential thing to tell a newly diagnosed family.

    Curated as a REFUTED phenotype, and deliberately carrying NO phenotype_term and NO
    frequency. The schema has no negation slot and FrequencyEnum has no EXCLUDED value, so
    binding HP:0000510 with a frequency here would export as the assertion that 80-99% of
    DFNA11 patients HAVE rod-cone dystrophy - the exact opposite of the point, and the most
    harmful edge this entry could emit given the MYO7A-Usher relationship. The REFUTE
    grading on the evidence item is claim-relative and never reaches the phenotype
    assertion, so it cannot substitute. This follows the pattern in
    Amyotrophic_Lateral_Sclerosis_27_Juvenile ("Absence of Sensory Neuropathy").
  evidence:
  - reference: PMID:11889386
    reference_title: "Phenotype of DFNA11: a nonsyndromic hearing loss caused by a myosin VIIA mutation."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "No evidence suggested retinitis pigmentosa."
    explanation: >-
      Graded REFUTE because the curated claim is the *absence* of retinitis pigmentosa in
      DFNA11. The finding refutes retinal degeneration as a feature of this disease.
  - reference: PMID:11889386
    reference_title: "Phenotype of DFNA11: a nonsyndromic hearing loss caused by a myosin VIIA mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Showing moderate hearing loss with asymptomatic variable vestibular dysfunction and no retinal degeneration, the DFNA11 phenotype is mildest among phenotypes caused by MYO7A mutations."
    explanation: Places DFNA11 as the mildest MYO7A phenotype, defined partly by this absence.
  notes: >-
    The absence is not a guarantee for every MYO7A carrier - it is a statement about the
    DFNA11 phenotype. The same gene causes Usher syndrome type 1B, where retinitis
    pigmentosa is a defining feature, so a patient carrying a MYO7A variant needs the
    allele type established, not the gene alone. See the diagnosis section for the
    ophthalmologic assessment that establishes it.
genetic:
- name: MYO7A
  notes: >-
    MYO7A is on 11q13.5, has 49 exons, and encodes the unconventional motor myosin VIIa,
    expressed in retina, lung, testis, kidney and inner and outer hair cells. It is an
    allelic series: DFNA11 (dominant, hearing only), DFNB2 (recessive, hearing only) and
    USH1B (recessive, deaf-blind). Of 882 reported MYO7A variants only 35 cause dominant
    nonsyndromic hearing loss. The allele classes segregate by disease - dominant cases
    carry exclusively missense or in-frame deletion variants, recessive nonsyndromic cases
    carry at least one missense, and nearly half of Usher patients carry biallelic nulls.

