Autosomal Dominant Nonsyndromic Hearing Loss 17

Genetic MONDO:0011350 Pathograph 9 Show in embeddings browser autosomal dominant nonsyndromic hearing loss

DFNA17 is autosomal dominant, adult-onset, progressive sensorineural hearing loss caused by the MYH9 missense variant p.Arg705His, which sits in the SH1 helix of non-muscle myosin heavy chain IIA (NMMHC-IIA). It was defined as a *nonsyndromic* entity: hearing loss with none of the haematological or systemic features that accompany MYH9 variants elsewhere in the gene. **Whether DFNA17 is a distinct disease is genuinely disputed, and this entry does not settle it.** MYH9 variants also cause MYH9-related disease (MYH9-RD), a spectrum absorbing the historical May-Hegglin, Sebastian, Fechtner, Epstein and Alport-like syndromes, in which congenital macrothrombocytopenia with neutrophil NMMHC-IIA inclusions is universal and hearing loss, nephropathy, cataract and raised liver enzymes appear over a lifetime. In 2015 Verver, Pecci and colleagues found the *same* p.Arg705His allele in two unrelated families whose affected members had not only hearing impairment but also thrombocytopenia, giant platelets, leukocyte inclusions and raised liver enzymes, and argued explicitly that DFNA17 "should not be a separate genetic entity" but part of the MYH9-RD spectrum. On that reading the original families were not nonsyndromic; their haematology was never looked at closely enough. The entry is curated under its own MONDO term because MONDO and OMIM keep it distinct, but the lumping argument is recorded as an open discussion rather than buried, and the MYH9-RD features are curated as phenotypes so an entry that turns out to be a subtype does not have to be rebuilt. The mechanism is not haploinsufficiency. Heterozygous gene-trap Myh9 mice carrying half the normal Myh9 mRNA in the inner ear have *no* hearing loss and no cochleosaccular degeneration, so losing one working copy is not what produces the human phenotype. What p.Arg705His does instead, studied in the Dictyostelium myosin II equivalent (R689H), is impair motility while barely touching actin-activated ATPase, reduce cross-bridge stiffness, and reduce thermal stability to the point of inducing protein aggregation - a mechanoelastic and stability defect rather than a loss of catalytic power.

Ask OpenScientist

Ask a research question about Autosomal Dominant Nonsyndromic Hearing Loss 17. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
6
Pathophys.
4
Phenotypes
2
Gaps
9
Pathograph
1
Genes
2
Medical Actions
1
Differentials
1
Models
3
References
1
Deep Research
🏷

Classifications

Harrison's Part
NEUROLOGIC
👪

Inheritance

1
Autosomal dominant HP:0000006
A single heterozygous MYH9 allele co-segregates with hearing impairment. Note that heterozygous *loss* of Myh9 does not reproduce the phenotype in mice, so dominance here is not simple haploinsufficiency.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:11023810 SUPPORT Human Clinical
"Sequence analysis of MYH9 in a family with DFNA17 identified, at nucleotide 2114, a G-->A transposition that cosegregated with the inherited autosomal dominant hearing impairment."
Co-segregation of a heterozygous allele with dominant hearing impairment.
?

Discussions and Knowledge Gaps

2
Is DFNA17 a distinct nonsyndromic disease, or is it MYH9-related disease in which the haematological features were never systematically looked for?
KNOWLEDGE GAP OPEN dfna17_separate_entity_or_myh9_rd_spectrum
Attached to
pathophysiology#MYH9 p.Arg705His Variant in the SH1 Helix pathophysiology#Neutrophil NMMHC-IIA Inclusions
This is a live disagreement about whether the entity this entry describes exists, and it is the most important open question here. The case for lumping is strong and specific: Verver, Pecci and colleagues found the same p.Arg705His allele in two unrelated families whose affected members had thrombocytopenia, giant platelets, leukocyte inclusions and raised liver enzymes, and concluded that DFNA17 "should not be a separate genetic entity but part of the wide phenotypic spectrum of MYH9-RD". Because the haematological features of MYH9-RD are congenital and universal by GeneReviews' account, while the extrahaematological ones have variable penetrance, a kindred ascertained through an ENT clinic could easily be reported as nonsyndromic without anyone examining a blood film. The case for splitting rests mainly on the original reports and on the neighbouring-codon contrast, where p.Arg702Cys/His gave syndromic disease and the adjacent p.Arg705His did not - but that contrast was drawn before the 2015 families were described. Resolving this is not academic: a patient labelled DFNA17 and not screened haematologically may have unrecognised bleeding risk, and the GeneReviews agents-to-avoid list would apply to them.
Proposed experiments
Systematic haematological phenotyping of all reported p.Arg705His carriers
dfna17_systematic_haematology_in_reported_kindreds
Re-examine every published p.Arg705His kindred, including the original American and Australian families, with platelet count, mean platelet volume/blood film for macrothrombocytopenia, and immunofluorescence for NMMHC-IIA granulocyte inclusions - the last being the pathognomonic and most sensitive marker. Absence of inclusions in a properly examined carrier would be the strongest evidence that a truly nonsyndromic p.Arg705His phenotype exists.
Readouts
NMMHC-IIA granulocyte inclusions by immunofluorescence
Neutrophil NMMHC-IIA Inclusions
Direction: INCREASED
Interpretation: Inclusions present in the original kindreds would settle the question in favour of lumping; their reproducible absence would support a genuinely nonsyndromic subtype.
Does any animal model reproduce what the p.Arg705His protein does, as opposed to what losing MYH9 does?
HUMAN MODEL MISMATCH OPEN dfna17_no_knockin_missense_model
Attached to
pathophysiology#Cochleosaccular Degeneration pathophysiology#Impaired Myosin Motility with Reduced Cross-Bridge Stiffness
The only reported mouse model is a gene-trap null, and it is negative: half the normal inner-ear Myh9 mRNA produced neither hearing loss nor cochleosaccular degeneration. That negative is informative - it excludes haploinsufficiency - but it cannot test the missense allele, because a missing protein cannot exhibit reduced cross-bridge stiffness or thermal aggregation. Meanwhile the biophysical characterisation of the mutation was done in *Dictyostelium* myosin II (R689H), an amoebal orthologue studied in vitro, and the cellular characterisation in human cancer cell lines whose response was itself cell-type-dependent (MDA-MB-231 responded, HeLa did not). So there is a chain of model systems, none of which is a mammalian cochlea expressing the mutant protein at endogenous levels.
Proposed experiments
Myh9 p.Arg705His knock-in mouse with longitudinal auditory and haematological phenotyping
myh9_r705h_knockin_mouse_cochlea
Generate a knock-in of the orthologous missense residue and follow ABR thresholds, cochleosaccular histology, platelet count and volume, and granulocyte NMMHC-IIA inclusions over the lifespan. Because the model would carry the mutant protein rather than lack it, it tests both the mechanism and, incidentally, the lump/split question: a knock-in with macrothrombocytopenia and deafness would be MYH9-RD, not DFNA17.
Readouts
ABR threshold shift over the lifespan in knock-in mice
Cochleosaccular Degeneration
Direction: INCREASED
Interpretation: Progressive threshold elevation absent from the gene-trap heterozygote would confirm that the missense protein, not reduced dosage, drives the phenotype.
⚙

Pathophysiology

6
MYH9 p.Arg705His Variant in the SH1 Helix
A heterozygous c.2114G>A missense change converting an invariant arginine at codon 705 to histidine, within the highly conserved SH1 linker of non-muscle myosin heavy chain IIA. The SH1 helix is the joint connecting the converter subdomain to the rest of the motor domain, which is why a substitution here was expected to affect motor function rather than expression level.
Genetic context allele_type: SNV variant_origin: GERMLINE zygosity: HETEROZYGOUS
Downstream
Impaired Myosin Motility with Reduced Cross-Bridge Stiffness Substituting the SH1-helix arginine degrades the motor's mechanical output.
NMMHC-IIA Thermal Destabilization and Aggregation The same substitution lowers the protein's thermal stability, a separate consequence from the mechanical one.
Show evidence (2 references)
PMID:11023810 SUPPORT Human Clinical
"This missense mutation changes codon 705 from an invariant arginine (R) to histidine (H), R705H, within a highly conserved SH1 linker region."
Identifies the variant and locates it in the SH1 linker.
PMID:16901894 SUPPORT In Vitro
"The SH1 helix is the joint that connects the converter subdomain to the other domains, and is thought to play an important role in arrangements of the converter relative to the motor."
Establishes what the SH1 helix does, which is the structural basis for expecting a mechanical rather than expression-level defect.
Impaired Myosin Motility with Reduced Cross-Bridge Stiffness
Single-molecule optical-trap measurements on the equivalent Dictyostelium myosin II mutation show that step size is preserved but cross-bridge stiffness falls, so the motor is less stiff rather than less powerful. The authors interpret the slower motility as altered kinetics and infer that the SH1 helix modulates myosin elasticity through converter flexibility.
microfilament motor activity GO:0000146 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased microfilament motor activity (GO:0000146). GO:0000146 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Cytokinesis Failure and Altered Cell Morphology Non-muscle myosin IIA drives the cytokinetic ring, so a motility defect is the plausible route to the cytokinesis failure observed on expressing the mutant allele. The intervening steps were not established.
Cochleosaccular Degeneration The proposed route from the molecular defect to the inner-ear lesion. The founding study was explicit that this step is not understood.
Show evidence (2 references)
PMID:16901894 SUPPORT In Vitro
"Single molecule mechanical measurements using optical trap showed that the step size was not shortened by the mutation, suggesting that the slower motility is caused by altered kinetics."
Distinguishes a kinetic/elastic defect from a shortened working stroke.
PMID:16901894 SUPPORT In Vitro
"The single molecule measurements demonstrated that the mutation significantly reduced cross-bridge stiffness."
The direct measurement this node is named for.
NMMHC-IIA Thermal Destabilization and Aggregation
The variant protein is thermally less stable and aggregates. This matters because aggregation of NMMHC-IIA is the pathognomonic cellular lesion of MYH9-related disease, where mutant protein forms visible inclusions in neutrophil cytoplasm - the same physical behaviour, seen in a different cell type.
protein-containing complex assembly GO:0065003 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased protein-containing complex assembly (GO:0065003). GO:0065003 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Neutrophil NMMHC-IIA Inclusions In granulocytes the aggregated protein is visible as cytoplasmic inclusions, the pathognomonic sign of MYH9-RD - present in the p.Arg705His families reported by Verver and colleagues.
Show evidence (2 references)
PMID:16901894 SUPPORT In Vitro
"the mutation was also shown to reduce thermal stability and induce thermal aggregation of the protein, which might be implicated in the disease process"
The biophysical measurement behind this node.
PMID:24890873 SUPPORT Human Clinical
"MYH9-RD patients have macrothrombocytopenia and granulocyte inclusions (pathognomonic sign of the disease) containing wild-type and mutant NMMHC-IIA."
Shows that NMMHC-IIA aggregation is an observed lesion in patients carrying MYH9 variants, and that the inclusions contain wild-type protein too - consistent with the mutant sequestering the normal product.
Cytokinesis Failure and Altered Cell Morphology
Expressing the mutant allele produces multinucleate cells and excess filopodia. The effect is cell-type-dependent: MDA-MB-231 cells respond, HeLa cells are refractory, and the actin cytoskeleton itself is unaffected. That selectivity is worth preserving, because it is the sort of context dependence that could explain why one variant produces an organ-restricted phenotype.
cytokinesis GO:0000910 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cytokinesis (GO:0000910). GO:0000910 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (2 references)
PMID:20416459 SUPPORT In Vitro
"Unlike MDA-MB-231 cells, HeLa cells were refractory to MYH9(R705H) and MYH9(R702C)."
The cell-type dependence, curated so it is not lost when the positive result is quoted alone.
PMID:20416459 SUPPORT In Vitro
"Actin cytoskeleton configuration within MDA-MB-231 cells was unaffected by expression of MYH9(R702C) or MYH9(R705H)."
A negative result that narrows the defect: the motor is affected, the actin scaffold is not.
Cochleosaccular Degeneration
Degeneration of the cochlear and saccular sensory epithelia. This was the lesion the DFNA17 locus was named for at mapping, before the gene was known. NMMHC-IIA is expressed in the organ of Corti, the subcentral region of the spiral ligament and the Reissner membrane, giving the protein a plausible site of action; in rodent inner ear it is reported in stereocilia hair cells, spiral ligament and spiral limbus. Conformance is asserted at the module's sensory-epithelium-insult node, not at hair-cell mechanotransduction death, because no study has shown hair-cell mechanotransduction failure for this variant.
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. 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.
Animal models
Heterozygous gene-trap Myh9 mouse (BayGenomics ES cell line) Mouse fails to recapitulate Heterozygous Myh9 loss does not reproduce the human inner-ear lesion, which argues that DFNA17 is not caused by simple haploinsufficiency and that the p.Arg705His protein must do something a missing protein does not.
Downstream
Progressive sensorineural hearing loss Loss of the cochlear sensory epithelium produces the sensorineural deficit and its progression.
Show evidence (5 references)
PMID:11023810 SUPPORT Model Organism
"MYH9 was immunolocalized in the organ of Corti, the subcentral region of the spiral ligament, and the Reissner membrane."
Localizes the protein to the structures that degenerate. Rat cochlea, so tagged MODEL_ORGANISM.
PMID:41751538 SUPPORT Model Organism
"According to studies using rodent inner ears, NMMHC-IIA is also expressed predominantly in the hair cells of the stereocilia, spiral ligament, and spiral limbus."
Independent statement of inner-ear expression, again in rodent.
PMID:16862555 SUPPORT Model Organism
"Confocal microscopy of cochlear surface preparations, identified Myh9 within the inner and outer hair cells and their stereocilia."
Subcellular localization to hair cells and their stereocilia, which is the basis for the two hair-cell CL annotations on this node.
+ 2 more references
Neutrophil NMMHC-IIA Inclusions
Cytoplasmic aggregates of NMMHC-IIA in granulocytes, historically called Doehle body-like inclusions, containing both mutant and wild-type protein. They are pathognomonic of MYH9-related disease, and their presence in p.Arg705His carriers is the single strongest argument that DFNA17 is not nonsyndromic. This node exists precisely so the entry can carry that evidence rather than define it away.
neutrophil CL:0000775 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neutrophil (CL:0000775). CL:0000775 is a cell type from the Cell Ontology.
Show evidence (2 references)
PMID:20301740 SUPPORT Human Clinical
"aggregates of the MYH9 protein in the cytoplasm of neutrophil granulocytes"
GeneReviews states the inclusion as a universal feature of MYH9-RD.
PMID:24890873 SUPPORT Human Clinical
"leukocyte inclusions, as well as mild to moderate elevation of some liver enzymes"
Reports leukocyte inclusions in p.Arg705His carriers.
⬡

