Autosomal Recessive Nonsyndromic Hearing Loss 30

Mendelian MONDO:0011774 Pathograph 12 Show in embeddings browser Nonsyndromic Hearing Loss

DFNB30 is autosomal recessive nonsyndromic sensorineural hearing loss caused by biallelic pathogenic MYO3A variants. Myosin IIIa combines an N-terminal regulatory kinase, an actin-based motor and a cargo-binding tail and localizes to hair-cell stereocilia tips. Bilateral, progressive, high-frequency hearing loss was described in the founding Iraqi Jewish family; congenital profound presentations also occur. Onset and severity vary, and available families do not establish a universal genotype-phenotype rule. Mouse and cell studies implicate stereocilia regulation and maintenance, but failed espin-1 delivery, loss of tip localization and normal mechanotransduction are not established universal features of DFNB30. In a nonsense knock-in mouse, hearing deficits precede visible hair-cell degeneration. The MYO3A variants associated with dominant hearing loss require separate allele-specific interpretation.

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Inheritance
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Pathophys.
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Phenotypes
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Gaps
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Pathograph
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Genes
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Medical Actions
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Differentials
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Models
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References
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Deep Research
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Inheritance

1
Autosomal recessive HP:0000007
Recessive MYO3A-associated hearing loss occurs with homozygous or compound heterozygous pathogenic variants. The founding family came from the endogamous Jewish community of Mosul, Iraq; 18 affected relatives included seven homozygotes and eleven compound heterozygotes. Other families were consanguineous. Distinct MYO3A alleles can cause dominant hearing loss, so gene identity alone does not determine inheritance.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:12032315 SUPPORT Human Clinical
"Of 18 affected relatives in Family N, 7 are homozygous and 11 are compound heterozygous for pairs of mutant alleles."
The founding family establishes recessive inheritance in both homozygous and compound heterozygous configurations.
PMID:27063751 SUPPORT Human Clinical
"A homozygous mutation, MYO3A:c.1841C>T (p.S614F), was identified to be responsible for the disease."
Independent confirmation of recessive inheritance in a consanguineous family.
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Discussions and Knowledge Gaps

3
How well has long-term retinal function been assessed in DFNB30?
KNOWLEDGE GAP dfnb30_longitudinal_retinal_assessment
Attached to
phenotypes#
The founding study explicitly reported normal vision and balance in affected relatives, and the Lys50Arg family report also described normal ocular and vestibular findings. These are positive reports of assessment, not merely absence of volunteered complaints. They do not establish systematic longitudinal electroretinography or lifelong absence of retinal disease; retinal expression alone does not establish a clinical retinal phenotype.
Is the espin-1 cargo-transport model the mechanism of DFNB30, given that espin-1 still reaches stereocilia tips in mice lacking both class III myosins?
HUMAN MODEL MISMATCH dfnb30_espin1_transport_model_mismatch
Attached to
pathophysiology#Altered Myosin IIIa Function at Stereocilia Tips
COS-7 and organotypic experiments demonstrate MYO3A/espin-1 interaction and construct-dependent protrusion elongation; the roughly tenfold effect used kinase-deleted MYO3A in COS-7 cells. Constitutive double-null mouse hair cells retained espin-1 tip localization and developed excessively long, poorly organized bundles. These model-to-model differences limit obligatory cargo-delivery failure as the mechanism in patients.
Do MYO3A kinase-domain alleles really separate congenital profound from late-onset progressive hearing loss?
KNOWLEDGE GAP dfnb30_kinase_domain_genotype_phenotype
Attached to
pathophysiology#MYO3A Loss of Function
Structural modelling proposes different consequences for kinase-specific impairment and wider protein dysfunction. The founding family showed a narrower genotype association between nonsense homozygotes and nonsense/splice compound heterozygotes, while the Japanese candidate series did not detect a correlation. These small and differently ascertained datasets neither validate a universal allele-domain rule nor establish a bimodal population onset distribution. Direct allele-resolved functional and longitudinal clinical evidence is needed.
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Pathophysiology