    Within the dominant alleles there is a further, prognostic correlation by protein
    domain. Dominant variants cluster in the motor and MyTH4 domains; motor-domain missense
    variants give later onset with an ascending audiogram, while tail-domain variants give a
    severe audiological phenotype. This is the finer-grained form of the entry's own
    allele-type thesis: allele class separates the three diseases, and within DFNA11 the
    affected domain modulates severity and onset.
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: MYO7A
    term:
      id: hgnc:7606
      label: MYO7A
  evidence:
  - reference: PMID:38594301
    reference_title: "The prevalence and clinical features of MYO7A-related hearing loss including DFNA11, DFNB2 and USH1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The MYO7A gene is known to be responsible for both syndromic hearing loss (Usher syndrome type1B:USH1B) and non-syndromic hearing loss including autosomal dominant and autosomal recessive inheritance (DFNA11, DFNB2)."
    explanation: Establishes the three-disease allelic series at this locus.
  - reference: PMID:35453549
    reference_title: "Clinical Heterogeneity Associated with MYO7A Variants Relies on Affected Domains."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fourteen variants causing autosomal dominant deafness were clustered in motor and MyTH4 domains of MYO7A protein."
    explanation: Locates the dominant alleles in two specific domains.
  - reference: PMID:35453549
    reference_title: "Clinical Heterogeneity Associated with MYO7A Variants Relies on Affected Domains."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Missense variants in the motor domain caused late onset of hearing loss with ascending tendency."
    explanation: >-
      The prognostic half of the correlation - motor-domain missense variants give later
      onset with an ascending audiogram.
  - reference: PMID:35453549
    reference_title: "Clinical Heterogeneity Associated with MYO7A Variants Relies on Affected Domains."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A severe audiological phenotype was apparent in individuals carrying tail domain variants."
    explanation: >-
      Graded PARTIAL. It reports the severe end of the domain correlation, but tail-domain
      variants are not confined to the dominant nonsyndromic phenotype, so the severity
      claim is not specific to DFNA11.
  - reference: PMID:38594301
    reference_title: "The prevalence and clinical features of MYO7A-related hearing loss including DFNA11, DFNB2 and USH1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the autosomal recessive cases, all patients had at least one missense variant."
    explanation: >-
      Completes the allele-class picture - even recessive nonsyndromic cases retain a
      missense allele, so total loss is reserved for Usher syndrome.
  - reference: PMID:29400105
    reference_title: "Identification of a MYO7A mutation in a large Chinese DFNA11 family and genotype-phenotype review for DFNA11."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also summarized and analyzed the phenotypes and genotypes of all DFNA11 families, four of nine are Chinese families, suggesting that MYO7A mutations are not rare."
    explanation: Genotype-phenotype review across the then-known DFNA11 families.
  variants:
  - name: p.R206C
    description: >-
      A recurrent dominant allele reported in unrelated Taiwanese and mainland Chinese
      families, likely a mutation hot spot or founder allele. Its pathogenicity was
      initially ambiguous and was resolved by the second, clearly dominant family.
    evidence:
    - reference: PMID:32428919
      reference_title: "The p.R206C Mutation in MYO7A Leads to Autosomal Dominant Nonsyndromic Hearing Loss."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The recurrent p.R206C variant in MYO7A is pathogenic and is likely in a mutation hot spot or due to a founder effect."
      explanation: Establishes recurrence and resolves the earlier ambiguity about pathogenicity.
  - name: p.R853C
    description: >-
      An IQ5 allele at an evolutionarily invariant residue that abolishes calmodulin
      binding to the fifth IQ motif.
    evidence:
    - reference: PMID:15300860
      reference_title: "Impaired calmodulin binding of myosin-7A causes autosomal dominant hearing loss (DFNA11)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A defect in CaM/MYO7A interaction represents a novel pathomechanism for genetic hearing loss."
      explanation: The mechanistic significance the authors attach to this allele class.
  - name: p.R668H
    description: >-
      A motor-domain allele that segregates dominantly in a family with the typical
      ascending DFNA11 audiogram, at a residue conserved across species and modelled as
      linking the lobes of the motor domain. Its measured effect is the one that does not
      fit the activation account: actin-activated ATPase activity is reduced, not raised.
      Curated because a dominant allele with diminished motor enzymology is the
      counterexample the allele-class discussion identifies as untested.
    evidence:
    - reference: PMID:23383098
      reference_title: "Identification and functional study of a new missense mutation in the motor head domain of myosin VIIA in a family with autosomal dominant hearing impairment (DFNA11)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A c.2003G→A (p.R668H) mutation of the MYO7A, is heterozygous in all affected family members and absent in 100 healthy individuals."
      explanation: Establishes dominant segregation of this allele in the reported family.
    - reference: PMID:23383098
      reference_title: "Identification and functional study of a new missense mutation in the motor head domain of myosin VIIA in a family with autosomal dominant hearing impairment (DFNA11)."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In the actin-activated ATPase activity assay, the rate of NADH oxidation was higher in the wild-type myosin VIIA, indicating that the ATPase activity in the p.R668H mutant myosin VIIA was significantly destroyed."
      explanation: >-
        The functional measurement. Graded IN_VITRO because it is an enzyme assay on
        recombinant protein, separate from the family segregation graded above.
prevalence:
- population: Japanese hearing loss patients
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 1360.0
  notes: >-
    1.36% of a 10,042-patient Japanese hearing loss cohort had MYO7A-associated hearing
    loss (137 patients). Note carefully what this figure is and is not: it is the
    proportion among people who already have hearing loss, covering all three MYO7A
    phenotypes together - DFNA11, DFNB2 and USH1B - not the population prevalence of
    DFNA11. A dominant-specific figure is curated as the second record below.
  evidence:
  - reference: PMID:38594301
    reference_title: "The prevalence and clinical features of MYO7A-related hearing loss including DFNA11, DFNB2 and USH1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As a result, 137 patients were identified with MYO7A-associated hearing loss so that the prevalence among Japanese hearing loss patients was 1.36%."
    explanation: >-
      Graded PARTIAL because the figure covers all MYO7A-associated hearing loss, not
      DFNA11 alone, and is a proportion within an ascertained hearing loss cohort rather
      than a population rate.
- population: Korean postlingual autosomal dominant nonsyndromic hearing loss families
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 4700.0
  notes: >-
    MYO7A variants in 4.7% of post-lingual families. This is the dominant-specific figure
    the first record lacks, but read it the same way: it is a proportion among families
    already ascertained for postlingual dominant hearing loss, not a population rate. The
    same sentence notes 12 of 14 families were multiplex, which is what an ascertainment
    scheme biased toward large segregating pedigrees would produce.
  evidence:
  - reference: PMID:35453549
    reference_title: "Clinical Heterogeneity Associated with MYO7A Variants Relies on Affected Domains."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MYO7A variants were detected in 4.7% of post-lingual families, and 12 of 14 families were multiplex."
    explanation: >-
      Graded PARTIAL. It gives a dominant-specific yield but within an ascertained family
      cohort, so it bounds how often MYO7A explains dominant postlingual hearing loss
      rather than how common DFNA11 is.
diagnosis:
- name: Ophthalmologic assessment to exclude Usher syndrome type 1B
  description: >-
    The step that makes the DFNA11 diagnosis rather than the MYO7A diagnosis. Finding a
    MYO7A variant does not distinguish DFNA11 from USH1B, and USH1B is the far commoner
    outcome at this locus, so retinal assessment - electroretinography plus ophthalmoscopy,
    with visual acuity, tonometry and slit-lamp examination - is what establishes the
    nonsyndromic label. It is the procedural basis of the entry's "Absence of Retinitis
    Pigmentosa" claim, and it is a longitudinal commitment rather than a one-off test in a
    child, since retinitis pigmentosa in Usher syndrome declares itself over years.
  evidence:
  - reference: PMID:11889386
    reference_title: "Phenotype of DFNA11: a nonsyndromic hearing loss caused by a myosin VIIA mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Selected subjects underwent additional examinations including speech discrimination scoring, acoustic reflex measurements, Békésy audiometry, evoked and distortion-product otoacoustic emissions, auditory brainstem responses, and bithermal caloric testing; visual acuity, ocular tonometry, slit-lamp examination, ophthalmoscopy, and electroretinography; and computed tomography of the temporal bone."
    explanation: >-
      The examination battery in the family from which the absence of retinopathy is
      curated, naming electroretinography and ophthalmoscopy specifically.
- name: Distortion-product otoacoustic emissions as an early marker
  description: >-
    Outer hair cell function measured by distortion-product otoacoustic emissions can be
    abnormal before pure-tone thresholds move. This matters for a progressive disorder in
    which the mechanism is a maintenance failure at the stereocilia: the cellular lesion
    precedes the audiometric one, so a normal audiogram in an at-risk family member does
    not establish that the cochlea is unaffected.
  evidence:
  - reference: PMID:32097363
    reference_title: "Clinical Profiles of DFNA11 at Diverse Stages of Development and Aging in a Large Family Identified by Linkage Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some subjects showed partly abnormal results in the distortion products of otoacoustic emissions before the elevation of hearing thresholds."
    explanation: >-
      The observation itself, in a large linkage-confirmed family. Graded SUPPORT rather
      than as a validated screening test - it is reported in "some subjects", not
      quantified as a sensitivity.
treatments:
- name: Hearing Amplification
  description: >-
    Hearing aids, the first-line intervention. There is no disease-modifying therapy. What
    is specific to this disorder is the timing question rather than the modality: the loss
    is postlingual and progressive, so the clinically useful commitment is long-term
    audiological follow-up that catches deterioration early rather than a single fitting
    decision.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: hearing aid fitting
  target_phenotypes:
  - preferred_term: Postlingual sensorineural hearing impairment
    term:
      id: HP:0008596
      label: Postlingual sensorineural hearing impairment
  notes: >-
    treatment_term carries no NCIT binding, and the gap is specific to amplification.
    NCIT:C183182 Hearing Aid is a device concept, not reachable from NCIT:C25218 Clinical
    Intervention or Procedure, and NCIT has no clinical-action term for hearing-aid fitting,
    so a free-text preferred_term is what the ontology contract asks for. Do not generalise
    this to cochlear implantation, curated separately below: that is a surgical procedure
    and does bind.
  evidence:
  - reference: PMID:37371710
    reference_title: "Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A long audiological follow-up is of paramount importance to identify hearing threshold deteriorations early and ensure prompt treatment with hearing aids or cochlear implants."
    explanation: >-
      Graded PARTIAL and cited at the group level deliberately. It is a narrative review of
      autosomal dominant nonsyndromic hearing loss as a class, not of DFNA11, so it
      supports the management approach for the class this disorder belongs to. No
      DFNA11-specific treatment study exists in the cache.
- name: Cochlear Implantation
  description: >-
    Cochlear implantation as thresholds deteriorate beyond what amplification can address.
    Curated separately from amplification because the two differ in what can be said about
    them: implantation is a surgical procedure with a bindable action term, and no
    DFNA11-specific outcome series exists, so the entry records the intervention without
    claiming an outcome for this genotype.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: cochlear implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Postlingual sensorineural hearing impairment
    term:
      id: HP:0008596
      label: Postlingual sensorineural hearing impairment
  evidence:
  - reference: PMID:37371710
    reference_title: "Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A long audiological follow-up is of paramount importance to identify hearing threshold deteriorations early and ensure prompt treatment with hearing aids or cochlear implants."
    explanation: >-
      Graded PARTIAL and cited at the group level deliberately. This is a narrative review of
      autosomal dominant nonsyndromic hearing loss as a class, not of DFNA11, so it supports
      implantation as the management approach for the class this disorder belongs to. No
      DFNA11-specific implantation outcome is reported anywhere in the cache.
- name: Genetic Counselling
  description: >-
    Dominant counselling with a 50% transmission risk, and - more consequentially here -
    counselling about what the MYO7A finding does and does not predict. The same gene
    causes Usher syndrome type 1B, so a family told they carry a MYO7A variant needs the
    allele type and the ophthalmologic result explained together, or the reasonable
    inference is that blindness is coming.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:38594301
    reference_title: "The prevalence and clinical features of MYO7A-related hearing loss including DFNA11, DFNB2 and USH1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The MYO7A gene is known to be responsible for both syndromic hearing loss (Usher syndrome type1B:USH1B) and non-syndromic hearing loss including autosomal dominant and autosomal recessive inheritance (DFNA11, DFNB2)."
    explanation: >-
      The allelic series that makes counselling at this locus a substantive task rather
      than a recurrence-risk figure.
progression:
- phase: Childhood to third decade
  notes: >-
    Gently sloping audiogram in childhood, flattening after about age 30. High frequencies
    are affected first and deteriorate slowly.
  evidence:
  - reference: PMID:32097363
    reference_title: "Clinical Profiles of DFNA11 at Diverse Stages of Development and Aging in a Large Family Identified by Linkage Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Audiograms tended to show gently sloping configuration in childhood and flat configuration after the age of 30 years."
    explanation: The audiogram configuration and the age at which it changes.
- phase: Later adult life
  notes: >-
    Low frequencies begin to deteriorate later than high frequencies but then progress more
    rapidly, which is what converts the sloping childhood audiogram into the flat adult
    one. Vestibular function was normal throughout in this family, although caloric
    abnormalities are reported in others - see the vestibular phenotype.
  evidence:
  - reference: PMID:32097363
    reference_title: "Clinical Profiles of DFNA11 at Diverse Stages of Development and Aging in a Large Family Identified by Linkage Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hearing loss at high frequencies progressed slowly, while hearing at low frequencies started to deteriorate later but progressed more rapidly."
    explanation: The differing rates by frequency, which is the mechanism of the configuration change.
  - reference: PMID:32097363
    reference_title: "Clinical Profiles of DFNA11 at Diverse Stages of Development and Aging in a Large Family Identified by Linkage Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vestibular function was within the normal range in all the subjects tested."
    explanation: >-
      Graded PARTIAL because it conflicts with the caloric abnormalities curated in the
      vestibular phenotype from another family. Quoted rather than omitted: vestibular
      involvement in DFNA11 is not uniform, and an entry that only carried the positive
      finding would overstate it.
differential_diagnoses:
- name: Usher syndrome type 1B
  description: >-
    The differential that matters at this locus, because it is the same gene. USH1B is
    caused by biallelic MYO7A variants and presents with congenital profound sensorineural
    hearing loss, vestibular areflexia, and retinitis pigmentosa. DFNA11 is heterozygous,
    postlingual and progressive, has at most subclinical vestibular involvement, and no
    retinopathy.