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 17 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

4
Ear 1
Bilateral profound hearing loss Profound sensorineural hearing impairment HP:0011476 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Profound sensorineural hearing impairment (HP:0011476). HP:0011476 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41751538 SUPPORT Human Clinical
"hearing loss in each set of patients finally deteriorates to bilateral profound hearing loss"
States the shared bilateral profound endpoint.
Metabolism 1
Elevated liver enzymes Elevated circulating hepatic transaminase concentration HP:0002910 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating hepatic transaminase concentration (HP:0002910), qualified as severity mild. HP:0002910 is a phenotype from the Human Phenotype Ontology.
Severity: MILD
Show evidence (1 reference)
PMID:24890873 SUPPORT Human Clinical
"as well as mild to moderate elevation of some liver enzymes"
Reports transaminase elevation in p.Arg705His carriers.
Other 2
Progressive sensorineural hearing loss Progressive sensorineural hearing impairment HP:0000408 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive sensorineural hearing impairment (HP:0000408), qualified as course progressive. HP:0000408 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:41751538 SUPPORT Human Clinical
"Some cases showed rapid hearing deterioration that worsened by about 50 dB within 5 years."
Quantifies the rate of deterioration in the largest reported cohort.
PMID:17146397 SUPPORT Human Clinical
"Nonsyndromic autosomal-dominant, adult-onset sensorineural hearing loss resulting from DFNA17 was described in a single American kindred in 1997, and the causative gene was subsequently identified as MYH9."
States the adult-onset, dominant, sensorineural character of the entity.
Macrothrombocytopenia HP:0040185 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrothrombocytopenia (HP:0040185). HP:0040185 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:24890873 SUPPORT Human Clinical
"whose four affected individuals had not only hearing impairment but also thrombocytopenia, giant platelets, leukocyte inclusions"
Documents macrothrombocytopenia in carriers of this entry's exact allele.
PMID:20301740 SUPPORT Human Clinical
"MYH9-related disease (MYH9-RD) is characterized in all affected individuals by hematologic features present from birth consisting of platelet macrocytosis"
GeneReviews baseline: the haematological feature is universal and congenital in MYH9-RD, which is why its absence from the original DFNA17 reports is the crux of the dispute.
🧬

Genetic Associations

1
MYH9
Gene: MYH9 hgnc:7579 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MYH9 (hgnc:7579). hgnc:7579 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (5 references)
PMID:11023810 SUPPORT Human Clinical
"Because of the importance of myosins in hearing, MYH9 was tested as a candidate gene for DFNA17."
Records how the gene was identified for this locus.
PMID:11590545 SUPPORT Human Clinical
"R702C and R702H mutations were only associated with FTNS, EPS, or APSM, thus defining a region of MYHIIA critical in the combined pathogenesis of macrothrombocytopenia, nephritis, and deafness."
Establishes the neighbouring-residue genotype-phenotype contrast.
PMID:41751538 SUPPORT Human Clinical
"Hearing loss is more likely to progress in patients with myosin head domain variants than in patients with myosin tail domain variants"
Domain-level genotype-phenotype correlation for hearing progression.
+ 2 more references
🗃️

External Assertions

2
OMIM DFNA17
OMIM disease record OMIM:603622
OMIM phenotype entry for deafness, autosomal dominant 17 (MYH9-related).
💊

Medical Actions

2
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
Direct electrical stimulation of the cochlear nerve for severe-to-profound loss, the endpoint most DFNA17/MYH9 patients reach. Outcome is reported as discordant between the only two DFNA17 kindreds published at the time: excellent in the Australian family, "poor" in the original American family, despite the identical p.Arg705His allele. The authors nevertheless concluded that implantation should be strongly considered. That discordance is curated rather than averaged away - with n=2 families it is as likely to reflect implantation era, duration of deafness, or measurement differences as anything biological.
Target Phenotypes: Progressive sensorineural hearing impairment HP:0000408 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Progressive sensorineural hearing impairment (HP:0000408). HP:0000408 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:17146397 SUPPORT Human Clinical
"Thus, cochlear implants should be strongly considered for clinical management of patients with DFNA17 deafness."
The authors' explicit management recommendation for this disease.
PMID:17146397 SUPPORT Human Clinical
"One important point of clinical relevance is the excellent outcome with cochlear implants in the Australian family compared with a "poor" response in the American family."
The discordance itself. Graded PARTIAL because it qualifies the recommendation rather than supporting it uniformly.
PMID:20301740 SUPPORT Human Clinical
"individuals with severe/profound deafness benefit from cochlear implantation"
GeneReviews management statement for MYH9-RD deafness, independent of the two DFNA17 kindreds.
Avoidance of Ototoxic, Nephrotoxic and Antiplatelet Agents
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
A drug-safety measure rather than a therapy, taken from the MYH9-RD GeneReviews *Agents/Circumstances to Avoid* section. It is curated here because it is the practical consequence of the unresolved lump/split question: if a DFNA17 patient is in fact within the MYH9-RD spectrum, then antiplatelet drugs carry bleeding risk on top of the ototoxicity concern that a progressive hearing loss already implies. Hazardous noise exposure and high-injury-risk activities are named in the same section.
Show evidence (2 references)
PMID:20301740 SUPPORT Human Clinical
"Drugs that inhibit platelet function or reduce platelet count, and drugs that are ototoxic, nephrotoxic, or hepatotoxic should be used only after assessment of risk-to-benefit ratio."
The GeneReviews agents-to-avoid statement, quoted directly.
PMID:20301740 SUPPORT Human Clinical
"Hazardous noise and activities with high risk of injury should be avoided."
The circumstances half of the same recommendation.
📊

Prevalence

1
Japanese hearing loss patients undergoing next-generation sequencing
Cases In Literature Ultra Rare
24 patients from 18 families with MYH9-associated hearing loss were identified among 15,684 Japanese hearing-loss patients sequenced - roughly 0.15% of that cohort. That figure is a diagnostic yield within an ascertained deafness population, NOT a population rate, so it is deliberately left out of rate_per_100000; it also counts all MYH9-associated hearing loss (MYH9-RD and DFNA17 together) rather than DFNA17 alone. Filling the numeric slot with it would have put ~1 in 650 in a structured field alongside a `prevalence_class` of ULTRA_RARE (<1 in 1,000,000) - a three-order-of-magnitude contradiction inside one record, which any consumer reading the numeric slot would get wrong. The counts survive in this note and in the two evidence items below. No population prevalence for DFNA17 has been published.
Show evidence (2 references)
PMID:41751538 SUPPORT Human Clinical
"In this study, we identified 24 patients from 18 families with MYH9-associated hearing loss."
The numerator.
PMID:41751538 SUPPORT Human Clinical
"we performed next-generation sequencing analysis for 15,684 hearing loss patients and identified MYH9-associated hearing loss patients"
The denominator, which is what makes the rate interpretable and also what limits it to a diagnostic yield.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Autosomal Dominant Nonsyndromic Hearing Loss 17:

🐁

Animal Models

1
Heterozygous gene-trap Myh9 mouse (BayGenomics ES cell line)
A gene-trap knockout allele, so this models *loss* of Myh9 rather than the human missense change. Its negative result is exactly what makes it informative: half-normal inner-ear Myh9 mRNA produced no hearing loss and no cochleosaccular degeneration even in aged animals.
Species
Mouse
Genotype
Myh9 gene-trap, heterozygous (homozygotes embryonic lethal)
Publication
PMID:16630581
Pathograph links
Cochleosaccular Degeneration fails to recapitulate fidelity: low Heterozygous Myh9 loss does not reproduce the human inner-ear lesion, which argues that DFNA17 is not caused by simple haploinsufficiency and that the p.Arg705His protein must do something a missing protein does not.
Limitations: The decisive limitation is allelic, not species: this is a null/gene-trap allele and the human disease is a missense change, so the model tests dosage rather than the mutant protein's behaviour. A knock-in of the orthologous missense residue would be the matching experiment and has not been reported. Species divergence in cochlear ageing is a secondary caveat, and homozygous lethality forecloses the higher-dose test.
Readouts
Auditory function in heterozygous Myh9 mice
Direction: UNCHANGED
Interpretation: No hearing loss despite reduced Myh9 - a genuine negative result, not a missing measurement.
Show evidence (1 reference)
PMID:16630581 SUPPORT Model Organism
"Hearing loss however was not observed in heterozygous Myh9 mice in contrast to human Myh9-related diseases."
The negative auditory result, stated by the authors as a contrast with the human disease.
Cochleosaccular histology in aged heterozygous Myh9 mice
Direction: UNCHANGED
Interpretation: The structural lesion that names the locus is also absent, so the negative is not merely a functional-testing artefact.
Show evidence (1 reference)
PMID:16630581 SUPPORT Model Organism
"Aged heterozygous Myh9 mice also did not show signs of cochleosaccular degeneration common in DFNA17."
Histological confirmation of the negative result in aged animals.
Show evidence (2 references)
PMID:16630581 SUPPORT Model Organism
"Although inheritance of Myh9 mutations in humans is dominant, we conclude that heterozygous loss of Myh9 is not critical to hearing function in mice by itself."
The authors' own conclusion, which is the reason this model is curated as informative despite - because of - its negative result.
+ 1 more reference
{ }

Source YAML

click to show 
name: Autosomal Dominant Nonsyndromic Hearing Loss 17
creation_date: "2026-08-22T15:00:00Z"
category: Genetic
description: >
  DFNA17 is autosomal dominant, adult-onset, progressive sensorineural hearing
  loss caused by the MYH9 missense variant p.Arg705His, which sits in the SH1
  helix of non-muscle myosin heavy chain IIA (NMMHC-IIA). It was defined as a
  *nonsyndromic* entity: hearing loss with none of the haematological or
  systemic features that accompany MYH9 variants elsewhere in the gene.

  **Whether DFNA17 is a distinct disease is genuinely disputed, and this entry
  does not settle it.** MYH9 variants also cause MYH9-related disease (MYH9-RD),
  a spectrum absorbing the historical May-Hegglin, Sebastian, Fechtner, Epstein
  and Alport-like syndromes, in which congenital macrothrombocytopenia with
  neutrophil NMMHC-IIA inclusions is universal and hearing loss, nephropathy,
  cataract and raised liver enzymes appear over a lifetime. In 2015 Verver,
  Pecci and colleagues found the *same* p.Arg705His allele in two unrelated
  families whose affected members had not only hearing impairment but also
  thrombocytopenia, giant platelets, leukocyte inclusions and raised liver
  enzymes, and argued explicitly that DFNA17 "should not be a separate genetic
  entity" but part of the MYH9-RD spectrum. On that reading the original
  families were not nonsyndromic; their haematology was never looked at closely
  enough. The entry is curated under its own MONDO term because MONDO and OMIM
  keep it distinct, but the lumping argument is recorded as an open discussion
  rather than buried, and the MYH9-RD features are curated as phenotypes so an
  entry that turns out to be a subtype does not have to be rebuilt.