5
MYO3A Loss of Function
Biallelic pathogenic MYO3A variants impair myosin IIIa function. The founding family carried a nonsense allele and two splice-acceptor alleles. Lymphoblast RNA showed exon 18 skipping for one splice allele and loss of stable message from the other; these are measured RNA effects outside the cochlea. Missense variants also occur in motor and kinase domains, but reduced kinase activity is not equivalent to loss of motor activity: experimentally engineered K50R retains motor activity and increases tip localization in COS-7 cells. The clinical K50R report combined family segregation with structural modelling and earlier in-vitro evidence. Its proposed distinction between kinase-specific impairment and whole-protein dysfunction is not a validated general predictor of onset or severity.
MYO3A hgnc:7601 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MYO3A (hgnc:7601). hgnc:7601 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context functional_impact_category: LOSS_OF_FUNCTION
Established truncating and splice alleles support loss of function; individual missense variants require allele-specific evidence and cannot all be assumed to abolish both kinase and motor activities.
Downstream
Altered Myosin IIIa Function at Stereocilia Tips Variant-specific loss or alteration of myosin IIIa disrupts its regulation of stereocilia; the surviving protein and localization depend on the allele.
Show evidence (4 references)
PMID:12032315 SUPPORT Human Clinical
"In an extended Israeli family, nonsyndromic progressive hearing loss is caused by three different recessive, loss-of-function mutations in myosin IIIA."
Establishes loss of myosin IIIA function as the initiating lesion in humans.
PMID:34423747 SUPPORT INDIRECT Computational
"Our results suggest that KD mutations could either cause a congenital profound form of HI, when particularly affecting the kinase activity and preventing the auto-phosphorylation of the motor, or a late onset and progressive form, when partially or completely inactivating the MYO3A protein."
Molecular-dynamics and structural modelling of kinase-domain variants; it proposes the allele-class split recorded in this node's description and is graded COMPUTATIONAL and INDIRECT because the phenotype claim follows from modelling rather than from measurement in patients.
PMID:19287378 SUPPORT In Vitro
"Full-length myosin IIIa K50R localizes more efficiently to the tips of filopodia in COS-7 cells"
Engineered kinase-dead construct; kinase impairment does not necessarily eliminate motor function or tip localization.
+ 1 more reference
Altered Myosin IIIa Function at Stereocilia Tips
Myosin IIIa regulates actin protrusions at stereocilia tips. Espin-1 binding and transport were demonstrated in COS-7 cells and organotypic hair-cell cultures. The roughly tenfold filopodial elongation used kinase-deleted MYO3A with espin-1; wild-type MYO3A and kinase-dead K50R produced smaller effects. These construct-dependent results do not establish obligatory espin-1 delivery failure in DFNB30. Espin-1 still localized to tips in constitutive Myo3a/Myo3b double-null mouse hair cells. In the nonsense knock-in, C-terminal myosin IIIa immunoreactivity was absent, but the antibody epitope lies beyond the truncation; this assay cannot exclude an N-terminal truncated protein or establish loss of localization for every disease allele.
stereocilium tip GO:0032426 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves stereocilium tip (GO:0032426). GO:0032426 is a cellular component from the Gene Ontology.
Animal models
Myo3a knock-in mouse (human nonsense allele equivalent) Mouse partially recapitulates Loss of C-terminal myosin IIIa staining after truncation.
Downstream
Disordered Stereocilia and Hair Bundle Architecture Loss or alteration of class III myosin regulation can disrupt bundle architecture in mice; timing and severity depend on allele, paralogue and developmental stage.
Cochlear Hearing Dysfunction An early functional deficit is supported by abnormal ABR thresholds before visible degeneration in the nonsense knock-in. The intervening cellular defect was not measured directly.
Progressive Hair Cell Degeneration Impaired myosin IIIa function is followed by hair-cell degeneration in knock-in mice; the molecular steps causing cell death remain unresolved.
Show evidence (4 references)
PMID:19287378 SUPPORT In Vitro
"This extraordinary filopodia elongation results from the transport of espin 1 to the plus ends of F-actin by myosin IIIa and depends on espin 1 WH2 activity."
Cargo binding and transport in experimental cells; the largest elongation effect used a kinase-deleted construct.
PMID:21165622 SUPPORT INDIRECT Model Organism
"Myosin IIIA, with a unique N-terminal kinase domain and a C-terminal actin-binding domain, localizes to the tips of stereocilia in wild-type mice but is absent in the mutant."
The assay detects a C-terminal epitope lost by truncation; absence of staining does not establish absence of every truncated protein species.
PMID:26754646 SUPPORT Model Organism
"Surprisingly, espin-1 is properly targeted to Myo3a(-/-)Myo3b(-/-) stereocilia tips."
Preserved espin-1 targeting limits the obligatory cargo-delivery hypothesis; it does not refute altered myosin function.
+ 1 more reference
Disordered Stereocilia and Hair Bundle Architecture
Constitutive deletion of both Myo3a and Myo3b causes embryonic and neonatal bundle abnormalities, including excess stereocilia length and number, altered height grading and bundle rounding or closure. This developmental double knockout is not equivalent to human single-gene DFNB30. The Y137C single-gene knock-in develops fused or shortened stereocilia and abnormal tips with age, whereas nonsense knock-in bundles appeared normal at P8, six months and 8.5 months despite earlier hearing deficits. In P7-P8 double-null apical hair cells selected initially for near-normal bundle shape, OHC peak mechanotransduction current was approximately halved and IHC/OHC response sensitivity was reduced; adaptation kinetics were preserved. Detectable currents therefore do not establish normal transduction across cells, ages or human alleles.