    The timing is what makes this a real diagnostic problem rather than a textbook
    distinction. Retinitis pigmentosa in USH1 develops in early adolescence, so a normal
    retinal examination in a young child does not distinguish the two - which is why the
    ophthalmologic assessment in this entry's diagnosis section is a longitudinal
    commitment and not a one-off test.
  distinguishing_features:
  - >-
    Zygosity and allele class: heterozygous missense or in-frame deletion in DFNA11,
    against biallelic variants often including nulls in USH1B.
  - >-
    Onset and course: postlingual and progressive in DFNA11, against congenital and
    profound in USH1B.
  - >-
    Vestibular function: normal to subclinically abnormal on caloric testing in DFNA11,
    against areflexia in USH1B.
  - >-
    Retinal status on longitudinal electroretinography and ophthalmoscopy - longitudinal
    because a normal childhood examination does not distinguish the two.
  evidence:
  - reference: PMID:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Usher syndrome type I (USH1) is characterized by congenital bilateral profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa (RP)."
    explanation: >-
      The full USH1 triad against which DFNA11 is defined - profound congenital hearing
      loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa. DFNA11 has none
      of the three in that form.
  - reference: PMID:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RP, a progressive bilateral symmetric degeneration of photoreceptors in the retina, develops in early adolescence, resulting in progressively constricted visual fields first, due to rod photoreceptor cell loss, followed by impaired visual acuity due to cone photoreceptor cell loss."
    explanation: >-
      The timing that makes a childhood retinal examination non-exclusionary, and therefore
      the basis for recommending longitudinal rather than single assessment. Quoted in full
      so the subject of "develops in early adolescence" travels with it.
  - reference: PMID:20301442
    reference_title: "Usher Syndrome Type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "five genes – MYO7A, USH1C, CDH23, PCDH15, and USH1G – confirms the diagnosis."
    explanation: >-
      Names MYO7A among the USH1 genes, which is what makes this differential
      gene-identical rather than merely phenotypically similar.
discussions:
- discussion_id: dfna11_no_in_vivo_model_of_activation
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Every in vivo model of MYO7A disease is a loss-of-function model, while DFNA11 is
    proposed to work by activating the motor. Does any animal reproduce the dominant
    activating mechanism, and until one does, what can the existing models actually be used
    to test?
  attaches_to:
  - pathophysiology#Constitutive Myosin VIIa Motor Activation
  - pathophysiology#Progressive Stereocilia Dysfunction
  rationale: >-
    This entry's central claim is that DFNA11 alleles activate myosin VIIa rather than
    removing it, and that this is why they are dominant while nulls are recessive. The
    direct evidence for activation is a cultured kidney epithelial cell assay - a
    heterologous system chosen because it makes motor-dependent targeting visible, not
    because it resembles a hair cell.

    The in vivo literature does not currently test that claim. The mouse models are
    deletions, which by construction model the recessive and Usher end of the allelic
    series; the tensioning study curated on the stereocilia node is an isoform deletion. A
    deletion model can tell you what myosin VIIa normally does, and this entry uses it for
    exactly that, but it cannot tell you what a constitutively activated motor does to a
    stereocilium over decades - which is the specific claim DFNA11 rests on.

    The consequence is concrete rather than academic. The proposed mechanism predicts that
    a therapy restoring autoinhibition would help in DFNA11 and be useless or harmful in
    DFNB2 and USH1B, and there is currently no in vivo system in which that prediction
    could be tested. A knock-in of a human activating allele is the missing experiment.
  evidence:
  - reference: PMID:39345484
    reference_title: "Select autosomal dominant DFNA11 deafness mutations activate Myo7A in epithelial cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In this study, we used cultured kidney epithelial cells to screen for mutations that activate the motor-dependent targeting of Myo7A to the tips of apical microvilli on these cells."
    explanation: >-
      Names the system in which the activation claim was established - cultured kidney
      epithelial cells, chosen for the readout rather than for fidelity to hair cells.
  - reference: PMID:39345484
    reference_title: "Select autosomal dominant DFNA11 deafness mutations activate Myo7A in epithelial cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Importantly, we demonstrate that many of the DFNA11 deafness mutations reported in patients activate Myo7A targeting, providing a potential explanation for the autosomal dominant genetics of this form of deafness."
    explanation: >-
      The activation result and the authors' own framing of it as a potential explanation.
      "Potential" is theirs, and it is the epistemic level this entry's mechanism sits at.
  - reference: PMID:32350269
    reference_title: "Myosin-VIIa is expressed in multiple isoforms and essential for tensioning the hair cell mechanotransduction complex."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "In mice with a specific deletion of the canonical isoform (Myo7a-ΔC mouse), MYO7A is severely diminished in inner hair cells (IHCs), while expression in outer hair cells is affected tonotopically."
    explanation: >-
      Graded INDIRECT and quoted to establish the mismatch rather than to support the
      mechanism. The best available in vivo model is a deletion, so it models absence of
      the motor, not activation of it.
- discussion_id: myo7a_allele_type_determines_disease
  kind: KNOWLEDGE_GAP
  prompt: >-
    Do all DFNA11 alleles act by activating myosin VIIa, and can allele class be used
    prospectively to predict which of the three MYO7A diseases a newly found variant will
    cause?
  attaches_to:
  - pathophysiology#Constitutive Myosin VIIa Motor Activation
  - genetic#MYO7A
  rationale: >-
    The correlation is unusually clean for an allelic series. Dominant cases carry only
    missense and in-frame deletion variants; nearly half of Usher patients carry biallelic
    nulls; recessive nonsyndromic cases sit between, retaining at least one missense. And
    a mechanism now exists that would explain it, since many DFNA11 alleles activate Myo7A
    targeting in cultured cells.