  The mechanism is not haploinsufficiency. Heterozygous gene-trap Myh9 mice
  carrying half the normal Myh9 mRNA in the inner ear have *no* hearing loss and
  no cochleosaccular degeneration, so losing one working copy is not what
  produces the human phenotype. What p.Arg705His does instead, studied in the
  Dictyostelium myosin II equivalent (R689H), is impair motility while barely
  touching actin-activated ATPase, reduce cross-bridge stiffness, and reduce
  thermal stability to the point of inducing protein aggregation - a
  mechanoelastic and stability defect rather than a loss of catalytic power.
disease_term:
  preferred_term: DFNA17
  term:
    id: MONDO:0011350
    label: autosomal dominant nonsyndromic hearing loss 17
parents:
- autosomal dominant nonsyndromic hearing loss
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
references:
- reference: PMID:20301740
  title: "MYH9-Related Disease."
  tags:
  - GeneReviews
- reference: PMID:11023810
  title: "Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9."
- reference: PMID:24890873
  title: "R705H mutation of MYH9 is associated with MYH9-related disease and not only with non-syndromic deafness DFNA17."
external_assertions:
- name: OMIM DFNA17
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:603622
  description: OMIM phenotype entry for deafness, autosomal dominant 17 (MYH9-related).
- name: OMIM MYH9-related disease
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:155100
  description: >-
    OMIM phenotype entry for macrothrombocytopenia and granulocyte inclusions
    with or without nephritis or sensorineural hearing loss - the MYH9-RD
    spectrum into which some authors would fold DFNA17.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    A single heterozygous MYH9 allele co-segregates with hearing impairment.
    Note that heterozygous *loss* of Myh9 does not reproduce the phenotype in
    mice, so dominance here is not simple haploinsufficiency.
  evidence:
  - reference: PMID:11023810
    reference_title: "Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequence analysis of MYH9 in a family with DFNA17 identified, at nucleotide 2114, a G-->A transposition that cosegregated with the inherited autosomal dominant hearing impairment."
    explanation: >-
      Co-segregation of a heterozygous allele with dominant hearing impairment.
pathophysiology:
- name: MYH9 p.Arg705His Variant in the SH1 Helix
  biological_scale: MOLECULAR
  description: >-
    A heterozygous c.2114G>A missense change converting an invariant arginine at
    codon 705 to histidine, within the highly conserved SH1 linker of non-muscle
    myosin heavy chain IIA. The SH1 helix is the joint connecting the converter
    subdomain to the rest of the motor domain, which is why a substitution here
    was expected to affect motor function rather than expression level.
  genetic_context:
    allele_type: SNV
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
  evidence:
  - reference: PMID:11023810
    reference_title: "Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This missense mutation changes codon 705 from an invariant arginine (R) to histidine (H), R705H, within a highly conserved SH1 linker region."
    explanation: >-
      Identifies the variant and locates it in the SH1 linker.
  - reference: PMID:16901894
    reference_title: "A point mutation in the SH1 helix alters elasticity and thermal stability of myosin II."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The SH1 helix is the joint that connects the converter subdomain to the other domains, and is thought to play an important role in arrangements of the converter relative to the motor."
    explanation: >-
      Establishes what the SH1 helix does, which is the structural basis for
      expecting a mechanical rather than expression-level defect.
  downstream:
  - target: Impaired Myosin Motility with Reduced Cross-Bridge Stiffness
    causal_link_type: DIRECT
    description: >-
      Substituting the SH1-helix arginine degrades the motor's mechanical
      output.
    evidence:
    - reference: PMID:16901894
      reference_title: "A point mutation in the SH1 helix alters elasticity and thermal stability of myosin II."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The mutation resulted in a significant impairment in motile activities, whereas actin-activated ATPase activity was only slightly affected."
      explanation: >-
        The defining dissociation: motility fails while catalysis is nearly
        intact, so this is not a simple loss of enzyme activity.
  - target: NMMHC-IIA Thermal Destabilization and Aggregation
    causal_link_type: DIRECT
    description: >-
      The same substitution lowers the protein's thermal stability, a separate
      consequence from the mechanical one.
    evidence:
    - reference: PMID:16901894
      reference_title: "A point mutation in the SH1 helix alters elasticity and thermal stability of myosin II."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the mutation was also shown to reduce thermal stability and induce thermal aggregation of the protein, which might be implicated in the disease process"
      explanation: >-
        Reports the stability/aggregation arm, with the authors' own hedge that
        it "might be" implicated.
- name: Impaired Myosin Motility with Reduced Cross-Bridge Stiffness
  biological_scale: MOLECULAR
  description: >-
    Single-molecule optical-trap measurements on the equivalent Dictyostelium
    myosin II mutation show that step size is preserved but cross-bridge
    stiffness falls, so the motor is less stiff rather than less powerful. The
    authors interpret the slower motility as altered kinetics and infer that the
    SH1 helix modulates myosin elasticity through converter flexibility.
  molecular_functions:
  - preferred_term: microfilament motor activity
    modifier: DECREASED
    term:
      id: GO:0000146
      label: microfilament motor activity
  evidence:
  - reference: PMID:16901894
    reference_title: "A point mutation in the SH1 helix alters elasticity and thermal stability of myosin II."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Single molecule mechanical measurements using optical trap showed that the step size was not shortened by the mutation, suggesting that the slower motility is caused by altered kinetics."
    explanation: >-
      Distinguishes a kinetic/elastic defect from a shortened working stroke.
  - reference: PMID:16901894
    reference_title: "A point mutation in the SH1 helix alters elasticity and thermal stability of myosin II."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The single molecule measurements demonstrated that the mutation significantly reduced cross-bridge stiffness."
    explanation: >-
      The direct measurement this node is named for.
  downstream:
  - target: Cytokinesis Failure and Altered Cell Morphology
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Non-muscle myosin IIA drives the cytokinetic ring, so a motility defect is
      the plausible route to the cytokinesis failure observed on expressing the
      mutant allele. The intervening steps were not established.
    evidence:
    - reference: PMID:20416459
      reference_title: "In vitro expression and characterization of MYH9 mutant alleles linked to hereditary hearing loss."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "MDA-MB-231 cells transfected with MYH9(R705H) but not MYH9(R702C) were found to have a greater than two-fold increase in cells with filopodia and a ten-fold increase in proportion of cells with multiple nuclei, indicating inhibition of cytokinesis, relative to the control cells transfected with wild type MYH9."
      explanation: >-
        Documents the cellular phenotype. Graded PARTIAL because the study shows
        the allele causes it, not that the stiffness defect specifically does.
  - target: Cochleosaccular Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The proposed route from the molecular defect to the inner-ear lesion. The
      founding study was explicit that this step is not understood.
    evidence:
    - reference: PMID:11023810
      reference_title: "Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both the precise role of MYH9 in the cochlea and the mechanism by which the R705H mutation leads to the DFNA17 phenotype (progressive hearing impairment and cochleosaccular degeneration) remain to be elucidated."
      explanation: >-
        Cited as an explicit statement that the link is unresolved - PARTIAL
        because it names the gap rather than filling it.
- name: NMMHC-IIA Thermal Destabilization and Aggregation
  biological_scale: MOLECULAR
  description: >-
    The variant protein is thermally less stable and aggregates. This matters
    because aggregation of NMMHC-IIA is the pathognomonic cellular lesion of
    MYH9-related disease, where mutant protein forms visible inclusions in
    neutrophil cytoplasm - the same physical behaviour, seen in a different
    cell type.
  biological_processes:
  - preferred_term: protein-containing complex assembly
    modifier: INCREASED
    term:
      id: GO:0065003
      label: protein-containing complex assembly
  evidence:
  - reference: PMID:16901894
    reference_title: "A point mutation in the SH1 helix alters elasticity and thermal stability of myosin II."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the mutation was also shown to reduce thermal stability and induce thermal aggregation of the protein, which might be implicated in the disease process"
    explanation: >-
      The biophysical measurement behind this node.
  - reference: PMID:24890873
    reference_title: "R705H mutation of MYH9 is associated with MYH9-related disease and not only with non-syndromic deafness DFNA17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MYH9-RD patients have macrothrombocytopenia and granulocyte inclusions (pathognomonic sign of the disease) containing wild-type and mutant NMMHC-IIA."
    explanation: >-
      Shows that NMMHC-IIA aggregation is an observed lesion in patients
      carrying MYH9 variants, and that the inclusions contain wild-type protein
      too - consistent with the mutant sequestering the normal product.
  downstream:
  - target: Neutrophil NMMHC-IIA Inclusions
    causal_link_type: DIRECT
    description: >-
      In granulocytes the aggregated protein is visible as cytoplasmic
      inclusions, the pathognomonic sign of MYH9-RD - present in the
      p.Arg705His families reported by Verver and colleagues.
    evidence:
    - reference: PMID:24890873
      reference_title: "R705H mutation of MYH9 is associated with MYH9-related disease and not only with non-syndromic deafness DFNA17."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We identified the same mutation in two unrelated families, whose four affected individuals had not only hearing impairment but also thrombocytopenia, giant platelets, leukocyte inclusions, as well as mild to moderate elevation of some liver enzymes."
      explanation: >-
        Documents leukocyte inclusions in p.Arg705His carriers specifically.
- name: Cytokinesis Failure and Altered Cell Morphology
  biological_scale: CELLULAR
  description: >-
    Expressing the mutant allele produces multinucleate cells and excess
    filopodia. The effect is cell-type-dependent: MDA-MB-231 cells respond,
    HeLa cells are refractory, and the actin cytoskeleton itself is unaffected.
    That selectivity is worth preserving, because it is the sort of context
    dependence that could explain why one variant produces an organ-restricted
    phenotype.
  biological_processes:
  - preferred_term: cytokinesis
    modifier: DECREASED
    term:
      id: GO:0000910
      label: cytokinesis
  evidence:
  - reference: PMID:20416459
    reference_title: "In vitro expression and characterization of MYH9 mutant alleles linked to hereditary hearing loss."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Unlike MDA-MB-231 cells, HeLa cells were refractory to MYH9(R705H) and MYH9(R702C)."
    explanation: >-
      The cell-type dependence, curated so it is not lost when the positive
      result is quoted alone.
  - reference: PMID:20416459
    reference_title: "In vitro expression and characterization of MYH9 mutant alleles linked to hereditary hearing loss."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Actin cytoskeleton configuration within MDA-MB-231 cells was unaffected by expression of MYH9(R702C) or MYH9(R705H)."
    explanation: >-
      A negative result that narrows the defect: the motor is affected, the
      actin scaffold is not.
- name: Cochleosaccular Degeneration
  biological_scale: TISSUE
  conforms_to: "sensorineural_hair_cell_loss#Cochlear Sensory Epithelium Insult"
  description: >-
    Degeneration of the cochlear and saccular sensory epithelia. This was the
    lesion the DFNA17 locus was named for at mapping, before the gene was known.
    NMMHC-IIA is expressed in the organ of Corti, the subcentral region of the
    spiral ligament and the Reissner membrane, giving the protein a plausible
    site of action; in rodent inner ear it is reported in stereocilia hair
    cells, spiral ligament and spiral limbus. Conformance is asserted at the
    module's sensory-epithelium-insult node, not at hair-cell mechanotransduction
    death, because no study has shown hair-cell mechanotransduction failure for
    this variant.
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  evidence:
  - reference: PMID:11023810
    reference_title: "Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "MYH9 was immunolocalized in the organ of Corti, the subcentral region of the spiral ligament, and the Reissner membrane."
    explanation: >-
      Localizes the protein to the structures that degenerate. Rat cochlea, so
      tagged MODEL_ORGANISM.
  - reference: PMID:41751538
    reference_title: "The Clinical Details of MYH9-Related Disease and DFNA17 in a Large Japanese Hearing Loss Cohort."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "According to studies using rodent inner ears, NMMHC-IIA is also expressed predominantly in the hair cells of the stereocilia, spiral ligament, and spiral limbus."
    explanation: >-
      Independent statement of inner-ear expression, again in rodent.
  - reference: PMID:16862555
    reference_title: "Expression of Myh9 in the mammalian cochlea: localization within the stereocilia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Confocal microscopy of cochlear surface preparations, identified Myh9 within the inner and outer hair cells and their stereocilia."
    explanation: >-
      Subcellular localization to hair cells and their stereocilia, which is the
      basis for the two hair-cell CL annotations on this node.
  - reference: PMID:16862555
    reference_title: "Expression of Myh9 in the mammalian cochlea: localization within the stereocilia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Localization of Myh9 within the stereocilia raises the possibility that mutations of MYH9 may effect hearing loss though disruption of the stereocilia structure."
    explanation: >-
      The stereocilia-disruption hypothesis, curated with the authors' own hedge
      intact - graded PARTIAL because "raises the possibility" is a proposal,
      not a demonstration.
  - reference: PMID:16862555
    reference_title: "Expression of Myh9 in the mammalian cochlea: localization within the stereocilia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The Myh9 antibody cross-reacts with the rat but not the human orthologue."
    explanation: >-
      Graded PARTIAL because this *limits* the localization evidence rather
      than supporting the node: the reagent underlying every localization claim
      here does not recognize human MYH9, so all of this anatomy is rodent.
  downstream:
  - target: Progressive sensorineural hearing loss
    causal_link_type: DIRECT
    description: >-
      Loss of the cochlear sensory epithelium produces the sensorineural
      deficit and its progression.
    evidence:
    - reference: PMID:41751538
      reference_title: "The Clinical Details of MYH9-Related Disease and DFNA17 in a Large Japanese Hearing Loss Cohort."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Hearing loss is more likely to progress in patients with myosin head domain variants than in patients with myosin tail domain variants, but hearing loss in each set of patients finally deteriorates to bilateral profound hearing loss."
      explanation: >-
        Documents progression to profound loss, and the head-versus-tail domain
        correlation that places p.Arg705His (a head-domain variant) in the
        faster-progressing group.
- name: Neutrophil NMMHC-IIA Inclusions
  biological_scale: CELLULAR
  description: >-
    Cytoplasmic aggregates of NMMHC-IIA in granulocytes, historically called
    Doehle body-like inclusions, containing both mutant and wild-type protein.
    They are pathognomonic of MYH9-related disease, and their presence in
    p.Arg705His carriers is the single strongest argument that DFNA17 is not
    nonsyndromic. This node exists precisely so the entry can carry that
    evidence rather than define it away.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  evidence:
  - reference: PMID:20301740
    reference_title: "MYH9-Related Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "aggregates of the MYH9 protein in the cytoplasm of neutrophil granulocytes"
    explanation: >-
      GeneReviews states the inclusion as a universal feature of MYH9-RD.
  - reference: PMID:24890873
    reference_title: "R705H mutation of MYH9 is associated with MYH9-related disease and not only with non-syndromic deafness DFNA17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "leukocyte inclusions, as well as mild to moderate elevation of some liver enzymes"
    explanation: >-
      Reports leukocyte inclusions in p.Arg705His carriers.
phenotypes:
- category: Auditory
  name: Progressive sensorineural hearing loss
  description: >-
    Adult-onset, progressive, bilateral sensorineural hearing loss. In the
    largest cohort some patients deteriorated by about 50 dB in five years, and
    both head- and tail-domain variant groups eventually reached bilateral
    profound loss.
  phenotype_term:
    preferred_term: Progressive sensorineural hearing impairment
    term:
      id: HP:0000408
      label: Progressive sensorineural hearing impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:41751538
    reference_title: "The Clinical Details of MYH9-Related Disease and DFNA17 in a Large Japanese Hearing Loss Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some cases showed rapid hearing deterioration that worsened by about 50 dB within 5 years."
    explanation: >-
      Quantifies the rate of deterioration in the largest reported cohort.
  - reference: PMID:17146397
    reference_title: "Cochlear implants for DFNA17 deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nonsyndromic autosomal-dominant, adult-onset sensorineural hearing loss resulting from DFNA17 was described in a single American kindred in 1997, and the causative gene was subsequently identified as MYH9."
    explanation: >-
      States the adult-onset, dominant, sensorineural character of the entity.
- category: Auditory
  name: Bilateral profound hearing loss
  description: >-
    The endpoint of progression, reached by patients with head-domain and
    tail-domain variants alike.
  phenotype_term:
    preferred_term: Profound sensorineural hearing impairment
    term:
      id: HP:0011476
      label: Profound sensorineural hearing impairment
  evidence:
  - reference: PMID:41751538
    reference_title: "The Clinical Details of MYH9-Related Disease and DFNA17 in a Large Japanese Hearing Loss Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hearing loss in each set of patients finally deteriorates to bilateral profound hearing loss"
    explanation: >-
      States the shared bilateral profound endpoint.
- category: Hematologic
  name: Macrothrombocytopenia
  description: >-
    Large platelets with a low platelet count, present from birth in MYH9-RD.
    Curated here because it was found in p.Arg705His carriers, which is the
    evidence against DFNA17 being nonsyndromic. It is NOT asserted to be present
    in every DFNA17 kindred - the original families were reported without it.
  phenotype_term:
    preferred_term: Macrothrombocytopenia
    term:
      id: HP:0040185
      label: Macrothrombocytopenia
  evidence:
  - reference: PMID:24890873
    reference_title: "R705H mutation of MYH9 is associated with MYH9-related disease and not only with non-syndromic deafness DFNA17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "whose four affected individuals had not only hearing impairment but also thrombocytopenia, giant platelets, leukocyte inclusions"
    explanation: >-
      Documents macrothrombocytopenia in carriers of this entry's exact allele.
  - reference: PMID:20301740
    reference_title: "MYH9-Related Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MYH9-related disease (MYH9-RD) is characterized in all affected individuals by hematologic features present from birth consisting of platelet macrocytosis"
    explanation: >-
      GeneReviews baseline: the haematological feature is universal and
      congenital in MYH9-RD, which is why its absence from the original DFNA17
      reports is the crux of the dispute.
- category: Hepatic
  name: Elevated liver enzymes
  description: >-
    Mild to moderate transaminase elevation, an MYH9-RD feature also found in
    the p.Arg705His families.
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
    severity: MILD
  evidence:
  - reference: PMID:24890873
    reference_title: "R705H mutation of MYH9 is associated with MYH9-related disease and not only with non-syndromic deafness DFNA17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "as well as mild to moderate elevation of some liver enzymes"
    explanation: >-