auditory hair cell CL:0000202 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves auditory hair cell (CL:0000202). CL:0000202 is a cell type from the Cell Ontology.
auditory receptor cell stereocilium organization GO:0060088 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal auditory receptor cell stereocilium organization (GO:0060088). GO:0060088 is a biological process from the Gene Ontology. ⚠ ABNORMAL
stereocilium GO:0032420 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves stereocilium (GO:0032420). GO:0032420 is a cellular component from the Gene Ontology.
Animal models
Myo3a Y137C knock-in mouse Mouse recapitulates Structural abnormality of cochlear hair cell stereocilia in a single-gene Myo3a mutant.
Myo3a/Myo3b double knockout mouse Mouse partially recapitulates Reproduces disordered bundle architecture, but only when both class III myosins are removed - so it speaks to the pathway rather than to the human single-gene disease.
Downstream
Cochlear Hearing Dysfunction Abnormal bundle mechanics can impair sensory responses. Mouse double-null currents retain adaptation but show reduced amplitude or sensitivity; patient physiology has not established the same intermediate.
Show evidence (3 references)
PMID:26754646 SUPPORT INDIRECT Model Organism
"These include abnormally tall and numerous microvilli or stereocilia, ungraded stereocilia bundles, and bundle rounding and closure."
The bundle-architecture phenotype of the class III myosin double mutant; INDIRECT because it is a mouse double knockout, whereas DFNB30 is a single-gene human disease.
PMID:30123247 SUPPORT INDIRECT Model Organism
"We also found structural abnormality in the cochlear hair cell stereocilia."
Age-dependent bundle abnormality in the Y137C knock-in; not evidence that bundle disorganization precedes hearing loss in all MYO3A models.
PMID:26754646 SUPPORT Model Organism
"The sensitivity of the MET response, measured by determining the maximum slope of the MET current-deflection relationship, was lower than that in controls for both IHCs and OHCs"
P7-P8 apical double-null recordings; preserved adaptation did not imply normal response sensitivity.
Progressive Hair Cell Degeneration
Age-dependent cochlear hair-cell loss occurs in two Myo3a knock-in lines. In the nonsense model, ABR deficits were significant at 2.5 months, but bundles appeared normally shaped through 8.5 months and degeneration was described at ten and seventeen months. Thus degeneration can contribute to later deterioration but does not explain the earliest measured deficit. In the Y137C model, hearing was normal at two months; hearing deficits, stereocilia abnormalities and hair-cell degeneration were present at six months and worsened at twelve months. Human cochlear tissue has not established this sequence directly.
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
Myo3a knock-in mouse (human nonsense allele equivalent) Mouse recapitulates Later outer-hair-cell loss recapitulates a plausible contributor to progressive cochlear dysfunction; human tissue pathology is not available.
Downstream
Cochlear Hearing Dysfunction Loss of cochlear hair cells reduces sensory capacity and can contribute to late hearing deterioration. It does not account for the earlier deficit in the nonsense knock-in.
Show evidence (3 references)
PMID:21165622 SUPPORT INDIRECT Model Organism
"Outer hair cells of Myo3a(KI/KI) mice degenerate with age in a pattern consistent with their progressive hearing loss."
Ties age-dependent outer hair cell loss to the progression of threshold elevation in the model carrying the human founding family's allele.
PMID:30123247 SUPPORT INDIRECT Model Organism
"We observed degeneration in the inner ear hair cells of 6-month-old Myo3a mutant mice, and the degeneration became more severe at the age of 12 months."
Independent replication of age-dependent hair cell loss in a second knock-in line.
PMID:21165622 SUPPORT Model Organism
"at 8 days, 6 months, and 8.5 months stereocilia hair bundles of mutant mice were shaped normally, with a well-organized stereocilia staircase, compared to wild-type littermates."
Normal-appearing bundles at these ages limit a universal structural-disorganization-first sequence.
Cochlear Hearing Dysfunction
Impaired cochlear function produces sensorineural hearing loss. Human audiometry establishes bilateral, often high-frequency and progressive loss, with congenital profound presentations in other families. Mouse ABR measures a functional deficit; it does not alone identify the defective cellular process.
sensory perception of sound GO:0007605 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased sensory perception of sound (GO:0007605). GO:0007605 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Myo3a knock-in mouse (human nonsense allele equivalent) Mouse recapitulates Progressive functional hearing deficit with a human disease-allele equivalent.
Downstream
Progressive Sensorineural Hearing Impairment Clinical expression of impaired auditory function; onset and course vary by family.
Bilateral Sensorineural Hearing Impairment Clinical expression of impaired auditory function; onset and course vary by family.
High-Frequency Predominant Audiometric Configuration Clinical expression of impaired auditory function; onset and course vary by family.
Show evidence (2 references)
PMID:12032315 SUPPORT Human Clinical
"Members of three generations of Family N have experienced bilateral progressive hearing loss, which first affects the high frequencies."
Direct human audiometric phenotype.
PMID:21165622 SUPPORT Model Organism
"In mutant mice, hearing loss is significant at 2.5 months and progresses first at high frequencies, then at all frequencies."
Functional hearing deficit precedes visible degeneration.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Autosomal Recessive Nonsyndromic Hearing Loss 30 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