    What is not established is whether the rule runs prospectively. Only a subset of DFNA11
    alleles has been tested in the activation assay, and "many" is the word used, not all -
    so it is unknown whether the untested dominant alleles activate, whether some act by a
    dominant-negative route instead, and critically whether a *recessive* missense allele
    would fail to activate in the same assay. That last comparison is the one that would
    turn a correlation into a usable predictor, and it does not appear to have been run.
    Until it is, a novel MYO7A missense variant in an isolated case cannot be assigned to
    DFNA11 rather than DFNB2 on allele class alone. The assay exists and the alleles are
    published, so this is tractable now.

    One published dominant allele already points the other way. p.R668H segregates in a
    family with the typical DFNA11 audiogram, and its actin-activated ATPase activity was
    measured as reduced rather than raised. The two results are not strictly contradictory
    - ATPase turnover in a recombinant enzyme assay and motor-dependent targeting in a
    cell are different quantities, and a variant could plausibly lower one while
    de-repressing the other - but nobody has run both assays on the same allele, so that
    reconciliation is a hypothesis rather than a finding. It is the concrete reason this
    entry treats activation as the leading explanation and not as the established
    mechanism of the allele class.
  evidence:
  - reference: PMID:39345484
    reference_title: "Select autosomal dominant DFNA11 deafness mutations activate Myo7A in epithelial cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we demonstrate that many of the DFNA11 deafness mutations reported in patients activate Myo7A targeting, providing a potential explanation for the autosomal dominant genetics of this form of deafness"
    explanation: >-
      Graded PARTIAL on the word "many" and on "potential explanation" - the mechanism is
      demonstrated for a subset and offered as an explanation, not established for the class.
  - reference: PMID:38594301
    reference_title: "The prevalence and clinical features of MYO7A-related hearing loss including DFNA11, DFNB2 and USH1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All variants identified in autosomal dominant cases were missense or in-frame deletion variants."
    explanation: The genetic correlation that the mechanism would explain.
  - reference: PMID:23383098
    reference_title: "Identification and functional study of a new missense mutation in the motor head domain of myosin VIIA in a family with autosomal dominant hearing impairment (DFNA11)."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In the actin-activated ATPase activity assay, the rate of NADH oxidation was higher in the wild-type myosin VIIA, indicating that the ATPase activity in the p.R668H mutant myosin VIIA was significantly destroyed."
    explanation: >-
      Graded PARTIAL against the activation account. A dominant DFNA11 allele with reduced
      motor enzymology is the untested case this discussion names, and it is why allele
      class is not yet a predictor.
- discussion_id: dfna11_audiometric_modifier
  kind: KNOWLEDGE_GAP
  prompt: >-
    What modifies DFNA11 severity and audiometric configuration within a single family
    carrying one MYO7A allele?
  attaches_to:
  - phenotypes#High-Frequency Hearing Impairment
  - pathophysiology#Progressive Stereocilia Dysfunction
  rationale: >-
    In one large American pedigree segregating a single MYO7A allele, low- and
    mid-frequency hearing loss ranges from mild to severe with roughly equal numbers at
    each end, and severity varies between generations. Vestibular function appears to track
    auditory severity in at least two individuals, which points to a modifier acting inside
    the inner ear rather than to measurement noise or environmental exposure. Two obvious
    candidates were tested and excluded: SNPs in ATP2B2 and WFS1 did not segregate with the
    mild versus severe phenotype. The authors infer a common polymorphism not tightly
    linked to the MYO7A allele, which is a hypothesis about a genome-wide-mappable
    modifier that has not since been mapped. The unusual low- and mid-frequency
    configuration of this pedigree, against the high-frequency pattern typical elsewhere,
    may itself be the modifier's signature rather than an allele effect.
  evidence:
  - reference: PMID:18667942
    reference_title: "In search of the DFNA11 myosin VIIA low- and mid-frequency auditory genetic modifier."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The degree of low- and mid-frequency hearing loss in HL2 family members segregating the MYO7A mutation varies from mild to more severe, with approximately the same number of HL2 family members falling at each end of the severity spectrum."
    explanation: Documents within-family variability under a single allele.
  - reference: PMID:18667942
    reference_title: "In search of the DFNA11 myosin VIIA low- and mid-frequency auditory genetic modifier."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The single-nucleotide polymorphisms examined within ATP2B2 and WFS1 did not segregate with the mild versus more severe auditory phenotype."
    explanation: >-
      Graded REFUTE against the two tested candidate modifiers - a negative result that
      narrows the search rather than advancing it.
  - reference: PMID:18667942
    reference_title: "In search of the DFNA11 myosin VIIA low- and mid-frequency auditory genetic modifier."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The putative MYO7A genetic modifier is likely to represent a common polymorphism that is not linked tightly to the MYO7A mutation on the MYO7A allele."
    explanation: The authors' hypothesis about the modifier's nature, still unmapped.
📚

References & Deep Research

References

2
PMID:20301442
Usher Syndrome Type I.
No top-level findings curated for this source.
PMID:9354784
Autosomal dominant non-syndromic deafness caused by a mutation in the myosin VIIA gene.
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Autosomal Dominant Nonsyndromic Hearing Loss 11 (DFNA11): Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 2 citations 2026-08-27T15:20:41.275261

Autosomal Dominant Nonsyndromic Hearing Loss 11 (DFNA11): Comprehensive Research Report

1. Disease Information

Overview: Autosomal Dominant Nonsyndromic Hearing Loss 11 (DFNA11; also written "Deafness, Autosomal Dominant 11") is a form of progressive, postlingual sensorineural hearing loss caused by heterozygous (dominant) pathogenic variants in MYO7A, the gene encoding unconventional myosin VIIa. It is one of three distinct clinical phenotypes produced by MYO7A mutations, situated at the mild end of the MYO7A disease spectrum: DFNA11 (dominant, nonsyndromic) < DFNB2 (recessive, nonsyndromic) < Usher syndrome type 1B (USH1B; recessive, syndromic — deafness plus retinitis pigmentosa and vestibular areflexia) (OMIM #601317; NIH GTR C1832475).

Key identifiers: | Resource | ID | |---|---| | OMIM (phenotype) | #601317 | | OMIM (gene, MYO7A) | 276903 | | Allelic OMIM phenotypes | DFNB2 #600060; Usher syndrome 1B #276900 | | MONDO | MONDO:0011032 | | MedGen | C1832475 | | HGNC (gene) | HGNC:7606 (MYO7A*) | | UniProt | Q13402 (MYO7A_HUMAN) | | Gene location | 11q13.5 |

Synonyms: Deafness, autosomal dominant 11; DFNA11; MYO7A-related nonsyndromic hearing loss (dominant form); myosin VIIA-associated deafness.

Evidence basis: Data on DFNA11 derive almost entirely from aggregated multi-generational pedigrees and clinical case series (audiometric cohort studies, family linkage studies) rather than large EHR-based population datasets, reflecting its rarity — it is described as "the rarest consequence of MYO7A variants" relative to DFNB2 and USH1B (Joo et al. 2022, PMID: 35453549).

2. Etiology

Disease causal factors: DFNA11 is purely genetic/monogenic — caused by heterozygous, typically missense or in-frame deletion, pathogenic variants in MYO7A acting via a dominant mechanism (see Mechanism, below). No environmental or infectious causal factors are described for this specific dominant condition (as opposed to acquired/environmental sensorineural hearing loss more broadly).