      Reports transaminase elevation in p.Arg705His carriers.
genetic:
- name: MYH9
  features: >-
    Non-muscle myosin heavy chain IIA. Head-domain (motor) variants including
    p.Arg705His and p.Arg702Cys/His are associated with more progressive hearing
    loss than tail-domain (coiled-coil) variants. p.Arg702Cys and p.Arg702His
    were found only in the syndromic phenotypes, marking that region as critical
    to the combined macrothrombocytopenia/nephritis/deafness presentation, while
    the immediately adjacent p.Arg705His was the DFNA17 allele - a striking
    genotype-phenotype boundary within three residues, and one that the 2015
    reassessment calls into question.
  gene_term:
    preferred_term: MYH9
    term:
      id: hgnc:7579
      label: MYH9
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:11023810
    reference_title: "Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because of the importance of myosins in hearing, MYH9 was tested as a candidate gene for DFNA17."
    explanation: >-
      Records how the gene was identified for this locus.
  - reference: PMID:11590545
    reference_title: "Nonmuscle myosin heavy chain IIA mutations define a spectrum of autosomal dominant macrothrombocytopenias: May-Hegglin anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "R702C and R702H mutations were only associated with FTNS, EPS, or APSM, thus defining a region of MYHIIA critical in the combined pathogenesis of macrothrombocytopenia, nephritis, and deafness."
    explanation: >-
      Establishes the neighbouring-residue genotype-phenotype contrast.
  - reference: PMID:41751538
    reference_title: "The Clinical Details of MYH9-Related Disease and DFNA17 in a Large Japanese Hearing Loss Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hearing loss is more likely to progress in patients with myosin head domain variants than in patients with myosin tail domain variants"
    explanation: >-
      Domain-level genotype-phenotype correlation for hearing progression.
  - reference: PMID:25505834
    reference_title: "c.G2114A MYH9 mutation (DFNA17) causes non-syndromic autosomal dominant hearing loss in a Brazilian family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutation identified in our study is the same described in the prior report."
    explanation: >-
      A third, Brazilian kindred carrying the identical c.G2114A p.R705H allele,
      independently ascertained - which is what makes the allele recurrent
      rather than private.
  - reference: PMID:25505834
    reference_title: "c.G2114A MYH9 mutation (DFNA17) causes non-syndromic autosomal dominant hearing loss in a Brazilian family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, the MYH9 variant segregated with the phenotype in all affected members, except the three individuals with different phenotype."
    explanation: >-
      The segregation caveat, curated rather than dropped: three family members
      with a high-frequency-only phenotype did not carry the variant, so
      segregation in this kindred was not complete across everyone labelled
      affected. Graded PARTIAL for that reason.
animal_models:
- name: Heterozygous gene-trap Myh9 mouse (BayGenomics ES cell line)
  species: Mouse
  genotype: Myh9 gene-trap, heterozygous (homozygotes embryonic lethal)
  publication: PMID:16630581
  description: >-
    A gene-trap knockout allele, so this models *loss* of Myh9 rather than the
    human missense change. Its negative result is exactly what makes it
    informative: half-normal inner-ear Myh9 mRNA produced no hearing loss and no
    cochleosaccular degeneration even in aged animals.
  modeled_mechanisms:
  - target: Cochleosaccular Degeneration
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      Heterozygous Myh9 loss does not reproduce the human inner-ear lesion,
      which argues that DFNA17 is not caused by simple haploinsufficiency and
      that the p.Arg705His protein must do something a missing protein does not.
    limitations: >-
      The decisive limitation is allelic, not species: this is a null/gene-trap
      allele and the human disease is a missense change, so the model tests
      dosage rather than the mutant protein's behaviour. A knock-in of the
      orthologous missense residue would be the matching experiment and has not
      been reported. Species divergence in cochlear ageing is a secondary
      caveat, and homozygous lethality forecloses the higher-dose test.
    readouts:
    - name: Auditory function in heterozygous Myh9 mice
      target: Cochleosaccular Degeneration
      direction: UNCHANGED
      interpretation: >-
        No hearing loss despite reduced Myh9 - a genuine negative result, not a
        missing measurement.
      evidence:
      - reference: PMID:16630581
        reference_title: "Absence of hearing loss in a mouse model for DFNA17 and MYH9-related disease: the use of public gene-targeted ES cell resources."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Hearing loss however was not observed in heterozygous Myh9 mice in contrast to human Myh9-related diseases."
        explanation: >-
          The negative auditory result, stated by the authors as a contrast with
          the human disease.
    - name: Cochleosaccular histology in aged heterozygous Myh9 mice
      target: Cochleosaccular Degeneration
      direction: UNCHANGED
      interpretation: >-
        The structural lesion that names the locus is also absent, so the
        negative is not merely a functional-testing artefact.
      evidence:
      - reference: PMID:16630581
        reference_title: "Absence of hearing loss in a mouse model for DFNA17 and MYH9-related disease: the use of public gene-targeted ES cell resources."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Aged heterozygous Myh9 mice also did not show signs of cochleosaccular degeneration common in DFNA17."
        explanation: >-
          Histological confirmation of the negative result in aged animals.
    evidence:
    - reference: PMID:16630581
      reference_title: "Absence of hearing loss in a mouse model for DFNA17 and MYH9-related disease: the use of public gene-targeted ES cell resources."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Although inheritance of Myh9 mutations in humans is dominant, we conclude that heterozygous loss of Myh9 is not critical to hearing function in mice by itself."
      explanation: >-
        The authors' own conclusion, which is the reason this model is curated
        as informative despite - because of - its negative result.
    - reference: PMID:16630581
      reference_title: "Absence of hearing loss in a mouse model for DFNA17 and MYH9-related disease: the use of public gene-targeted ES cell resources."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We provide evidence that adult heterozygous Myh9 mouse inner ears contain half wild-type levels of Myh9 mRNA."
      explanation: >-
        Confirms the allele did reduce inner-ear Myh9, so the negative auditory
        result is not explained by a failed knockdown.
treatments:
- name: Cochlear Implantation
  description: >
    Direct electrical stimulation of the cochlear nerve for severe-to-profound
    loss, the endpoint most DFNA17/MYH9 patients reach. Outcome is reported as
    discordant between the only two DFNA17 kindreds published at the time:
    excellent in the Australian family, "poor" in the original American family,
    despite the identical p.Arg705His allele. The authors nevertheless concluded
    that implantation should be strongly considered. That discordance is
    curated rather than averaged away - with n=2 families it is as likely to
    reflect implantation era, duration of deafness, or measurement differences
    as anything biological.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: cochlear implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Progressive sensorineural hearing impairment
    term:
      id: HP:0000408
      label: Progressive sensorineural hearing impairment
  evidence:
  - reference: PMID:17146397
    reference_title: "Cochlear implants for DFNA17 deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thus, cochlear implants should be strongly considered for clinical management of patients with DFNA17 deafness."
    explanation: >-
      The authors' explicit management recommendation for this disease.
  - reference: PMID:17146397
    reference_title: "Cochlear implants for DFNA17 deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One important point of clinical relevance is the excellent outcome with cochlear implants in the Australian family compared with a \"poor\" response in the American family."
    explanation: >-
      The discordance itself. Graded PARTIAL because it qualifies the
      recommendation rather than supporting it uniformly.
  - reference: PMID:20301740
    reference_title: "MYH9-Related Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "individuals with severe/profound deafness benefit from cochlear implantation"
    explanation: >-
      GeneReviews management statement for MYH9-RD deafness, independent of the
      two DFNA17 kindreds.
- name: Avoidance of Ototoxic, Nephrotoxic and Antiplatelet Agents
  description: >
    A drug-safety measure rather than a therapy, taken from the MYH9-RD
    GeneReviews *Agents/Circumstances to Avoid* section. It is curated here
    because it is the practical consequence of the unresolved lump/split
    question: if a DFNA17 patient is in fact within the MYH9-RD spectrum, then
    antiplatelet drugs carry bleeding risk on top of the ototoxicity concern
    that a progressive hearing loss already implies. Hazardous noise exposure
    and high-injury-risk activities are named in the same section.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301740
    reference_title: "MYH9-Related Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Drugs that inhibit platelet function or reduce platelet count, and drugs that are ototoxic, nephrotoxic, or hepatotoxic should be used only after assessment of risk-to-benefit ratio."
    explanation: >-
      The GeneReviews agents-to-avoid statement, quoted directly.
  - reference: PMID:20301740
    reference_title: "MYH9-Related Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hazardous noise and activities with high risk of injury should be avoided."
    explanation: >-
      The circumstances half of the same recommendation.
prevalence:
- population: Japanese hearing loss patients undergoing next-generation sequencing
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    24 patients from 18 families with MYH9-associated hearing loss were
    identified among 15,684 Japanese hearing-loss patients sequenced - roughly
    0.15% of that cohort. That figure is a diagnostic yield within an
    ascertained deafness population, NOT a population rate, so it is
    deliberately left out of rate_per_100000; it also counts all
    MYH9-associated hearing loss (MYH9-RD and DFNA17 together) rather than
    DFNA17 alone. Filling the numeric slot with it would have put ~1 in 650 in
    a structured field alongside a `prevalence_class` of ULTRA_RARE (<1 in
    1,000,000) - a three-order-of-magnitude contradiction inside one record,
    which any consumer reading the numeric slot would get wrong. The counts
    survive in this note and in the two evidence items below. No population
    prevalence for DFNA17 has been published.
  evidence:
  - reference: PMID:41751538
    reference_title: "The Clinical Details of MYH9-Related Disease and DFNA17 in a Large Japanese Hearing Loss Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, we identified 24 patients from 18 families with MYH9-associated hearing loss."
    explanation: >-
      The numerator.
  - reference: PMID:41751538
    reference_title: "The Clinical Details of MYH9-Related Disease and DFNA17 in a Large Japanese Hearing Loss Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we performed next-generation sequencing analysis for 15,684 hearing loss patients and identified MYH9-associated hearing loss patients"
    explanation: >-
      The denominator, which is what makes the rate interpretable and also what
      limits it to a diagnostic yield.
discussions:
- discussion_id: dfna17_separate_entity_or_myh9_rd_spectrum
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is DFNA17 a distinct nonsyndromic disease, or is it MYH9-related disease in
    which the haematological features were never systematically looked for?
  attaches_to:
  - "pathophysiology#MYH9 p.Arg705His Variant in the SH1 Helix"
  - "pathophysiology#Neutrophil NMMHC-IIA Inclusions"
  rationale: >-
    This is a live disagreement about whether the entity this entry describes
    exists, and it is the most important open question here. The case for
    lumping is strong and specific: Verver, Pecci and colleagues found the same
    p.Arg705His allele in two unrelated families whose affected members had
    thrombocytopenia, giant platelets, leukocyte inclusions and raised liver
    enzymes, and concluded that DFNA17 "should not be a separate genetic entity
    but part of the wide phenotypic spectrum of MYH9-RD". Because the
    haematological features of MYH9-RD are congenital and universal by
    GeneReviews' account, while the extrahaematological ones have variable
    penetrance, a kindred ascertained through an ENT clinic could easily be
    reported as nonsyndromic without anyone examining a blood film. The case for
    splitting rests mainly on the original reports and on the neighbouring-codon
    contrast, where p.Arg702Cys/His gave syndromic disease and the adjacent
    p.Arg705His did not - but that contrast was drawn before the 2015 families
    were described. Resolving this is not academic: a patient labelled DFNA17
    and not screened haematologically may have unrecognised bleeding risk, and
    the GeneReviews agents-to-avoid list would apply to them.
  proposed_experiments:
  - experiment_id: dfna17_systematic_haematology_in_reported_kindreds
    name: Systematic haematological phenotyping of all reported p.Arg705His carriers
    description: >-
      Re-examine every published p.Arg705His kindred, including the original
      American and Australian families, with platelet count, mean platelet
      volume/blood film for macrothrombocytopenia, and immunofluorescence for
      NMMHC-IIA granulocyte inclusions - the last being the pathognomonic and
      most sensitive marker. Absence of inclusions in a properly examined
      carrier would be the strongest evidence that a truly nonsyndromic
      p.Arg705His phenotype exists.
    readouts:
    - name: NMMHC-IIA granulocyte inclusions by immunofluorescence
      target: Neutrophil NMMHC-IIA Inclusions
      direction: INCREASED
      interpretation: >-
        Inclusions present in the original kindreds would settle the question in
        favour of lumping; their reproducible absence would support a genuinely
        nonsyndromic subtype.
- discussion_id: dfna17_no_knockin_missense_model
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does any animal model reproduce what the p.Arg705His protein does, as
    opposed to what losing MYH9 does?
  attaches_to:
  - "pathophysiology#Cochleosaccular Degeneration"
  - "pathophysiology#Impaired Myosin Motility with Reduced Cross-Bridge Stiffness"
  rationale: >-
    The only reported mouse model is a gene-trap null, and it is negative: half
    the normal inner-ear Myh9 mRNA produced neither hearing loss nor
    cochleosaccular degeneration. That negative is informative - it excludes
    haploinsufficiency - but it cannot test the missense allele, because a
    missing protein cannot exhibit reduced cross-bridge stiffness or thermal
    aggregation. Meanwhile the biophysical characterisation of the mutation was
    done in *Dictyostelium* myosin II (R689H), an amoebal orthologue studied in
    vitro, and the cellular characterisation in human cancer cell lines whose
    response was itself cell-type-dependent (MDA-MB-231 responded, HeLa did
    not). So there is a chain of model systems, none of which is a mammalian
    cochlea expressing the mutant protein at endogenous levels.
  proposed_experiments:
  - experiment_id: myh9_r705h_knockin_mouse_cochlea
    name: Myh9 p.Arg705His knock-in mouse with longitudinal auditory and haematological phenotyping
    description: >-
      Generate a knock-in of the orthologous missense residue and follow ABR
      thresholds, cochleosaccular histology, platelet count and volume, and
      granulocyte NMMHC-IIA inclusions over the lifespan. Because the model
      would carry the mutant protein rather than lack it, it tests both the
      mechanism and, incidentally, the lump/split question: a knock-in with
      macrothrombocytopenia and deafness would be MYH9-RD, not DFNA17.
    readouts:
    - name: ABR threshold shift over the lifespan in knock-in mice
      target: Cochleosaccular Degeneration
      direction: INCREASED
      interpretation: >-
        Progressive threshold elevation absent from the gene-trap heterozygote
        would confirm that the missense protein, not reduced dosage, drives the
        phenotype.
differential_diagnoses:
- name: MYH9-related disease (macrothrombocytopenia and granulocyte inclusions spectrum)
  description: >-
    Not merely a differential but a candidate identity: this is the entity into
    which some authors would fold DFNA17 entirely. MYH9-RD absorbed the
    historical May-Hegglin anomaly and the Fechtner, Sebastian, Epstein and
    Alport-like syndromes once all were found to be MYH9. Its haematological
    features are congenital and universal; its hearing loss, nephropathy,
    cataract and liver-enzyme elevation are variably penetrant lifetime
    manifestations. The discriminating test is not the audiogram but the blood
    film and granulocyte immunofluorescence.
  disease_term:
    preferred_term: MYH9-related disease
    term:
      id: MONDO:0015912
      label: macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss
  distinguishing_features:
  - Congenital macrothrombocytopenia with NMMHC-IIA granulocyte inclusions is universal in MYH9-RD; DFNA17 is defined by its absence - but that absence has been asserted rather than systematically excluded in the original kindreds.
  - The same p.Arg705His allele has now been reported with full MYH9-RD haematology, so the allele itself does not discriminate.
  - p.Arg702Cys and p.Arg702His, three residues away, were found only in the syndromic phenotypes - the historical basis for treating 705 as a nonsyndromic position.
  - Glomerular nephropathy and presenile cataract are MYH9-RD lifetime manifestations with variable penetrance; neither was reported in the p.Arg705His families, so they discriminate MYH9-RD from DFNA17 as currently reported - and are the features whose appearance in a DFNA17 patient would settle the lump/split question against a separate entity.
  evidence:
  - reference: PMID:20301740
    reference_title: "MYH9-Related Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including sensorineural hearing loss, renal disease (manifesting initially as glomerular nephropathy), presenile cataracts, and/or elevation of liver enzymes"
    explanation: >-
      GeneReviews enumerates the extrahematologic manifestations that develop
      over a lifetime in MYH9-RD. Curated on the differential rather than as
      DFNA17 phenotypes: nephropathy and presenile cataract have not been
      reported in p.Arg705His carriers, so asserting them in this entry's
      `phenotypes:` would export an unsupported disease-phenotype claim.
  - reference: PMID:24890873
    reference_title: "R705H mutation of MYH9 is associated with MYH9-related disease and not only with non-syndromic deafness DFNA17."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data suggest that DFNA17 should not be a separate genetic entity but part of the wide phenotypic spectrum of MYH9-RD characterized by congenital hematological manifestations and variable penetrance and expressivity of the extra-hematological features."
    explanation: >-
      The explicit argument that this entry's subject is not a separate entity,
      curated in the entry it argues against.
  - reference: PMID:11590545
    reference_title: "Nonmuscle myosin heavy chain IIA mutations define a spectrum of autosomal dominant macrothrombocytopenias: May-Hegglin anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Altogether, our data suggest that MHA, SBS, FTNS, EPS, and APSM comprise a phenotypic spectrum of disorders, all caused by MYH9 mutations."
    explanation: >-
      The earlier lumping event that created MYH9-RD out of five named
      syndromes - the precedent for lumping DFNA17 into it as well.
notes: >-
  Lump/split status: UNRESOLVED, and deliberately left so. MONDO and OMIM both
  keep DFNA17 (MONDO:0011350, OMIM:603622) distinct from MYH9-RD
  (MONDO:0015912, OMIM:155100), which is why this entry exists under its own
  term. But PMID:24890873 argues directly that it should not, and that argument
  is curated as a `KNOWLEDGE_GAP` discussion and as the leading differential
  diagnosis rather than being resolved by curator preference. The MYH9-RD
  spectrum phenotypes that are directly evidenced in p.Arg705His carriers
  (macrothrombocytopenia, raised liver enzymes) are curated on this entry, so
  that if the lumping view prevails it converts to a `has_subtypes` entry on an
  MYH9-RD parent without the evidence having to be re-gathered. Nephropathy and
  presenile cataract are NOT curated here - they are carried on the MYH9-RD
  differential instead, because they rest only on GeneReviews statements about
  MYH9-RD and have not been reported in carriers of this allele. On the
  differential they do more work anyway: they are the features whose appearance
  in a DFNA17 patient would settle the lump/split question. If a curator
  later creates an MYH9-RD entry, the two should be reconciled deliberately
  rather than left to drift.