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Bilateral Sensorineural Hearing Impairment Auditory HP:0008619 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral sensorineural hearing impairment (HP:0008619). HP:0008619 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12032315 SUPPORT Human Clinical
"Members of three generations of Family N have experienced bilateral progressive hearing loss, which first affects the high frequencies."
Direct human audiometric phenotype.
Progressive Sensorineural Hearing Impairment Auditory 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
All eight clinically characterized Japanese probands reported progression. Two genotypes included a VUS and family segregation was unavailable. The age-threshold plot was cross-sectional rather than serial audiometry of the same patients; no disease-wide frequency or annual rate follows from it.
Show evidence (2 references)
PMID:39858639 SUPPORT Human Clinical
"The severity of their HL varied from mild to profound, and all patients were aware of HL progression at the time of their genetic testing."
Self-reported progression and prose severity range in a small candidate cohort; Table 2 lists moderate-to-profound loss in the eight characterized probands.
PMID:12032315 SUPPORT Human Clinical
"In an extended Israeli family, nonsyndromic progressive hearing loss is caused by three different recessive, loss-of-function mutations in myosin IIIA."
The founding description of the phenotype as nonsyndromic and progressive.
Postlingual Onset Hearing Loss Auditory HP:0008596 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postlingual sensorineural hearing impairment (HP:0008596). HP:0008596 is a phenotype from the Human Phenotype Ontology.
Eight characterized Japanese candidate probands reported onset at ages 10-30 years. These referral-cohort observations are not a population frequency.
Show evidence (1 reference)
PMID:39858639 SUPPORT Human Clinical
"The onset age of their HL varied from 10 to 30 years old (mean age: 19.6 years old), and all of them presented with post-lingual deterioration in hearing."
Numerator, onset range and post-lingual character in one sentence.
Congenital Profound Sensorineural Hearing Loss Auditory HP:0011476 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital profound sensorineural hearing impairment, annotated with Profound sensorineural hearing impairment (HP:0011476), qualified as congenital onset. HP:0011476 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Profound hearing impairment is bound to HPO and congenital onset is represented separately. The Lys50Arg clinical segregation supports the combined phenotype; the Ser614Phe abstract supports congenital onset only. These families do not establish a frequency or a general kinase-domain genotype-phenotype rule.
Show evidence (2 references)
PMID:34423747 SUPPORT Human Clinical
"This Lys50Arg mutation segregated with congenital profound non-syndromic HI."
The segregation observation in the reported family; graded HUMAN_CLINICAL because this sentence reports patients, unlike the same paper's modelling results.
PMID:27063751 SUPPORT Human Clinical
"In this study, we characterized a consanguineous Kazakh family with congenital hearing loss."
A second, independently reported congenital presentation. It supports the congenital onset only - this report does not grade the severity, so it is not a source for "profound".
High-Frequency Predominant Audiometric Configuration Auditory HP:0001757 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High-frequency sensorineural hearing impairment (HP:0001757). HP:0001757 is a phenotype from the Human Phenotype Ontology.
The founding family had high-frequency loss initially. Six of eight characterized Japanese candidate probands had down-sloping audiograms and two had flat audiograms; this small series includes uncertain variants and is not a disease-wide frequency estimate.
Show evidence (2 references)
PMID:39858639 SUPPORT Human Clinical
"The types of HL were categorized as down-sloping in six, and flat in two patients."
Numerator and denominator for the audiometric configuration.
PMID:12032315 SUPPORT Human Clinical
"Members of three generations of Family N have experienced bilateral progressive hearing loss, which first affects the high frequencies."
Direct human audiometric phenotype.
Vertigo Vestibular HP:0002321 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vertigo (HP:0002321). HP:0002321 is a phenotype from the Human Phenotype Ontology.
Table 2 identifies the symptomatic probands as Family 1 (p.Glu770Lys VUS with a likely pathogenic splice allele) and Family 4 (homozygous p.Ala238Thr VUS). The 2/8 proportion must not be treated as the frequency of vestibular disease in confirmed DFNB30. A 57-year-old man homozygous for the founding nonsense allele had normal formal ocular-motor and vestibular testing; normal findings in that individual do not refute symptoms in other genotypes.
Show evidence (1 reference)
PMID:39858639 SUPPORT Human Clinical
"Two individuals complained of vertigo, but the specifics are unknown."
Reported symptoms in two uncertain genotypes; not proof of MYO3A-related vestibular dysfunction.
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Genetic Associations