Genetic risk factors: - Causal variants: heterozygous missense and small in-frame deletion variants in MYO7A, clustering predominantly in the motor domain (aa 65–741) and, less commonly, the MyTH4 (aa 1017–1253, 1747–1895) and IQ motif/coiled-coil regions. In a Korean cohort, motor-domain variants accounted for 66.7% (12/18) of DFNA11 variants identified (Joo et al. 2022, PMID: 35453549). - All reported autosomal dominant MYO7A variants in this cohort were missense or in-frame deletions — no truncating/nonsense variants were dominant-acting, consistent with a gain-of-function/dominant-activation mechanism rather than simple haploinsufficiency (see Mechanism). - Representative pathogenic variants: p.Arg853His (Kubota et al. 2020, PMID: 32097363); p.Arg244Pro-adjacent motor-domain variants; p.Thr1234Ser and p.Pro1244Arg in MyTH4 (associated with earlier-onset, more severe phenotypes) (PMID: 35453549); a missense variant in the motor head domain reported in a separate DFNA11 family (PMC3558421).

Environmental risk factors: Not specifically implicated in DFNA11; as with other progressive sensorineural hearing losses, noise exposure is generically counseled against to avoid accelerating any residual hearing decline, though this is extrapolated from general ADNSHL management guidance rather than DFNA11-specific data.

Protective factors: No genetic or environmental protective factors specific to DFNA11 have been identified in the literature reviewed.

Gene-environment interactions: None specifically documented for DFNA11.

3. Phenotypes

Primary phenotype — Sensorineural hearing loss (symptom/clinical sign): - Onset: Postlingual — after complete speech acquisition, "often in the first decade of life" per OMIM, though other cohorts describe onset in the second decade or later (second–fifth decade for motor-domain variants) (Joo et al. 2022, PMID: 35453549; malacards/OMIM #601317). - Severity: Mild to moderate at onset in most families; can progress to severe (Kubota 2002, PMID: 11889386, describes "moderate cochlear hearing loss beginning in the second decade"). MyTH4-domain variants are associated with more severe/profound loss (PMID: 35453549). - Progression: Gradual, progressive, affecting all frequencies over time. A detailed multi-generational study (Kim et al. 2020, PMID: 32097363) found audiometric configuration evolves with age: a "gently sloping configuration" in early childhood transitioning to a "flat configuration" after age 30; high-frequency thresholds deteriorate slowly while low-frequency thresholds, though affected later, "progressed more rapidly" once involved. Abnormal distortion product otoacoustic emissions (DPOAEs) were detectable before standard pure-tone threshold elevation in some subjects, suggesting DPOAE as a potential early/preclinical biomarker. - Laterality: Bilateral. - Suggested HP term: HP:0000407 (Sensorineural hearing impairment) or more specific HP:0000408 (Progressive sensorineural hearing impairment); HP:0000360 (Hearing impairment, general).

Vestibular dysfunction (secondary/variable phenotype): - Variably present; described as "mild" or "asymptomatic" vestibular dysfunction in some series (OMIM #601317) while a separate large-pedigree study found vestibular function "remained normal across all tested subjects" (PMID: 32097363) — indicating inter-family variability. When present, severity of vestibular impairment appears to parallel severity of the auditory phenotype within a family. - Suggested HP term: HP:0000762 (Vestibular hypofunction) or HP:0000740/HP:0002321 (Vertigo).

Absent phenotypes (distinguishing DFNA11 from allelic conditions): No retinal degeneration/retinitis pigmentosa — this is the key clinical distinguishing feature versus USH1B (OMIM #601317; PMID: 11889386). Suggested negated term: absence of HP:0000510 (Rod-cone dystrophy).

Quality of life impact: Not separately quantified for DFNA11 in the literature surveyed; general ADNSHL guidance notes progressive postlingual hearing loss affects communication, education (if pediatric onset), and social functioning, with hearing aids/cochlear implants indicated for functional impact management (PMC10296186).

Frequency among affected individuals: As an autosomal dominant condition, all variant carriers are expected to develop hearing loss (segregation in described pedigrees is consistent with high penetrance), though age of onset and severity are variable even within families.

4. Genetic/Molecular Information

Causal gene: MYO7A (HGNC:7606; OMIM *276903), chromosome 11q13.5, spans ~87 kb genomic sequence, 49 exons (48 coding). Encodes myosin VIIa, a 254 kDa, 2,215-amino-acid unconventional myosin motor protein (UniProt Q13402) (PMID: 35453549 domain data).

Protein domain architecture (from Joo et al. 2022, PMID: 35453549): - Motor domain (aa 65–741): ATP- and actin-binding; site of majority of DFNA11 variants - Neck domain (aa 745–857): five IQ motifs (calmodulin-binding lever arm) - SAH domain (aa 858–935): single alpha-helix, lever-arm extension - Coiled-coil region: between SAH and tail - Tail domain: two MyTH4 domains (aa 1017–1253; 1747–1895), two FERM domains (aa 1258–1602; 1900–2205), one SH3 domain (aa 1603–1672) - MYO7A functions as a monomer (unlike many conventional myosins), with the tail folding back onto the head-neck region in an autoinhibited state.

Variant classification and type: DFNA11 variants are exclusively missense or small in-frame deletions (never truncating) — consistent with the requirement for a stably folded, dominantly acting mutant protein (PMID: 35453549). By contrast, DFNB2 (recessive) alleles retain partial function and localize correctly to stereocilia, while USH1B alleles are typically more severely disruptive (often null/truncating) and fail to localize properly — "DFNB2 and USH1B are different ends of the same disease spectrum" (search synthesis referencing GeneReviews/PreventionGenetics data).

Allele frequency: Population-level allele frequency data specific to DFNA11-causing variants were not identified in gnomAD searches during this review; as private/family-specific dominant missense variants, they are expected to be rare/absent in gnomAD population databases, consistent with pathogenicity assessment under ACMG/AMP criteria (PM2).

Functional consequence — dominant mechanism: A 2024–2025 mechanistic study (bioRxiv 10.1101/2024.09.17.613491; PubMed: 39345484, "Select autosomal dominant DFNA11 deafness mutations activate Myo7A targeting in epithelial cells") reports that many DFNA11-patient mutations activate Myo7A targeting/trafficking in epithelial cell assays — i.e., these variants relieve the normal autoinhibited (folded-back) conformation of the myosin, causing constitutive activation/mistargeting of the motor protein. This provides a mechanistic explanation for dominant inheritance: rather than simple haploinsufficiency, mutant Myo7A is hyperactive/mistargeted, which is proposed to interfere with normal mechanotransduction complex assembly or tip-link tensioning in a dominant-negative or gain-of-function manner. A companion structure-function study found that specific IQ motifs within the myosin's lever arm regulate this targeting, at least partly independent of tail sequence.

Modifier genes: A genetic modifier of DFNA11 audiometric phenotype (affecting low- and mid-frequency thresholds) has been sought in linkage studies (Naz et al., PMID: 18667942, "In search of the DFNA11 myosin VIIA low- and mid-frequency auditory genetic modifier"), indicating intrafamilial phenotypic variability may be partly modifier-gene-driven, though the specific modifier locus was not conclusively identified in the search results retrieved.

Epigenetic information: No DFNA11-specific epigenetic (DNA methylation/histone) data were identified.

Chromosomal abnormalities: DFNA11 is caused by point/small indel variants, not large chromosomal rearrangements; no aneuploidy/translocation mechanism is described.

5. Environmental Information

No specific environmental, lifestyle, or infectious causal or exacerbating factors for DFNA11 were identified in the literature surveyed — it is a purely monogenic dominant condition. General noise-avoidance counseling applies as standard practice for progressive sensorineural hearing loss but is not DFNA11-specific evidence.