  A lesson this entry paid for, worth keeping because it generalizes. The
  prevalence record originally carried `rate_per_100000: 153.0` next to
  `prevalence_class: ULTRA_RARE`, three orders of magnitude apart, with a note
  beside the slot that already said "a rate per 100,000 in this slot invites
  being read as a population prevalence, which it is not" - and the slot was
  populated anyway. **Prose disclaiming a structured value does not neutralise
  it; the structured value is what exports.** The same test is what moved
  nephropathy and cataract off `phenotypes:` and onto the differential.

  The same reasoning was applied to two phenotypes on the reviewer's
  suggestion. `Nephropathy` and `Presenile cataract` were supported only by
  GeneReviews statements about MYH9-RD and have not been reported in
  p.Arg705His carriers, so their `phenotypes:` entries asserted something the
  evidence did not support however carefully the descriptions hedged. Both are
  now carried on the MYH9-RD differential, where they do real work - they are
  the features whose appearance in a DFNA17 patient would settle the lump/split
  question. Macrothrombocytopenia and elevated liver enzymes stay as
  phenotypes, being directly evidenced in carriers of this allele.

  `Bilateral profound hearing loss` is bound to HP:0011476 (Profound
  sensorineural hearing impairment) and carries no `severity:` qualifier: the
  term already encodes *profound*, and `SeverityQualifierEnum` tops out at
  `SEVERE`, which HPO grades as the adjacent *lower* band (HP:0012828 vs
  HP:0012829). Adding it would have made the record say two slightly different
  things. Laterality drops out of the structured slot in that swap but survives
  in the phenotype name, the snippet, and the first phenotype's description;
  severity was the real discriminator between the two.

  GeneReviews baseline. There is no GeneReviews chapter for DFNA17. The
  MYH9-Related Disease chapter (PMID:20301740) was used as the phenotype
  baseline and is tagged `GeneReviews` in `references:`, on the reasoning that
  the lumping argument makes it the relevant expert source. Its
  *Agents/Circumstances to Avoid* section is curated as a treatment entry rather
  than left in prose, because the antiplatelet-drug warning is exactly what a
  patient mislabelled as nonsyndromic would not receive. Its Clinical
  Characteristics list was cross-referenced and all four extrahaematologic
  manifestations it names are represented as phenotypes.

  Evidence-source tagging. The biophysical mechanism (PMID:16901894) was
  measured on *Dictyostelium* myosin II carrying R689H, the orthologous residue,
  in single-molecule and biochemical assays - tagged IN_VITRO rather than
  MODEL_ORGANISM because the experiments are on purified protein and in vitro
  motility rather than in a living organism. Cochlear MYH9 immunolocalization
  (PMID:11023810, PMID:41751538) is rat/rodent and tagged MODEL_ORGANISM.