1
MYO3A
Gene: MYO3A hgnc:7601 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MYO3A (hgnc:7601). hgnc:7601 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:12032315 SUPPORT Human Clinical
"Here, we show that normal hearing in humans requires myosin IIIA, the human homolog of NINAC."
The gene-disease assertion in its founding form.
PMID:12032315 SUPPORT Human Clinical
"Between ages 25 and 50, hearing across all frequencies was significantly poorer among individuals homozygous for the nonsense mutation"
Within-family genotype association, comparing nonsense homozygotes with nonsense/splice compound heterozygotes.
PMID:39858639 SUPPORT Human Clinical
"As we were not able to conduct segregation analyses on the families of the probands due to a lack of peripheral blood samples, it is possible that the HL was due to other causes"
Authors explicitly acknowledge uncertain attribution in the Japanese candidate series.
💊

Medical Actions

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Hearing Aid Amplification
Action: hearing aid amplificationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hearing aid amplification, annotated with Rehabilitation (NCIT:C15315), qualified as medical device hearing aid. NCIT:C15315 is a clinical intervention from the NCI Thesaurus. Ontology label: Rehabilitation NCIT:C15315
Platform: Device
Hearing aids can improve access to sound when appropriate for measured hearing levels and communication goals. Acoustic amplification uses residual auditory function; it does not bypass hair cells or correct MYO3A dysfunction. The Japanese series recommends rehabilitation but does not measure DFNB30-specific hearing-aid outcomes.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT Other
"customized by an audiologist to the degree and frequency of hearing loss, can be used in individuals with mild-to-severe hearing loss."
General hereditary-hearing-loss guidance, not a DFNB30 outcome study.
Cochlear Implantation
Action: cochlear device implantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cochlear device implantation, annotated with Surgical Procedure (NCIT:C15329), qualified as medical device cochlear implant. NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Cochlear implantation may be considered for severe-to-profound hearing loss after specialist assessment of candidacy and aided benefit. It electrically stimulates the auditory pathway, bypassing hair-cell transduction. The Japanese DFNB30 study recommends considering implantation but does not provide implant outcomes or prove preserved auditory-nerve function in every patient.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT Other
"Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months."
General GeneReviews guidance; eligibility depends on individual clinical assessment.
PMID:39858639 SUPPORT Other
"In addition, the evaluation of the outcomes of hearing aids or cochlear implantation will also be useful."
The authors identify treatment outcome measurement as future work.
Genetic Counselling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Provide nondirective counseling after molecular confirmation. Recurrence risk is conditional on established parental pathogenic genotypes, and testing relatives requires identification of the familial variants. Distinguish recessive DFNB30 from allele-specific dominant MYO3A-associated hearing loss.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT Other
"If both parents are known to be heterozygous for an autosomal recessive hearing loss-related pathogenic variant, each sib of the proband has at conception a 25% chance of having hearing loss, a 50% chance of having no hearing loss and being a carrier, and a 25% chance of having no hearing loss..."
General recessive recurrence risk, conditional on established parental pathogenic variants.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT Other
"Carrier testing for relatives who may have a hearing loss-related pathogenic variant requires prior identification of the pathogenic variants in the family."
Prerequisite for informative family testing.
Communication and language support
Establish communication goals and provide appropriate language access, speech-language services and educational support. These are general measures for hearing loss, not evidence of a primary neurodevelopmental syndrome caused by MYO3A.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT Other
"On initial evaluation of individuals with hearing loss, the goals for communication must be established with a focus on equipping individuals with language and appropriate access to language."
General hearing-loss management.
🔬

Diagnosis

4
Age-appropriate audiometry
Age-appropriate audiometry characterizes degree, configuration and sensorineural status. The Japanese cohort used pure-tone audiometry from age five and behavioral or evoked-response approaches in younger children. Audiogram shape alone does not establish MYO3A causation.
audiometric assessment NCIT:C38036 NCI Thesaurus (NCIT)
Results: Sensorineural loss, mild to profound, usually down-sloping.
Show evidence (1 reference)
PMID:39858639 SUPPORT Human Clinical
"Pure-tone audiometry was used to assess hearing thresholds for patients aged 5 years and above, whereas auditory steady state response (ASSR), conditioned orientation response audiometry (COR: one type of the behavioral audiometry), or play audiometry were used for individuals under 5 years old."
The audiometric methods used in the largest series, including the age threshold at which they switch.
Serial audiometric follow-up
Repeated audiometry documents change and guides rehabilitation. It is useful for monitoring suspected or confirmed progressive hearing loss, but serial deterioration is not a prerequisite for molecular diagnosis and congenital presentations occur.
serial audiometric follow-up NCIT:C38036 NCI Thesaurus (NCIT)
Results: Individual trajectory assessed over time; no validated DFNB30-specific deterioration rate.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT Other
"Regular follow up is recommended for all individuals with genetic hearing loss in order to:"
General management guidance supports continued audiologic assessment.
PMID:39858639 SUPPORT Human Clinical
"A further prospective study will be useful in evaluating hearing deterioration through the use of the serial audiometric testing results from the same patient."
The Japanese study lacked same-patient longitudinal audiometry; it recommends prospective measurement.
Massively parallel sequencing of a hearing-loss gene panel
A hearing-loss multigene panel or genomic testing can assess MYO3A alongside other hearing-loss genes. The Japanese study used a 158-gene panel and read-depth copy-number analysis. Interpretation requires pathogenicity assessment and, where possible, confirmation that two variants are in trans. MYO3A need not be tested only after excluding each more common gene.
massively parallel sequencing of a targeted hearing-loss gene panel NCIT:C101293 NCI Thesaurus (NCIT)
Results: Biallelic pathogenic or likely pathogenic MYO3A variants consistent with recessive inheritance support DFNB30; unresolved variants or phase require further assessment.
Show evidence (2 references)
PMID:39858639 SUPPORT Human Clinical
"Among these subjects, we selected patients with biallelic MYO3A variants through MPS of 158 target genes."
The testing modality and the biallelic requirement in one sentence.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT Other
"can often identify the cause of genetic hearing loss while limiting identification of pathogenic variants and variants of uncertain significance in genes that are irrelevant to the underlying phenotype."
General guidance for hearing-loss panels.
Variant interpretation under the ClinGen hearing-loss specification
Variant classification, segregation and phase distinguish a molecular diagnosis from an uncertain candidate genotype. The Japanese series used ACMG/AMP criteria with hearing-loss specifications, but p.Glu770Lys and p.Ala238Thr remained uncertain and family segregation was unavailable. A VUS does not establish or exclude DFNB30; dominant MYO3A-associated hearing loss must also be considered for appropriate alleles and pedigrees.
variant classification NCIT:C19770 NCI Thesaurus (NCIT)
Results: Allele-specific classification and inheritance assessment; uncertain genotypes remain unresolved.
Show evidence (2 references)
PMID:39858639 SUPPORT Human Clinical
"The pathogenicity of identified variants was evaluated according to the American College of Medical Genetics (ACMG) standards and guidelines"
Study classification framework; Table 1 and segregation limitations must accompany its interpretation.
PMID:39858639 SUPPORT Human Clinical
"As we were not able to conduct segregation analyses on the families of the probands due to a lack of peripheral blood samples, it is possible that the HL was due to other causes"
Authors explicitly acknowledge uncertain attribution in the Japanese candidate series.
📈