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream): 1. Molecular trigger: Heterozygous missense/in-frame-deletion variant in MYO7A, predominantly in the motor domain, alters normal myosin VIIa autoregulation. 2. Molecular dysfunction: Mutant Myo7A protein shows activated/constitutive targeting rather than normal regulated (autoinhibited) trafficking, per epithelial-cell reporter assays (bioRxiv 2024.09.17.613491 / PubMed 39345484). This is distinct from the loss-of-targeting seen in USH1B-causing alleles. 3. Cellular/subcellular dysfunction: Myosin VIIa normally functions at the stereocilia upper tip-link density (UTLD) of cochlear hair cells, where a cluster of ~8+ Myo7A molecules maintains tip-link tension at rest and is required for hair-cell mechanoelectrical transduction (MET) — specifically for maintaining resting open probability of MET channels and enabling proper onset kinetics of MET currents (Nature Communications 2020, PMID: 32350269; PNAS 2024, "MYO7A is required for the functional integrity of the mechanoelectrical transduction complex in hair cells of the adult cochlea"). MYO7A also participates in ankle-link positioning in the stereocilia bundle and co-localizes with PDZD7 at the ankle-link region (eLife 2016, PMC5005036). 4. Consequence in DFNA11: Dysregulated/dominantly acting mutant myosin disrupts normal tip-link tensioning and MET complex integrity in a dose-dependent, progressive manner — producing progressive loss of MET current and progressive threshold elevation, without the profound congenital dysfunction and stereocilia disorganization seen in USH1B (where myosin VIIa is essentially non-functional/mislocalized). 5. Tissue-level consequence: Progressive cochlear hair cell (particularly stereocilia bundle) dysfunction across the cochlear frequency map, manifesting audiometrically as the age-dependent shift from sloping to flat threshold configuration described clinically (PMID: 32097363). 6. Organism-level consequence: Progressive, postlingual, bilateral sensorineural hearing loss, with variable, generally milder vestibular involvement than in USH1B (reflecting that the vestibular hair cell MET/tip-link apparatus is less severely affected by the "activating" dominant variants than by the loss-of-function USH1B alleles).

Cell types involved: Cochlear inner and outer hair cells (auditory); vestibular hair cells (variably, for the vestibular component). Suggested CL term: CL:0000855 (sensory hair cell) / CL:0002620 (skeletal muscle satellite — N/A) — more precisely CL:0000201 (auditory hair cell) if available in the ontology used, or UBERON-anchored hair cell terms.

Biological processes: Suggested GO terms: - GO:0007605 (sensory perception of sound) - GO:0060088 (auditory receptor cell stereocilium organization) - GO:0036158 (outer dynein arm assembly — N/A, not relevant) — more appropriately GO:0032420 (stereocilium) as a cellular component and GO:0060113 (inner ear receptor cell differentiation) - Molecular function: GO:0003774 (cytoskeletal motor activity) / GO:0000146 (microfilament motor activity, actin-based motor)

Protein dysfunction category: Altered regulation/autoinhibition (a form of activating/gain-of-function dysregulation) rather than classic loss-of-function or aggregation-based misfolding — distinguishing DFNA11's mechanism from typical dominant-negative structural-protein diseases.

Subcellular localization (GO Cellular Component): Stereocilia (GO:0032420, stereocilium; specifically the upper tip-link density region of the stereocilium tip).

Not applicable/not identified in this review: No specific immune-system involvement, no described metabolic pathway alterations, and no transcriptomic/proteomic/metabolomic/lipidomic profiling datasets specific to DFNA11 human hair cells were identified (human inner-ear tissue is inherently difficult to biopsy, so most molecular profiling in this field derives from animal/organoid models rather than human patients).

7. Anatomical Structures Affected

Organ level: - Primary organ: Inner ear — specifically the cochlea (organ of Corti) for the hearing phenotype, and the vestibular labyrinth (semicircular canals, utricle, saccule) for the variable vestibular phenotype. - Body system: Auditory/vestibular sensory system (special senses). - No other organ systems are affected — this distinguishes nonsyndromic DFNA11 from syndromic USH1B (which additionally involves the retina). - Suggested UBERON terms: UBERON:0001846 (cochlea), UBERON:0002105 (vestibular organ) / UBERON:0009038 (vestibular labyrinth), UBERON:0000030 (sensory system, general).

Tissue/cell level: - Sensory epithelium of the organ of Corti — inner hair cells and outer hair cells and their stereociliary bundles. - Suggested Cell Ontology term: cochlear hair cell (best available CL term for auditory hair cells; e.g., CL:0000201, "auditory hair cell").

Subcellular level: - Stereocilia (actin-based mechanosensory protrusions on the hair-cell apical surface) — the principal subcellular site of Myo7A dysfunction. - The tip link and upper tip-link density (UTLD), a specialized subdomain at the stereocilium tip. - Suggested GO Cellular Component terms: GO:0032420 (stereocilium), GO:0032421 (stereocilium bundle), GO:0002131 (stereocilium tip [if present in ontology]).

Localization: Bilateral, symmetric involvement of both cochleae (and both vestibular labyrinths when vestibular dysfunction is present) — no lateralization pattern is described.

8. Temporal Development

Onset: Postlingual — after speech has been acquired. Reports vary: OMIM describes onset "often in the first decade of life"; other cohort/pedigree studies describe onset in the second decade (Kubota et al., PMID: 11889386) through the second-to-fifth decade depending on the specific variant/domain affected (motor-domain variants: later onset, second–fifth decade; MyTH4-domain variants: earlier onset, teens–20s) (Joo et al. 2022, PMID: 35453549).

Onset pattern: Insidious/gradual rather than acute or episodic.

Progression: Slowly progressive at high frequencies initially; low frequencies become involved later but then progress more rapidly once affected (PMID: 32097363). Audiometric configuration evolves over decades from sloping (childhood) to flat (after age ~30).

Disease course pattern: Progressive, not relapsing-remitting or episodic. No spontaneous remission is described.

Disease duration: Chronic and lifelong/progressive — hearing loss does not resolve and is expected to continue worsening with age.

Critical periods / early biomarker window: Abnormal DPOAEs can be detected before conventional audiometric threshold shifts, suggesting a preclinical detection window that could inform earlier monitoring or intervention timing (PMID: 32097363).

9. Inheritance and Population

Epidemiology: - Hearing loss overall affects approximately 1–3 per 1,000 live births, with more than half attributable to genetic causes. - Non-syndromic hearing loss is predominantly autosomal recessive (75–80% of Mendelian cases); autosomal dominant nonsyndromic hearing loss (ADNSHL, the DFNA category) accounts for roughly 20% of nonsyndromic hereditary hearing loss cases; X-linked accounts for 2–5%, mitochondrial ~1%. - Within ADNSHL specifically, 46 causative genes have been identified to date, of which MYO7A (DFNA11) is one. - DFNA11 is explicitly characterized as "the rarest consequence of the MYO7A gene variant" relative to DFNB2 and USH1B — i.e., among the three MYO7A-associated phenotypes, dominant DFNA11 is the least frequently observed clinically (Joo et al. 2022, PMID: 35453549, synthesis). - In a large post-lingual ADNSHL diagnostic cohort (Korea), MYO7A/DFNA11 variants were identified in 2.0% (6/300) of families overall and 4.1% (6/148) of multiplex families (PMID: 35453549).

Inheritance pattern: Autosomal dominant.

Penetrance: Appears high/complete within described pedigrees (all variant carriers develop hearing loss), though formal penetrance estimates were not located in this review.

Expressivity: Variable — age of onset, severity, audiometric configuration, and presence/absence of vestibular involvement vary between and within families, correlating in part with which protein domain is affected (motor vs. MyTH4 vs. IQ/coiled-coil) (PMID: 35453549).