  Deep-research ontology suggestions were checked, not copied. The report
  suggested CL:0002167 and CL:0002165 for the cochlear hair cells; OAK resolves
  those to *olfactory epithelial cell* and *phalangeal cell* respectively.
  Neither is a hair cell. The terms used here are CL:0000589 (cochlear inner
  hair cell) and CL:0000601 (cochlear outer hair cell). Note also that a plain
  lookup of "hair cell" resolves to CL:0000374 *trichogen cell*, an insect
  hair-forming cell - a trap for anyone binding auditory hair cells by label
  alone. This is the second entry in this curation batch where a deep-research
  report proposed a real-but-wrong ontology identifier, which is worth flagging
  as a pattern: the suggested identifiers resolve, so nothing but a lookup
  catches them.

  The report's one unresolved reference is a parsing artifact, not a
  fabrication. Its `reference_validation` block sets `needs_review: true` on a
  single unresolved identifier,
  `DOI:10.3390/genes17020154)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12941242/`
  - a DOI with a markdown link tail glued onto it. The underlying DOI
  10.3390/genes17020154 is Genes (Basel) 2026, i.e. PMID:41751538, which this
  entry already cites directly and correctly. `just preflight-dr` returned PASS
  (MYH9 mentioned 56 times, report OMIM 603622 matching the MONDO xref).

  Kindred count. PMID:17146397 (2006) described its Australian family as "only
  the second DFNA17 family to be reported". A third, Brazilian kindred with the
  identical allele was published in 2014 (PMID:25505834), so that count is
  superseded - and in that family the variant did not segregate with three
  relatives who had a high-frequency-only phenotype, which is curated as a
  PARTIAL evidence item rather than smoothed over.

  Not curated. PMID:9915977 (the 1999 locus-mapping paper naming
  cochleosaccular degeneration) and PMID:12408071 (Auditory phenotype of
  DFNA17) both cache with no retrievable content, so neither could supply a
  quotable snippet despite being directly on topic; they are recorded here as
  leads for a curator with full-text access. The cochleosaccular-degeneration
  claim is instead carried by PMID:11023810, which names the lesion in its
  abstract.

  Prevalence caution. The one `prevalence` record is a diagnostic yield among
  sequenced Japanese hearing-loss patients and covers all MYH9-associated
  hearing loss, not DFNA17 alone. It is entered with `measure_type:
  CASES_IN_LITERATURE` and a note saying so, because a rate per 100,000 in this
  slot invites being read as a population prevalence, which it is not.
📚

References & Deep Research

References

3
PMID:20301740
MYH9-Related Disease.
No top-level findings curated for this source.
PMID:11023810
Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9.
No top-level findings curated for this source.
PMID:24890873
R705H mutation of MYH9 is associated with MYH9-related disease and not only with non-syndromic deafness DFNA17.
No top-level findings curated for this source.

Deep Research

1
Claude Code ▸
Autosomal Dominant Nonsyndromic Hearing Loss 17 (DFNA17) — Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 24 citations 2026-08-22T14:17:22.025101

Autosomal Dominant Nonsyndromic Hearing Loss 17 (DFNA17) — Comprehensive Research Report

1. Disease Information

Overview. DFNA17 (Deafness, Autosomal Dominant 17) is a form of nonsyndromic, progressive, high-frequency-predominant sensorineural hearing loss caused by heterozygous missense mutation in MYH9, the gene encoding non-muscle myosin heavy chain IIA (NMMHC-IIA), on chromosome 22q12.3 (OMIM #603622). It was originally mapped as a novel autosomal dominant deafness locus in a five-generation American kindred with hearing loss due to histopathologically confirmed cochleosaccular degeneration (CSD) — collapse of Reissner's membrane with degeneration of the organ of Corti, saccular epithelium, and stria vascularis (Lalwani et al., 1999, PMID:9915977). The causative gene was identified the following year: sequencing of MYH9 in the same kindred revealed a heterozygous c.2114G>A (p.Arg705His, R705H) mutation that cosegregated with deafness (Lalwani et al., 2000, PMID:11023810; full text PMC1288554).

Critically, MYH9 mutations more broadly cause MYH9-related disease (MYH9-RD) — a syndromic disorder combining congenital macrothrombocytopenia with variable, later-onset sensorineural hearing loss, presenile cataracts, and progressive nephropathy, historically split into four eponymous entities (May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome, Sebastian syndrome) now recognized as one clinical continuum (GeneReviews, NBK2689). Subsequent work showed that even the R705H variant originally described as causing "pure" nonsyndromic DFNA17 can, on closer hematologic/renal evaluation, present with subtle MYH9-RD features — i.e., DFNA17 and MYH9-RD lie on a phenotypic spectrum rather than being fully distinct entities (Verver et al., 2015, PMID:24890873).

Key identifiers: - OMIM: #603622 (DEAFNESS, AUTOSOMAL DOMINANT 17; DFNA17) - Gene: MYH9 — HGNC:7579, NCBI Gene ID 4627, chromosome 22q12.3, 41 exons, ~107 kb, encoding a 1,960-amino-acid protein (GeneCards) - MONDO/Orphanet/GARD: listed as "autosomal dominant nonsyndromic hearing loss 17" (NORD/GARD); MYH9-RD as a whole is Orphanet ORPHA:182050 (umbrella) with related individual disorder entries for May-Hegglin/Fechtner/Sebastian/Epstein syndromes - Disease Ontology: DOID:0110548 - GTR condition: C1863659

Synonyms: DFNA17; deafness, autosomal dominant, cochleosaccular type; nonsyndromic hereditary hearing impairment, DFNA17 type. Note the broader disease-family synonyms (not equivalent, but genetically allelic): May-Hegglin anomaly, Fechtner syndrome, Epstein syndrome, Sebastian (platelet) syndrome — all subsumed under MYH9-related disease (GeneReviews); (Nature Genetics, Seri et al. 2000, ng0900_103).

Source of information: Aggregated disease-level knowledge from OMIM, GeneReviews (systematic literature synthesis + registry data), and peer-reviewed case series/family reports (individually ascertained pedigrees) — not primary EHR data.

2. Etiology

Disease causal factor: Purely genetic. DFNA17 is caused by heterozygous, typically missense, gain-of-function/dominant-negative mutations in MYH9 (non-muscle myosin heavy chain IIA). No environmental or infectious cause is implicated in the nonsyndromic (isolated hearing loss) presentation.

Genetic risk factors: - The R705H mutation (exon 16, SH1 helix/linker region of the motor head domain) is the best-characterized DFNA17-causing allele, independently identified in an American kindred (PMID:11023810), a five-generation Australian family (cochlear-implant outcome paper, PMID:17146397), and a Brazilian family (PMID:25505834). - Other MYH9 missense variants across the motor head (exons 1–19) and coiled-coil tail (exons 21–40) cause the broader MYH9-RD spectrum; genotype strongly predicts phenotype severity (see Section 4/9) (GeneReviews). - Approximately 65% of MYH9-RD probands have an affected parent (true autosomal dominant transmission); ~35% arise as de novo mutations, with documented parental germline/somatic mosaicism in some kindreds (GeneReviews). - A large 2026 Japanese cohort study (Genes, 24 patients/18 families) found hearing loss progresses faster in patients with myosin head-domain variants than tail-domain variants, though both eventually reach bilateral profound loss (PMC12941242 / DOI:10.3390/genes17020154).

Environmental risk factors: None established as disease-causing. However, ototoxic exposure is a documented risk factor for accelerated hearing decline in MYH9-RD/DFNA17 patients — aminoglycosides, high-dose salicylates, and loop diuretics are specifically flagged in management guidance as agents to avoid because they may exacerbate the underlying cochlear vulnerability (GeneReviews).

Protective factors: None specifically documented for hearing loss in MYH9-RD. (Note: the well-known MYH9 "E-1" risk haplotype associated with chronic kidney disease/FSGS susceptibility in African-ancestry populations is a distinct, common-variant association unrelated to the rare dominant MYH9-RD/DFNA17-causing mutations — it should not be conflated with DFNA17 causal genetics (Nelson et al., PMC2901326).)

Gene-environment interactions: Not specifically characterized for DFNA17; the ototoxic-drug avoidance recommendation implies a genotype (MYH9-compromised cochlear cytoskeleton) × environment (ototoxin exposure) interaction affecting rate of hearing decline, though this is based on expert clinical guidance rather than a formal interaction study.

3. Phenotypes

Primary phenotype: Progressive sensorineural hearing loss

  • Type: Clinical sign / audiometric abnormality (symptom: perceived hearing loss; sign: abnormal pure-tone audiometry)
  • HPO term suggestion: HP:0000407 (Sensorineural hearing impairment); more specific: HP:0000362 (Progressive sensorineural hearing impairment) or HP:0000410 (Progressive hearing impairment); HP:0008527 (Congenital sensorineural hearing impairment) is not typically applicable — onset is postlingual.
  • Age of onset: In the original American DFNA17 kindred, onset was reported at ~10 years of age, beginning in the high frequencies (PMC1288554). Across the broader MYH9-RD population, hearing loss develops later and more variably: ~36% before age 20, ~33% between ages 20–40, ~31% after 40, with ~50% of individuals affected by a mean age of 33 (GeneReviews).
  • Progression/severity: Classically described as beginning as mild, high-frequency loss in childhood/adolescence that progresses to moderate-to-severe/profound deafness by the third decade (OMIM #603622); (PMC1288554). A 2026 Japanese cohort documented cases with rapid deterioration (~50 dB worsening within 5 years), ultimately reaching bilateral profound loss regardless of head- vs. tail-domain mutation, though head-domain variants progressed faster (Genes 2026). Overall in MYH9-RD, ~80–85% eventually develop sensorineural hearing loss (GeneReviews).
  • Frequency among affected individuals: Near-complete for R705H-type DFNA17 kindreds (fully penetrant by adulthood); ~80–85% across the full MYH9-RD spectrum.
  • Laterality: Bilateral, generally symmetric.
  • Quality of life impact: Progression to severe-profound deafness by young adulthood; the condition "interferes with daily functioning in ~90% of affected individuals with abnormal audiometry" per GeneReviews summary data.

Related/associated audiovestibular pathology

  • Cochleosaccular degeneration on temporal bone histopathology: collapsed Reissner's membrane, degeneration of the organ of Corti, saccular epithelium, and stria vascularis — the anatomic substrate of DFNA17 hearing loss in the original kindred (PMID:9915977); (PMC1288554). HPO suggestion: no precise dedicated term; HP:0011471 (Reissner membrane rupture/absence — check OMIM CS) or free-text/anatomic annotation may be more appropriate; broadly HP:0000359 (Abnormality of the inner ear).

Phenotypes seen only in syndromic MYH9-RD (relevant for differential/pleiotropy, not part of "pure" DFNA17 nonsyndromic presentation)

  • Macrothrombocytopenia (congenital, ~100% penetrant) — HP:0040218 (Macrothrombocytopenia)
  • Presenile cataracts (~20%, mean onset 37) — HP:0000518 (Cataract)
  • Progressive nephropathy/glomerulopathy with proteinuria, progressing to ESRD in ~43% of those affected (~25% overall) — HP:0000093 (Proteinuria), HP:0000112 (Nephropathy)
  • Neutrophil Döhle-like inclusion bodies (42–84%) — a laboratory/histologic finding, not applicable to nonsyndromic DFNA17 (GeneReviews)

4. Genetic/Molecular Information

Causal gene: MYH9 (HGNC:7579; NCBI Gene 4627; chromosome 22q12.3). Encodes non-muscle myosin heavy chain IIA (NMMHC-IIA), a 1,960-amino-acid actin-binding motor protein.

Protein domain structure (MYH9 structure review, PMID:29679756): - N-terminal motor/head domain (exons 1–19): globular ATPase motor head that binds actin and hydrolyzes ATP to generate force; subdivided into an SH3-like motif, upper subdomain, lower subdomain, and converter region. - Neck domain (exon 20): binds essential and regulatory myosin light chains (ELC/RLC). - Coiled-coil rod/tail domain (exons 21–40): mediates bipolar filament self-assembly via a 28-residue heptad repeat pattern. - Non-helical tailpiece (exon 41): C-terminal region.

DFNA17 causal variant: c.2114G>A, p.Arg705His (R705H) — a missense change at an invariant, highly conserved arginine within the SH1 helix/linker region of the motor head domain, considered critical for myosin ATPase activity (PMC1288554). Same variant independently found in American, Australian, and Brazilian kindreds (PMID:11023810); (PMID:25505834); (PMID:17146397). Verver et al. (2015) subsequently showed that R705H is not exclusively "nonsyndromic" — some carriers show subtle macrothrombocytopenia/other MYH9-RD features on closer evaluation, arguing R705H sits at the mild end of the MYH9-RD spectrum rather than being a truly separate nonsyndromic entity (PMID:24890873).

Variant classification (ACMG/AMP): R705H — Pathogenic/Likely Pathogenic (ClinVar; segregates with disease across 3 independent families, absent/extremely rare in population databases, affects a highly conserved functional residue). MYH9 variants broadly are missense or small in-frame indels; ~70% of MYH9-RD cases cluster in six hotspot residues (predominantly within exons 2, 17, 25–27, 31, 39) (GeneReviews).

Allele frequency: MYH9 pathogenic variants causing hearing loss are rare in population databases — a 2025 audiological-phenotype study reported minor allele frequencies < 0.5×10⁻⁵ for the variants identified, consistent with pathogenicity (Scientific Reports 2025, PMC12219520). (Note: the common MYH9 E-1 kidney-risk haplotype, at high frequency in African-ancestry populations, is a distinct non-Mendelian susceptibility variant unrelated to DFNA17/MYH9-RD causal mutations — see Section 2.)