Progression

2
Onset
Age: congenital to third decade
Reported onset spans congenital hearing loss and postlingual onset. The Japanese candidate series reported 10-30 years; small selected families do not demonstrate a bimodal population distribution.
Show evidence (2 references)
PMID:39858639 SUPPORT Human Clinical
"The onset age of their HL varied from 10 to 30 years old (mean age: 19.6 years old), and all of them presented with post-lingual deterioration in hearing."
The late-onset arm of the range.
PMID:34423747 SUPPORT Human Clinical
"This Lys50Arg mutation segregated with congenital profound non-syndromic HI."
The congenital arm of the range.
Deterioration
Age: adulthood
Progression to severe or profound loss was observed in reported families and described in the Japanese series. Its cross-sectional age-threshold relationship and self-reported progression do not establish an individual deterioration rate or an inevitable outcome for every allele.
Show evidence (1 reference)
PMID:39858639 SUPPORT Human Clinical
"In particular, most of the cases identified in this study and previous reports showed progressive HL, eventually progressing to severe-to-profound HL."
States the trajectory across this series and prior reports.
📊

Prevalence

1
Japanese hearing-loss patients screened by massively parallel sequencing
Unknown Unknown
Nine candidate probands were identified among 15,684 Japanese hearing-loss patients (reported 0.06%). Two genotypes included a VUS and familial segregation was unavailable, so this is a candidate detection proportion in a referral cohort, not confirmed diagnostic yield or population prevalence. Eight probands had clinical data. Literature case summaries cannot be treated as a complete count of affected individuals: the founding family alone contained eighteen affected relatives.
Show evidence (2 references)
PMID:39858639 SUPPORT Human Clinical
"MYO3A is a relatively rare causative gene, and the prevalence of MYO3A-associated HL among Japanese HL patients is 0.06% (9/15,684)."
Numerator, denominator and proportion in one sentence.
PMID:39858639 SUPPORT Human Clinical
"As we were not able to conduct segregation analyses on the families of the probands due to a lack of peripheral blood samples, it is possible that the HL was due to other causes"
Authors explicitly acknowledge uncertain attribution in the Japanese candidate series.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Autosomal Recessive Nonsyndromic Hearing Loss 30:

Idiopathic sudden sensorineural hearing loss
Overlapping Features The Japanese study lists idiopathic sudden sensorineural hearing loss among competing explanations for later-onset hearing loss. Clinical chronology helps distinguish abrupt loss from a progressive inherited course.
Distinguishing Features
  • Abrupt onset over hours to days rather than progressive deterioration over years
Show evidence (1 reference)
PMID:39858639 SUPPORT Human Clinical
"However, the elucidation of HL causation becomes more challenging when related to late-onset HL, as multiple factors, such as presbycusis, idiopathic sudden SNHL, environmental risk factors, etc., can be involved."
The same sentence names it as a competing explanation for late-onset hearing loss.
Other autosomal recessive nonsyndromic hearing loss, principally GJB2, SLC26A4 and CDH23
Overlapping Features Other hearing-loss genes can produce overlapping nonsyndromic presentations. Multigene testing evaluates these alternatives together; DFNB30 is not a diagnosis of exclusion after each common gene is tested.
Distinguishing Features
  • Pathogenic variants and appropriate segregation in the causative gene
  • Onset and audiometric configuration overlap and cannot by themselves assign the gene
Show evidence (1 reference)
PMID:39858639 SUPPORT Human Clinical
"The major causative genes of ARSNHL in Japanese patients are GJB2 (16%), SLC26A4 (5%) and CDH23 (4%), and the detection of causative genes for HL has become significantly more achievable through the introduction of massively parallel DNA sequencing (MPS) analysis [5]."
Cohort-specific contributions motivate multigene assessment, not a required sequence of gene exclusions.
🐁