Genetic anticipation: Not described for DFNA11 (not a repeat-expansion disorder).

Germline mosaicism: Not specifically reported for DFNA11 in this review.

Founder effects: Not specifically documented for DFNA11 variants in the sources reviewed (contrast with some MYO7A-DFNB2/USH1B populations where founder alleles are described in specific ethnic groups, e.g., South African and Chinese cohorts).

Carrier frequency: As an autosomal dominant condition with (presumably) private family-specific variants, a general population "carrier frequency" concept (as used for recessive disease) is not applicable in the same way; rather, prevalence reflects de novo occurrence plus transmission within affected pedigrees.

Consanguinity role: Not relevant to this dominant condition (relevant instead to the recessive DFNB2/USH1B end of the MYO7A spectrum).

Population demographics: DFNA11 has been reported in diverse populations including Dutch, Japanese, Korean, and Chinese pedigrees, without an established predominant ethnic enrichment specific to the dominant (as opposed to recessive) phenotype, based on the geographic spread of cited cohort studies.

Sex ratio: No sex-specific skewing is described — consistent with autosomal (non-X-linked) inheritance.

10. Diagnostics

Clinical tests: - Pure-tone audiometry: primary diagnostic tool; characteristic evolving configuration (sloping → flat) with age, as described above. - Distortion product otoacoustic emissions (DPOAE): identified as potentially useful for early/preclinical detection, showing abnormalities before conventional threshold elevation in some DFNA11 subjects (PMID: 32097363). - Vestibular function testing (e.g., caloric testing, vestibular-evoked myogenic potentials/VEMP, video head-impulse testing): used to characterize the variable vestibular component; results are family-specific (normal in some pedigrees, abnormal in others). - Ophthalmologic examination (including electroretinography): important to formally exclude retinitis pigmentosa/USH1B, given allelism at the MYO7A locus — a normal ERG supports the nonsyndromic DFNA11 diagnosis over USH1B.

Genetic testing: - Diagnosis is established by identifying a heterozygous pathogenic/likely pathogenic MYO7A variant, typically via next-generation sequencing (NGS) hearing-loss gene panels, whole-exome sequencing, or single-gene MYO7A sequence analysis, in the context of a family history consistent with autosomal dominant inheritance and a characteristic audioprofile. - GTR (Genetic Testing Registry) lists 37 clinical tests for this condition, including 31 sequence-analysis tests of the entire coding region, 23 deletion/duplication analyses, 4 targeted variant analyses, and 1 select-exon sequence analysis (NIH GTR C1832475). - Chromosomal microarray, karyotyping, and mitochondrial DNA testing are not primary diagnostic modalities for this single-gene point-variant disorder.

Differential diagnosis: Other ADNSHL genes (e.g., COCH/DFNA9, WFS1, MYO6, MYO15A, NCOA3), age-related hearing loss, noise-induced hearing loss, and — critically — USH1B (must be excluded via ophthalmologic/ERG evaluation given allelic overlap at MYO7A) and DFNB2 (excluded by dominant vs. recessive family segregation pattern).

Screening: Newborn hearing screening (universal, non-gene-specific) would detect congenital/early hearing loss but DFNA11's typically postlingual onset means it is more often identified through childhood/young-adult audiometric surveillance in known-affected families plus cascade genetic testing once a familial variant is identified. At-risk relatives can be tested to guide early monitoring (annual audiograms are recommended for progression tracking in ADNSHL generally).

11. Outcome/Prognosis

Survival/mortality: DFNA11 is not associated with increased mortality — it is an isolated sensory (auditory ± vestibular) disorder with no systemic organ involvement.

Morbidity/function: Progressive bilateral sensorineural hearing loss leading, over decades, to moderate-to-severe (and potentially profound in some MyTH4-variant cases) hearing impairment; functional impact centers on communication and, if vestibular involvement is present, balance/gait.

Disease course/complications: No systemic complications are described. The main "complication" is progression to a degree of hearing loss requiring amplification or cochlear implantation.

Recovery potential: Hearing loss is not reversible without intervention (hearing aids/cochlear implant); there is no evidence of spontaneous recovery.

Prognostic factors: Domain of the causative variant appears prognostic — motor-domain variants are associated with later onset, milder severity, and slower progression, while MyTH4-domain variants are associated with earlier onset, greater severity, and more rapid progression (PMID: 35453549). Abnormal DPOAE prior to threshold shift may serve as an early prognostic/monitoring biomarker (PMID: 32097363).

12. Treatment

DFNA11 has no gene-specific or disease-modifying pharmacotherapy; management is supportive/rehabilitative, following general ADNSHL practice:

  • Hearing aids — for mild-to-moderate hearing loss (amplification). Suggested NCIT term: consider a general audiologic rehabilitation/hearing-aid-fitting procedure term if present in NCIT (no MAXO/NCIT-specific "hearing aid" clinical-action term is confirmed to exist per this repository's own documented gap — see CLAUDE.md note on lack of an NCIT equivalent for hearing-aid usage).
  • Cochlear implantation — considered when hearing loss progresses to severe-to-profound levels; NCIT candidate: NCIT:C15329 (Surgical Procedure) as the closest general clinical-action term, or a more specific cochlear-implantation term if available in NCIT.
  • Hybrid (electro-acoustic) devices — combining acoustic amplification for residual low-frequency hearing with electrical stimulation for high-frequency loss, relevant given DFNA11's sloping-then-flat audiometric evolution.
  • Genetic counseling — NCIT:C15240 (Genetic Counseling); important for informing at-risk relatives, given autosomal dominant transmission (~50% risk to offspring of an affected individual) and variable expressivity.
  • Audiologic surveillance — at least annual audiograms recommended to track progression; DPOAE monitoring may allow earlier detection of decline (PMID: 32097363).
  • Noise avoidance counseling — to minimize any additional/superimposed noise-induced component to the progressive genetic loss (general ADNSHL guidance, PMC10296186).

Experimental/advanced therapeutics: No DFNA11-specific gene therapy trials were identified. However, the allelic and mechanistically related USH1B (severe MYO7A loss-of-function) has active preclinical and early clinical gene-therapy development that is instructive for the broader MYO7A therapeutic landscape: - Dual-AAV8(Y733F) vector delivery of full-length MYO7A cDNA (split into 5′/3′ halves due to the ~6.7 kb cDNA exceeding single-AAV packaging capacity) has shown improved vestibular hair-cell stereocilium morphology and vestibular function in the shaker-1 (USH1B) mouse model, though cochlear stereocilia organization and auditory function were not similarly rescued (Molecular Therapy Methods & Clinical Development, 2023). - A Phase 1/2 human trial of dual-AAV MYO7A delivery to the retina in USH1B patients ("UshTher") was designed but was placed on hold after Sanofi withdrew from the program in December 2018; the sponsor sought an out-licensing partner as of February 2019. - Third-generation lentiviral gene therapy (UshStat, EIAV-based) has also been studied preclinically in the shaker-1 mouse model. - These approaches target loss-of-function USH1B alleles and are not directly applicable to DFNA11's proposed dominant-activation mechanism, which would more likely require an allele-specific knockdown or gene-silencing (rather than gene-replacement) strategy if a targeted therapy were pursued — though no such DFNA11-specific therapeutic program was identified in this review.

Personalized medicine: Not currently applicable beyond domain-based prognostic counseling (motor vs. MyTH4 variant location informing expected course, per PMID: 35453549).