Origin: Germline (constitutional heterozygous), autosomal dominant. Somatic mosaicism has been documented in some MYH9-RD kindreds among apparently unaffected/mildly affected parents (GeneReviews).

Functional consequence: Dominant-negative mechanism — mutant NMMHC-IIA monomers co-assemble with wild-type monomers into bipolar filaments, disrupting normal filament assembly, ATPase motor function, and/or subcellular localization, thereby impairing cytoskeletal force-generating processes in megakaryocytes, podocytes, lens epithelium, and cochlear structures (structure/mechanism review, PMC7348894); (rod-mutation assembly study, Blood, PMID for ASH article).

Genotype-phenotype correlation (established across MYH9-RD, informative for DFNA17 counseling): | Mutation region | Hearing loss risk | Nephropathy risk | Cataract risk | Notes | |---|---|---|---|---| | Arg702 (head domain) | Severe, early | High, rapid to ESRD | Present | Most severe overall phenotype | | Arg705 (head domain, incl. R705H) | High | Low-moderate | Variable | Classic "DFNA17" allele | | Arg1165 | All by age 60 | Low | Low | Hearing-predominant | | Asp1424His | All by age 60 | Most | Elevated | Intermediate-high risk | | Asp1424Asn, Glu1841Lys | Low | Low | Low | Macrothrombocytopenia often sole feature | | Exon 41 (nonsense/frameshift, tail) | Rare | Rare | Rare | Thrombocytopenia-limited | (GeneReviews genotype-phenotype table); consistent with the 2026 Japanese cohort finding of faster progression for head-domain vs. tail-domain variants (PMC12941242).

Modifier genes: None specifically established for DFNA17/MYH9-RD hearing loss.

Epigenetics / chromosomal abnormalities: Not implicated; DFNA17 is a single-gene missense disorder, not a copy-number or epigenetic condition.

5. Environmental Information

  • Environmental factors: No environmental agent causes DFNA17; the disease is fully genetic. The clinically relevant environmental modifier is avoidance of ototoxic drugs (aminoglycoside antibiotics, high-dose salicylates, loop diuretics), recommended because these agents may accelerate hearing decline in a cochlea already structurally compromised by MYH9 dysfunction (GeneReviews).
  • Lifestyle factors: No specific lifestyle risk/protective factors documented.
  • Infectious agents: Not applicable — DFNA17 is a monogenic, non-infectious disorder.

6. Mechanism / Pathophysiology

Causal chain (proposed): 1. Heterozygous MYH9 missense mutation (e.g., R705H in the motor head SH1-linker) → altered NMMHC-IIA structure/ATPase function within actomyosin motor complexes. 2. Dominant-negative incorporation of mutant heavy chains into non-muscle myosin IIA bipolar filaments → impaired filament assembly/disassembly dynamics and cytoskeletal force generation (PMC7348894). 3. In the cochlea, MYH9 is normally expressed in the organ of Corti (sensory and supporting hair cells), the spiral ligament, the spiral limbus, and Reissner's membrane — but notably not in the stria vascularis proper (though CSD ultimately involves the stria as a secondary/downstream finding) (PMID:15079858); (PMID:16862555 — stereocilia localization); (original DFNA17 paper). MYH9 protein is specifically localized within the stereocilia of hair cells, implicating a role in stereocilia bundle architecture and mechanotransduction. 4. Progressive structural failure manifests histopathologically as cochleosaccular degeneration: collapse of Reissner's membrane, degeneration of the organ of Corti, and degeneration of the saccular epithelium — a pattern classically termed Scheibe dysplasia when seen developmentally, but here representing a postnatal degenerative process (PMID:9915977). 5. Progressive, high-frequency-first sensorineural hearing loss results, consistent with a basal-turn (high-frequency) predilection of degeneration.

Upstream vs. downstream: The genetic lesion (MYH9 mutation) is upstream; loss of normal actomyosin-based cytoskeletal support in cochlear epithelial/hair-cell structures is intermediate; cochleosaccular degeneration and consequent mechanotransduction failure are downstream, directly producing the audiometric phenotype.

Cell types involved: - Inner and outer hair cells of the organ of Corti (CL:0002165 outer hair cell of Corti's organ; CL:0002167 inner hair cell of Corti's organ) - Supporting cells of the organ of Corti - Spiral ligament fibrocytes - Reissner's membrane epithelial cells - Saccular epithelial cells

Molecular functions / biological processes (GO term suggestions): - GO:0000146 (microfilament motor activity) / GO:0003774 (cytoskeletal motor activity) - GO:0031982 — n/a; more relevant: GO:0007015 (actin filament organization) - GO:0032796 (uropod organization) — n/a; better: GO:0030036 (actin cytoskeleton organization) - GO:0016459 (myosin complex) - GO:0032060 (bleb assembly) — n/a - Relevant curated GO BP: GO:0007605 (sensory perception of sound) as the phenotypic endpoint; mechanistically GO:0030048 (actin filament-based movement) and GO:0060121 (inner ear receptor stereocilium organization) are strong candidates for stereocilia-related MYH9 function.

Protein dysfunction: Altered ATPase motor activity / filament assembly due to a missense substitution at a catalytically important residue (R705H — SH1 linker, essential for the converter/lever-arm mechanism that couples ATP hydrolysis to force generation).

Tissue damage mechanism: Degenerative (not inflammatory or vascular) — progressive structural collapse of cytoskeleton-dependent inner-ear membranous structures, consistent with a chronic mechanical/structural-support failure model rather than oxidative stress or ischemia.

Molecular profiling / advanced technologies: No human cochlear single-cell, transcriptomic, proteomic, or spatial-omics data specific to DFNA17 were identified in this search; mechanistic data derive largely from rodent expression studies (RT-PCR/immunohistochemistry in rat cochlea) (PMC1288554) and mouse models (Section 15).

Important negative/complicating mechanistic finding: A knockout-first ES-cell-derived heterozygous Myh9-null mouse model showed no hearing loss and no cochleosaccular degeneration, in contrast to human DFNA17/MYH9-RD — homozygous nulls were embryonic lethal, and heterozygotes (modeling haploinsufficiency) were phenotypically normal audiologically (Parker et al., 2006, PMID:16630581). This strongly supports a dominant-negative (rather than simple haploinsufficiency) mechanism for human MYH9-RD/DFNA17 hearing loss — i.e., the mutant protein must be expressed and incorporated into filaments to cause disease, not merely reduced gene dosage.

7. Anatomical Structures Affected

Organ level: - Primary organ: Inner ear (cochlea and vestibular labyrinth — specifically saccule) — UBERON:0001846 (cochlea), UBERON:0002071 (auditory system component) - Body system: Auditory/special sensory system (nonsyndromic form). In the broader MYH9-RD spectrum, additionally: hematologic system (platelets/megakaryocytes), renal system (glomerulus), and ocular lens.

Tissue/cell level: - Organ of Corti (sensory epithelium) — UBERON:0001844 - Reissner's (vestibular) membrane — UBERON:0002068 - Spiral ligament — UBERON:0002261 - Spiral limbus - Saccular epithelium (vestibular sensory epithelium of the saccule) — UBERON:0001846-adjacent structure - Stria vascularis (secondarily affected in CSD histopathology) - Cell types: inner/outer hair cells (CL:0002167, CL:0002165), supporting cells, spiral ligament fibrocytes

Subcellular level: - Stereocilia (actin-rich mechanotransduction organelles) — MYH9 is specifically localized within stereocilia (PMID:16862555); GO Cellular Component: GO:0032420 (stereocilium) - Actomyosin cytoskeleton / cortical actin network — GO:0042995 (cell projection), GO:0015629 (actin cytoskeleton)

Localization/laterality: Bilateral, generally symmetric sensorineural hearing loss; no lateralization pattern reported.

8. Temporal Development

  • Onset: Postlingual, typically childhood-to-adolescent onset (as early as age 10 in the original kindred) for the high-frequency component; onset across broader MYH9-RD hearing loss spans childhood through the sixth decade, with roughly even distribution across age bands (<20, 20–40, >40) (GeneReviews).
  • Onset pattern: Insidious and progressive, not acute or episodic.
  • Progression: Classic pattern is mild high-frequency loss progressing to moderate-severe-to-profound deafness affecting all frequencies by the third decade (OMIM #603622). Some patients show rapid deterioration (up to ~50 dB within 5 years) (Genes 2026 cohort). Progression rate correlates with mutation location (head-domain variants progress faster than tail-domain variants), though ultimate endpoint (bilateral profound loss) is similar across genotypes.
  • Disease course: Chronic, progressive, lifelong; not relapsing-remitting.
  • Duration: Lifelong (no spontaneous remission reported).
  • Critical periods: Early identification during the high-frequency-only phase is clinically important for timely audiologic intervention/genetic counseling before progression to more disabling levels.

9. Inheritance and Population

Epidemiology: - DFNA17 itself is exceedingly rare — reported in only a handful of kindreds worldwide (American, Australian, Brazilian, and additional cases identified in Japanese and Chinese cohorts of dominant nonsyndromic hearing loss). - MYH9-RD as a whole: Italian national registry–based prevalence estimate of 3.75 per 1,000,000; broader estimates based on population genetic databases suggest a potentially higher true frequency, on the order of 1:20,000–25,000 (GeneReviews). - Screening of MYH9 exons in general "nonsyndromic deafness" cohorts finds it an infrequent cause overall (e.g., a Japanese screening study of MYH9 exons 1, 16, 26, 30 found few positive cases) (PMID:19645626), underscoring that MYH9 mutations are a rare but recurrent cause of ADNSHL requiring targeted or panel-based testing to detect.

Inheritance pattern: Autosomal dominant.

Penetrance: Complete to near-complete for hearing loss by adulthood in classic DFNA17 kindreds carrying R705H; across the wider MYH9-RD spectrum, penetrance/expressivity for hearing loss (and nephropathy, cataract) is variable and age-dependent, in contrast to the fully penetrant congenital macrothrombocytopenia (GeneReviews).

Expressivity: Highly variable across families and even within families — illustrated by markedly different cochlear-implant outcomes between the American (poor outcome) and Australian (excellent outcome) R705H kindreds despite an identical mutation (PMID:17146397).

Genetic anticipation: Not reported/applicable (not a repeat-expansion disorder).

Germline mosaicism: Documented in some MYH9-RD families among parents of de novo cases.

Founder effects: Not specifically reported for DFNA17/R705H — the mutation has arisen (or been inherited) independently in geographically distinct (American, Australian, Brazilian) kindreds, more consistent with a recurrent mutational hotspot at a critical conserved residue than a single founder event, though formal haplotype analysis to confirm this was not identified in this search.

Carrier frequency: Not applicable in the traditional sense (autosomal dominant, not recessive carrier state); population allele frequency for pathogenic MYH9 hearing-loss variants is <0.5×10⁻⁵ (Scientific Reports 2025).

Population demographics: - No specific ethnic/geographic predilection established for DFNA17 (R705H) beyond the independently ascertained American, Australian, and Brazilian families. - Sex ratio: no sex bias reported (autosomal, not X-linked). - Age distribution: skewed toward pediatric/adolescent-to-young-adult presentation for hearing symptoms, consistent with progressive postlingual onset.

10. Diagnostics

Clinical tests: - Audiometry (pure-tone and speech audiometry): Serial audiograms document the characteristic bilateral, symmetric, progressive, initially high-frequency-predominant sensorineural pattern. LOINC-coded audiometry panels apply (general audiometric LOINC codes, e.g., LOINC:28569-6 class); no disease-specific biomarker exists. - Temporal bone imaging: High-resolution CT/MRI may be used to exclude structural/syndromic causes but is not diagnostic for MYH9-associated CSD, which is a histopathologic (not typically radiologically visible in vivo) diagnosis. - Temporal bone histopathology (research/autopsy only): demonstrates cochleosaccular degeneration — collapsed Reissner's membrane, organ of Corti degeneration. - Peripheral blood smear / platelet morphometry: essential for distinguishing isolated DFNA17 from broader MYH9-RD — mean platelet diameter >3.7 µm and >40% of platelets >3.9 µm are diagnostic thresholds for MYH9-RD (86–87% sensitivity/specificity) (GeneReviews). - Immunofluorescence for MYH9 protein aggregates in neutrophils: near-100% sensitivity/specificity for MYH9-RD; a key ancillary test to determine whether a "nonsyndromic" hearing-loss patient actually has occult MYH9-RD.

Genetic testing: - Recommended approach: Given genetic heterogeneity of ADNSHL, a hearing-loss gene panel (including MYH9) or exome/genome sequencing is typically first-line; single-gene MYH9 sequencing is appropriate when clinical suspicion is high (e.g., known family history of the R705H mutation, or coexisting subtle platelet/renal/lens findings). - Sequence analysis: detects ~98% of MYH9 pathogenic variants; deletion/duplication analysis reserved for sequence-negative cases (GeneReviews). - Cascade/family testing: appropriate for at-risk relatives given autosomal dominant inheritance and variable expressivity.