Animal Models

3
Myo3a knock-in mouse (human nonsense allele equivalent)
C57BL/6 knock-in of the human founding nonsense allele equivalent, compared with wild-type littermates. ABR deficits begin at 2.5 months and progress; bundles appear normally shaped through 8.5 months, followed by hair-cell degeneration at ten and seventeen months. Vestibular reaching and forced-swim tests were normal.
Species
Mouse
Genotype
Myo3a(KI/KI), knock-in of the mouse equivalent of the human MYO3A nonsense allele
Publication
PMID:21165622
Pathograph links
Progressive Hair Cell Degeneration recapitulates fidelity: moderate Later outer-hair-cell loss recapitulates a plausible contributor to progressive cochlear dysfunction; human tissue pathology is not available.
Limitations: The model carries one nonsense allele on a mouse background. Early hearing loss precedes visible degeneration, and mouse ages do not predict human onset. Outer-hair-cell counts used three animals per genotype; inner hair cells could not be counted consistently.
Readouts
Outer hair cell survival
Direction: DECREASED
Interpretation: Structural correlate of the degeneration node in this model.
Show evidence (1 reference)
PMID:21165622 SUPPORT Model Organism
"Outer hair cells of Myo3a(KI/KI) mice degenerate with age in a pattern consistent with their progressive hearing loss."
The histological measurement behind this readout.
Show evidence (1 reference)
PMID:21165622 SUPPORT Model Organism
"The phenotype of the Myo3a(KI/KI) mouse parallels the phenotype of human DFNB30."
The authors' own assessment that this model is informative for the human disease.
Altered Myosin IIIa Function at Stereocilia Tips partially recapitulates fidelity: low Loss of C-terminal myosin IIIa staining after truncation.
Limitations: The antibody recognizes the C-terminal epitope removed by the mutation; it cannot exclude residual N-terminal protein.
Readouts
C-terminal myosin IIIa immunoreactivity at stereocilia tips
Direction: ABOLISHED
Interpretation: C-terminal staining is absent; complete absence or failed targeting of every mutant protein species is not demonstrated.
Show evidence (1 reference)
PMID:21165622 SUPPORT Model Organism
"Myosin IIIA, with a unique N-terminal kinase domain and a C-terminal actin-binding domain, localizes to the tips of stereocilia in wild-type mice but is absent in the mutant."
Epitope-dependent localization assay; interpreted with the methods.
Show evidence (1 reference)
PMID:21165622 SUPPORT Model Organism
"against a synthetic peptide (NPYDYRRLLRKTSQRQR) that matches the C-terminus sequence of the mouse myosin IIIA."
The methods identify the epitope and its relevance to interpreting negative staining.
Cochlear Hearing Dysfunction recapitulates fidelity: moderate Progressive functional hearing deficit with a human disease-allele equivalent.
Limitations: ABR is not a direct assay of the cellular cause of the early deficit.
Readouts
Auditory brainstem response threshold
Direction: INCREASED
Interpretation: ABR thresholds rise from 2.5 months, before visible hair-cell degeneration.
Show evidence (1 reference)
PMID:21165622 SUPPORT Model Organism
"In mutant mice, hearing loss is significant at 2.5 months and progresses first at high frequencies, then at all frequencies."
Functional hearing deficit precedes visible degeneration.
Myo3a Y137C knock-in mouse
CBA/CaJ kinase-domain Y137C knock-in made by CRISPR/Cas9. ABR thresholds were normal at two months and elevated at six and twelve months, when stereocilia abnormalities and hair-cell loss were present. A noise challenge at 4.5 months showed no significant genotype difference in threshold shifts under that protocol, so it does not establish increased noise susceptibility.
Species
Mouse
Genotype
Myo3a Y137C kinase-domain missense knock-in, generated by CRISPR/Cas9
Publication
PMID:30123247
Pathograph links
Disordered Stereocilia and Hair Bundle Architecture recapitulates fidelity: moderate Structural abnormality of cochlear hair cell stereocilia in a single-gene Myo3a mutant.
Limitations: The CBA/CaJ mouse Y137C substitution was designed to model human Y129C, but the human family data were not shown in this paper. Stereocilia were intact at two months and abnormal at six and twelve months. Positive FM1-43 uptake is a proxy, not proof of normal mechanotransduction currents across age. The paper did not directly measure mutant kinase activity.
Readouts
Cochlear hair cell stereocilia structure
Direction: ALTERED
Interpretation: Structural correlate of the bundle-architecture node.
Show evidence (1 reference)
PMID:30123247 SUPPORT Model Organism
"We also found structural abnormality in the cochlear hair cell stereocilia."
The structural measurement behind this readout.
Show evidence (1 reference)
PMID:30123247 SUPPORT Model Organism
"Our results showed that Myo3a is essential for normal hearing by maintaining the intact structure of hair cell stereocilia, and the kinase domain plays a critical role in the normal functions of Myo3a."
The authors' statement of what the model establishes about the mechanism.
Myo3a/Myo3b double knockout mouse
Not a model of DFNB30 but of class III myosin function generally: removing both paralogues produces profound deafness and a grossly abnormal hair bundle, and it is the source of the finding that these motors limit rather than only promote stereocilia elongation.
Species
Mouse
Genotype
Myo3a(-/-)Myo3b(-/-) double knockout
Publication
PMID:26754646
Pathograph links
Disordered Stereocilia and Hair Bundle Architecture partially recapitulates fidelity: low Reproduces disordered bundle architecture, but only when both class III myosins are removed - so it speaks to the pathway rather than to the human single-gene disease.
Limitations: Constitutive deletion of both paralogues causes a developmental phenotype distinct from human single-gene DFNB30. In the same study, Myo3a deletion beginning postnatally on a Myo3b-null background left ABR and DPOAE normal through six months, while postnatal Myo3a loss with Myo3b intact raised ABR thresholds. Timing and paralogue context therefore preclude a simple lifelong protective-compensation model.
Readouts
Hair bundle morphology
Direction: ALTERED
Interpretation: Abnormally tall and numerous stereocilia with loss of height grading, in the double mutant.
Show evidence (1 reference)
PMID:26754646 SUPPORT Model Organism
"These include abnormally tall and numerous microvilli or stereocilia, ungraded stereocilia bundles, and bundle rounding and closure."
The morphological measurement behind this readout.
Show evidence (1 reference)
PMID:26754646 SUPPORT Model Organism
"We show that Myo3a(-/-)Myo3b(-/-) mice lacking myosin IIIa and myosin IIIb are profoundly deaf, whereas Myo3a-cKO Myo3b(-/-) mice lacking myosin IIIb and losing myosin IIIa postnatally have normal hearing."
The comparison that both establishes the double mutant's deafness and limits how far it can be read as a MYO3A model.
{ }