13. Prevention

  • Primary prevention: Not applicable in the sense of preventing occurrence of a germline dominant variant; genetic counseling and reproductive options (e.g., preimplantation genetic testing) can be discussed with affected families who wish to reduce transmission risk, though this is standard ADNSHL counseling rather than DFNA11-specific literature.
  • Secondary prevention: Early identification via audiometric (and potentially DPOAE) surveillance in known-affected families/genetically confirmed carriers, enabling earlier fitting of amplification devices and earlier educational/communication support.
  • Tertiary prevention: Avoidance of additional noise exposure to prevent superimposed noise-induced threshold shifts; prompt escalation from hearing aids to cochlear implantation as thresholds decline, to minimize functional/communicative morbidity.
  • Genetic/carrier screening: Cascade testing of at-risk relatives once a familial MYO7A variant is identified; prenatal/preimplantation genetic testing is an option for informed families given the well-defined dominant Mendelian pattern.
  • Public health/behavioral/immunization/prophylaxis: Not applicable — DFNA11 is not preventable by vaccination, environmental intervention, or prophylactic medication.

14. Other Species / Natural Disease

Taxonomy: Mouse (Mus musculus, NCBITaxon:10090) and zebrafish (Danio rerio, NCBITaxon:7955) are the principal model species; no naturally occurring companion-animal or wildlife DFNA11-equivalent disease was identified in this review (note: some veterinary myosin-related deafness models exist for other myosin genes, but not specifically an autosomal dominant Myo7a condition analogous to DFNA11).

Orthologous gene: Mouse Myo7a (MGI ortholog of human MYO7A); zebrafish myo7aa (and paralog myo7ab).

Comparative biology: The mouse and zebrafish Myo7a-null/loss-of-function models (below) primarily recapitulate the USH1B/DFNB2 end of the phenotypic spectrum (profound congenital deafness plus vestibular dysfunction, with only mild/attenuated retinal phenotypes in mouse and zebrafish compared to human USH1B). A model specifically representing the dominant, activating DFNA11 mechanism (as opposed to loss-of-function) was not identified in the literature surveyed — this is a modeling gap, since the shaker-1 and mariner models are loss-of-function (recessive-equivalent), not dominant-activating alleles.

Transmission/zoonotic potential: Not applicable — this is a non-infectious, monogenic disorder.

15. Model Organisms

Mouse — Shaker-1 (sh1): - The first identified USH locus model (1995); a spontaneous nonsense mutation in Myo7a. - Phenotype: profound, lifelong deafness; vestibular dysfunction manifesting as head-tossing and circling behavior; disorganized cochlear hair-cell stereocilia; only minor/mild retinal defects are observed despite the human USH1B phenotype including significant retinitis pigmentosa — a notable human-model translational mismatch for the retinal component. - Represents the severe loss-of-function end of the Myo7a spectrum (USH1B-like), not the dominant-activating DFNA11 mechanism. - AAV-mediated Myo7a rescue (dual-AAV8(Y733F)) in shaker-1 mice improves vestibular hair-cell stereocilium morphology and vestibular function (reduced circling, improved VsEP thresholds) but does not similarly rescue cochlear stereocilia organization or auditory function — indicating differential rescuability of vestibular versus auditory hair cells.

Zebrafish — myo7aa mariner mutant: - Ernest et al. (2000) described a myo7aa premature-stop-codon zebrafish model of USH1B; homozygous mutants show circular swimming, defective balance, morphological/functional inner-ear hair-cell defects, and absence of the acoustic startle response. - myo7aa⁻/⁻ zebrafish also show mild photoreceptor degeneration and reduced electroretinographic responses (PMID: 24698764), again modeling USH1B rather than DFNA11 specifically. - A more recent study (Frontiers in Molecular Neuroscience, 2024) implicates zebrafish myo7aa in congenital hearing via Rho-GTPase signaling regulation, adding a signaling-pathway dimension to the mechanistic picture.

Cell-based/epithelial models: Heterologous expression systems (e.g., kidney epithelial cell lines such as MDCK-type cells) have been used to directly test DFNA11 patient-derived missense variants for their effect on Myo7A subcellular targeting/trafficking, providing the closest available model to the dominant DFNA11 mechanism itself (bioRxiv 2024.09.17.613491 / PubMed 39345484) — these assays found that DFNA11 mutations activate (rather than abolish) Myo7A targeting, distinguishing the cellular mechanism from the USH1B mistargeting phenotype.

Model limitations: No available animal model directly and specifically recapitulates the dominant, gain-of-function/activating DFNA11 mechanism in vivo (as opposed to the standard loss-of-function shaker-1/mariner alleles) — an important human-model mismatch to flag for any DFNA11 knowledge-base entry: existing Myo7a animal models are informative for general hair-cell MET biology and for the USH1B/DFNB2 severe end of the spectrum, but their applicability to DFNA11's proposed dominant-activation mechanism and its comparatively mild, slowly progressive phenotype is not established.

Resources: MGI (Mouse Genome Informatics) for shaker-1 allele records; ZFIN for zebrafish myo7aa mariner allele records; IMSR/EMMA for repository access to Myo7a mouse strains.

Summary of Key Primary Citations

Citation Topic
Liu et al., Nat Genet 1997;17:268–269 (PMID: 9354784) Original identification of MYO7A mutation causing autosomal dominant nonsyndromic deafness (DFNA11)
Weil et al., Nat Genet 1997;16:191–193 MYO7A as allelic cause of DFNB2/USH1B
Kubota et al. 2002 (PMID: 11889386) Phenotype of DFNA11: moderate cochlear hearing loss from second decade, variable vestibular dysfunction, no retinal degeneration
Naz et al. 2008 (PMID: 18667942) Search for DFNA11 low/mid-frequency genetic modifier
Kim et al. 2020 (PMID: 32097363) Clinical profile across ages in a large DFNA11 family; DPOAE as early marker; p.Arg853His variant
Joo et al., Biomedicines 2022;10(4):798 (PMID: 35453549) Domain-specific genotype-phenotype correlations (motor vs. MyTH4 vs. IQ/coiled-coil) across DFNA11/DFNB2/USH1B
bioRxiv 10.1101/2024.09.17.613491 (PubMed: 39345484) Mechanistic study: DFNA11 mutations activate Myo7A targeting in epithelial cells
Nature Communications 2020 (PMID: 32350269) Myosin-VIIa tensions the hair-cell mechanotransduction complex
eLife 2016 (PMC5005036) PDZD7–MYO7A complex at stereocilia ankle-link region
PNAS 2024/2025 MYO7A required for MET complex integrity in adult cochlear hair cells

Notes on Information Gaps

  • Direct OMIM #601317 full-text clinical synopsis and the primary GeneReviews MYO7A chapter could not be fetched directly (403/cookie-wall errors); content above synthesizes OMIM/GTR summaries obtained via search snippets and secondary sources, and should be cross-checked against the primary OMIM clinical synopsis and GeneReviews "MYO7A-Related Hearing Loss and Retinitis Pigmentosa" chapter when curating a formal knowledge-base entry.
  • No gnomAD constraint metrics (pLI/LOEUF/missense Z) specific to MYO7A were retrieved in this pass; these should be pulled directly from gnomAD for the knowledge-base entry.
  • No dedicated DFNA11 prevalence/incidence rate (cases per 100,000) was located; only the general ADNSHL proportion (~20% of nonsyndromic hereditary hearing loss) and MYO7A's cohort-level diagnostic yield (2.0–4.1% of postlingual ADNSHL families in one Korean cohort) are available as proxies.
  • The mechanistic bioRxiv paper (39345484) appears to have been a preprint at the time of search; verify final peer-reviewed publication status/PMID before final curation.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 10
Resolved 10
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 0
Quoted claims not found in source 1
References weighed for topical relevance 10
On topic 7
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:32097363 (abstract only): "remained normal across all tested subjects"
  • closest text in source: "Vestibular function was within the normal range in all the subjects tested"