Clinical criteria / differential diagnosis: - Must be distinguished from other DFNA (autosomal dominant nonsyndromic) loci — e.g., DFNA14/34 gene MYH14 (a paralogous myosin gene with a very similar progressive high-frequency phenotype) (Scientific Reports 2025 comparison study); (Donaudy et al. MYH14 discovery paper, PMID:28221712). - Must be distinguished from Alport syndrome (also autosomal-pattern progressive SNHL + nephropathy, but caused by COL4A3/4/5 and lacking the platelet abnormality that is pathognomonic for MYH9-RD) (GeneReviews). - Isolated apparent "DFNA17" presentations should prompt evaluation for occult MYH9-RD (platelet count/morphology) given the Verver et al. finding that R705H is not always purely nonsyndromic (PMID:24890873).

Screening: No population newborn-screening program specifically targets MYH9-RD/DFNA17 (postlingual onset limits utility of newborn hearing screening for early detection); genetic cascade testing in known families is the primary screening modality.

11. Outcome/Prognosis

  • Survival/mortality: DFNA17 (isolated nonsyndromic form) does not affect survival or life expectancy. In the broader MYH9-RD spectrum, mortality risk relates to complications of progressive renal failure (in genotypes with high nephropathy risk) and, rarely, severe hemorrhage — not to the hearing loss itself.
  • Morbidity/function: Progressive bilateral deafness by young adulthood is the dominant functional morbidity; profound communicative disability without intervention.
  • Complications: Social/educational/vocational impact of progressive childhood-onset hearing loss; risk of misdiagnosis (e.g., as isolated presbycusis-pattern or as unrelated ADNSHL) delaying appropriate genetic counseling.
  • Recovery potential: No spontaneous recovery; hearing aids and cochlear implantation are effective interventions (see Treatment).
  • Prognostic factors: Mutation location (head-domain variants → faster progression) is the clearest prognostic genotype-phenotype correlate identified (Genes 2026 cohort); earlier age of hearing-loss onset in MYH9-RD broadly correlates with faster deterioration and higher likelihood of eventual severe-to-profound deafness (GeneReviews).

12. Treatment

No disease-modifying/curative therapy exists for MYH9-associated hearing loss; management is supportive/rehabilitative.

  • Hearing aids: First-line for mild-moderate loss. NCIT suggestion: NCIT:C122435 (Hearing Aid) — no dedicated NCIT clinical-action term historically existed for hearing-aid usage in this KB's controlled set (per project convention, DEVICE modality cannot always be inferred mechanically).
  • Cochlear implantation: Recommended and effective for progression to severe-to-profound deafness. Outcomes reported as variable between kindreds — poor in the original American R705H family, excellent in the Australian R705H family — but the literature concludes CI "should be strongly considered" for DFNA17/MYH9-RD deafness (Kim et al., 2007, PMID:17146397). NCIT suggestion: cochlear implantation maps most closely to NCIT:C15329 (Surgical Procedure) with device-specific detail in therapeutic_modality: DEVICE.
  • Avoidance of ototoxic agents (aminoglycosides, high-dose salicylates, loop diuretics) as a preventive/supportive measure to avoid accelerating hearing decline (GeneReviews) — maps to NCIT:C49236 (Therapeutic Procedure)/behavioral-modality counseling rather than a drug treatment per se.
  • Genetic counseling: NCIT:C15240 (Genetic Counseling) — essential given autosomal dominant inheritance, variable expressivity, and the potential for occult syndromic (MYH9-RD) features.
  • Audiologic surveillance: GeneReviews management guidance recommends hearing evaluation approximately every 3 years in known MYH9 mutation carriers (more frequently if symptomatic) to track progression and time intervention.
  • No gene therapy, RNA-based therapy, or targeted pharmacotherapy for MYH9-associated hearing loss has reached clinical trials at the time of this search (searches for MYH9 hearing-loss-specific clinical trials on ClinicalTrials.gov were not separately queried in this pass but no such trials surfaced in the literature reviewed).
  • Note: For the broader MYH9-RD syndrome (not applicable to isolated nonsyndromic hearing loss but relevant to the allelic disease family), eltrombopag (thrombopoietin-receptor agonist) is used perioperatively for severe thrombocytopenia, and ACE inhibitors/ARBs are used for early nephropathy — these are not hearing-loss treatments.

Treatment algorithm: Stepwise — amplification (hearing aids) → cochlear implantation upon progression to severe/profound loss, paired with ongoing audiologic surveillance and avoidance of ototoxins; genetic counseling throughout.

13. Prevention

  • Primary prevention: Not applicable in the classic sense (germline genetic disease); genetic counseling and reproductive options (e.g., prenatal or preimplantation genetic testing) are available to at-risk families given known familial mutation status but were not specifically documented as widely utilized in the literature reviewed.
  • Secondary prevention: Early identification via cascade genetic testing in known families and vigilant audiologic surveillance enables earlier intervention (hearing aids) before profound loss develops.
  • Tertiary prevention: Avoidance of ototoxic medications; timely cochlear implantation to prevent secondary developmental/communicative morbidity from progressing deafness in pediatric patients.
  • Immunization: Not applicable.
  • Screening: No dedicated population screening program; genetic testing driven by family history/clinical suspicion, not universal newborn screening (given postlingual onset).
  • Genetic counseling: Central preventive strategy — informing at-risk relatives of 50% transmission risk, enabling early surveillance planning, and evaluating for occult syndromic MYH9-RD features that would change surveillance recommendations (nephropathy, cataract, platelet monitoring).
  • Public health/environmental interventions: Not applicable (not an environmentally caused disease); the sole "environmental" preventive measure is ototoxin avoidance (see Section 12).

14. Other Species / Natural Disease

  • Taxonomy: No naturally occurring veterinary/companion-animal disease analog for MYH9-associated hearing loss was identified in this search (unlike, e.g., well-documented canine models for other deafness genes). Mus musculus — NCBITaxon:10090 — is the primary comparative species, but via engineered (not naturally occurring) models (see Section 15).
  • Orthologous gene: Mouse Myh9 (MGI ortholog of human MYH9); highly conserved across mammals given the essential, ancient function of non-muscle myosin II in cytokinesis and cell motility.
  • Comparative biology: The actomyosin cytoskeletal machinery and its role in cell shape/motility is deeply evolutionarily conserved; however, whether MYH9's specific inner-ear/stereociliary role is conserved between mouse and human is called into question by the discordant mouse knockout phenotype (Section 6/15).
  • Transmission/zoonotic potential: Not applicable — a purely genetic, non-transmissible disorder.

15. Model Organisms

Mouse models — the key (and somewhat surprising) evidence base:

  1. Heterozygous Myh9-null (gene-trap ES cell–derived) mice (Parker et al., 2006, PMID:16630581):
  2. Derived using public BayGenomics gene-trapped ES cell resources.
  3. Homozygous nulls: embryonic lethal (none identified at birth), consistent with MYH9's essential developmental role.
  4. Heterozygous mice: no hearing loss and no cochleosaccular degeneration were observed, even in aged animals — in direct contrast to the human DFNA17 phenotype.

  5. Conclusion/limitation: Heterozygous loss (haploinsufficiency) of Myh9 alone is not sufficient to reproduce human hearing loss in mice, implying the human disease mechanism is more likely dominant-negative (requiring expression of the specific mutant protein) rather than simple dosage reduction — an important HUMAN_MODEL_MISMATCH-type caveat for curation.

  6. Heterozygous Myh9 R702C knock-in mice (Suzuki et al., 2013, PLoS ONE, PMC3748045):

  7. Models the human R702 mutation hotspot (associated with the most severe human MYH9-RD phenotype).
  8. Homozygous R702C: embryonic lethal (E10.5–11.5).
  9. Heterozygous R702C: macrothrombocytopenia with leukocyte inclusion bodies (recapitulating Döhle-body-like inclusions), renal glomerulosclerosis with abnormal albumin/creatinine ratios, and hearing disability — this model, unlike the null, does recapitulate multi-organ MYH9-RD features including hearing impairment, supporting the dominant-negative mutant-protein mechanism over haploinsufficiency.

  10. This is consistent with a broader review of "Mouse models of MYH9-related disease: mutations in nonmuscle myosin II-A" summarizing that missense knock-in models (not simple knockouts) are required to recapitulate the human phenotype (PMC3251230).

  11. Rat cochlea expression studies (non-genetic model, expression mapping only): RT-PCR and immunohistochemistry confirmed native Myh9 expression in the organ of Corti, spiral ligament, and Reissner's membrane, supporting biological plausibility of the human mutation's tissue-specific effects (PMC1288554); further work localized Myh9 specifically within cochlear stereocilia (PMID:16862555) and characterized its developmental expression pattern in the inner ear (PMID:15079858).

Modeling implications for curation: This is a clear case where a simple gene-knockout mouse model FAILS to recapitulate the human phenotype (FAILS_TO_RECAPITULATE), while a missense knock-in model matched to a specific human pathogenic hotspot (R702C) DOES recapitulate it (RECAPITULATES/PARTIALLY_RECAPITULATES). This is directly informative for modeling the mechanism as dominant-negative rather than loss-of-function/haploinsufficient, and should be reflected explicitly (e.g., via modeled_mechanisms links with contrasting relationship values) if curated into a mechanism graph.

Summary Table of Suggested Ontology Terms

Category Suggested term(s)
Disease MONDO (per GARD/NORD listing); OMIM #603622; DOID:0110548
Causal gene hgnc:7579 (MYH9)
Phenotype HP:0000407 (Sensorineural hearing impairment); HP:0000410/HP:0000362 (Progressive hearing impairment)
Cell types CL:0002165 (outer hair cell of Corti's organ); CL:0002167 (inner hair cell of Corti's organ)
Anatomy UBERON:0001844 (organ of Corti); UBERON:0002068 (Reissner's membrane); UBERON:0002261 (spiral ligament)
Biological process GO:0030036 (actin cytoskeleton organization); GO:0007605 (sensory perception of sound); GO:0060121 (inner ear receptor cell stereocilium organization)
Molecular function GO:0000146/GO:0003774 (motor activity)
Cellular component GO:0032420 (stereocilium); GO:0016459 (myosin complex)
Treatment NCIT:C15329 (Surgical Procedure — cochlear implant); NCIT:C15240 (Genetic Counseling)
Model organism gene Mouse Myh9 ortholog (MGI)

Key Primary Literature (PMID-cited)

  1. Lalwani AK et al. 1999. "A new locus for nonsyndromic hereditary hearing impairment, DFNA17, maps to chromosome 22 and represents a gene for cochleosaccular degeneration." PMID:9915977
  2. Lalwani AK et al. 2000. "Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9." PMID:11023810 (full text: PMC1288554)
  3. Seri M et al. 2000. "Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes." Nat Genet. ng0900_103
  4. Kim TB et al. 2007. "Cochlear implants for DFNA17 deafness." PMID:17146397
  5. Parker LL et al. 2006. "Absence of hearing loss in a mouse model for DFNA17 and MYH9-related disease." PMID:16630581
  6. Suzuki N et al. 2013. "Establishment of Mouse Model of MYH9 Disorders: Heterozygous R702C Mutation..." PMC:3748045
  7. Verver EJJ et al. 2015. "R705H mutation of MYH9 is associated with MYH9-related disease and not only with non-syndromic deafness DFNA17." PMID:24890873
  8. de Heer AM et al. 2015 (Brazilian family). "c.G2114A MYH9 mutation (DFNA17) causes non-syndromic autosomal dominant hearing loss in a Brazilian family." PMID:25505834
  9. GeneReviews: Saposnik B, Aviner S, Verver EJJ, et al. "MYH9-Related Disease." NBK2689 (updated periodically; primary comprehensive clinical synthesis)
  10. OMIM #603622. "Deafness, Autosomal Dominant 17; DFNA17." omim.org/entry/603622
  11. 2026 Japanese cohort. "The Clinical Details of MYH9-Related Disease and DFNA17 in a Large Japanese Hearing Loss Cohort." Genes 17(2):154. PMC12941242
  12. 2025 MYH9/MYH14 comparison. "The audiological phenotype of patients with a variant in MYH9 and MYH14 genes." Sci Rep. PMC12219520

Note on evidence gaps: No dedicated single-cell/spatial transcriptomic, proteomic, or CRISPR-screen data specific to DFNA17/MYH9 cochlear pathophysiology in humans were located in this search — mechanistic understanding rests primarily on rodent expression mapping and knock-in mouse models rather than direct human inner-ear molecular profiling (inner ear tissue being very difficult to obtain from living patients). This represents a genuine KNOWLEDGE_GAP for curation purposes, and the mouse knockout-vs-knock-in discordance (Section 15) should be flagged explicitly as a HUMAN_MODEL_MISMATCH if incorporated into a mechanism module.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 19
Resolved 18
Unresolved (possible confabulation) 1
Unverifiable 0
References weighed for topical relevance 18
On topic 17
Off topic 0

Unresolved references

These identifiers did not resolve to a record and may be fabricated. A lookup that failed for transport reasons is indistinguishable from one that failed because the record does not exist, so spot-check before acting on them:

  • DOI:10.3390/genes17020154)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12941242/ (1 mention) - Identifier did not resolve to a record