Source YAML

click to show 
name: Autosomal Recessive Nonsyndromic Hearing Loss 30
category: Mendelian
creation_date: "2026-09-04T00:00:00Z"
synonyms:
- DFNB30
- Deafness, autosomal recessive 30
- MYO3A-associated hearing loss
- Autosomal recessive nonsyndromic deafness 30
description: >-
  DFNB30 is autosomal recessive nonsyndromic sensorineural hearing loss caused by biallelic pathogenic MYO3A
  variants. Myosin IIIa combines an N-terminal regulatory kinase, an actin-based motor and a cargo-binding
  tail and localizes to hair-cell stereocilia tips. Bilateral, progressive, high-frequency hearing loss was
  described in the founding Iraqi Jewish family; congenital profound presentations also occur. Onset and severity
  vary, and available families do not establish a universal genotype-phenotype rule. Mouse and cell studies
  implicate stereocilia regulation and maintenance, but failed espin-1 delivery, loss of tip localization and
  normal mechanotransduction are not established universal features of DFNB30. In a nonsense knock-in mouse,
  hearing deficits precede visible hair-cell degeneration. The MYO3A variants associated with dominant hearing
  loss require separate allele-specific interpretation.
disease_term:
  preferred_term: autosomal recessive nonsyndromic hearing loss 30
  term:
    id: MONDO:0011774
    label: autosomal recessive nonsyndromic hearing loss 30
parents:
- Nonsyndromic Hearing Loss
notes: >-
  Human evidence consists of families and small referral cohorts. The 2025 Japanese series reported nine candidate
  probands among 15,684 hearing-loss patients, with clinical data for eight. Two genotypes include variants
  classified as uncertain, and family segregation was unavailable. Its proportions describe this selected series
  rather than phenotype frequencies in genetically confirmed DFNB30. Reported normal vision and balance in
  the founding family support its nonsyndromic characterization; these observations do not establish lifelong
  retinal protection. Vertigo reported in two Japanese probands remains uncertain because both carried a VUS
  and neither had characterized vestibular testing. Mouse and cell experiments inform the mechanisms, with
  explicit limits on transfer to patients.
references:
- reference: PMID:12032315
  title: "From flies' eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30."
- reference: PMID:27063751
  title: Identification of a novel homozygous mutation in MYO3A in a Chinese family with DFNB30 non-syndromic hearing impairment.
- reference: PMID:34423747
  title: Molecular insights into MYO3A kinase domain variants explain variability in both severity and progression of DFNB30 hearing impairment.
- reference: PMID:39858639
  title: The Prevalence and Clinical Characteristics of MYO3A-Associated Hearing Loss in 15,684 Hearing Loss Patients.
- reference: PMID:19287378
  title: Myosin IIIa boosts elongation of stereocilia by transporting espin 1 to the plus ends of actin filaments.
- reference: PMID:26754646
  title: Class III myosins shape the auditory hair bundles by limiting microvilli and stereocilia growth.
- reference: PMID:21165622
  title: A mouse model for human hearing loss DFNB30 due to loss of function of myosin IIIA.
- reference: PMID:30123247
  title: Knock-In Mice with Myo3a Y137C Mutation Displayed Progressive Hearing Loss and Hair Cell Degeneration in the Inner Ear.
- reference: PMID:26841241
  title: MYO3A Causes Human Dominant Deafness and Interacts with Protocadherin 15-CD2 Isoform.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
  title: "Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf"
  tags:
  - GeneReviews
inheritance:
- name: Autosomal recessive
  description: >-
    Recessive MYO3A-associated hearing loss occurs with homozygous or compound heterozygous pathogenic variants.
    The founding family came from the endogamous Jewish community of Mosul, Iraq; 18 affected relatives included
    seven homozygotes and eleven compound heterozygotes. Other families were consanguineous. Distinct MYO3A
    alleles can cause dominant hearing loss, so gene identity alone does not determine inheritance.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:12032315
    reference_title: "From flies' eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of 18 affected relatives in Family N, 7 are homozygous and 11 are compound heterozygous for pairs of mutant alleles."
    explanation: >-
      The founding family establishes recessive inheritance in both homozygous and compound
      heterozygous configurations.
  - reference: PMID:27063751
    reference_title: Identification of a novel homozygous mutation in MYO3A in a Chinese family with DFNB30 non-syndromic hearing impairment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A homozygous mutation, MYO3A:c.1841C>T (p.S614F), was identified to be responsible for the disease."
    explanation: Independent confirmation of recessive inheritance in a consanguineous family.
pathophysiology:
- name: MYO3A Loss of Function
  description: >-
    Biallelic pathogenic MYO3A variants impair myosin IIIa function. The founding family carried a nonsense
    allele and two splice-acceptor alleles. Lymphoblast RNA showed exon 18 skipping for one splice allele and
    loss of stable message from the other; these are measured RNA effects outside the cochlea. Missense variants
    also occur in motor and kinase domains, but reduced kinase activity is not equivalent to loss of motor
    activity: experimentally engineered K50R retains motor activity and increases tip localization in COS-7
    cells. The clinical K50R report combined family segregation with structural modelling and earlier in-vitro
    evidence. Its proposed distinction between kinase-specific impairment and whole-protein dysfunction is
    not a validated general predictor of onset or severity.
  role: trigger
  biological_scale: MOLECULAR
  genes:
  - preferred_term: MYO3A
    term:
      id: hgnc:7601
      label: MYO3A
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Established truncating and splice alleles support loss of function; individual missense variants require
      allele-specific evidence and cannot all be assumed to abolish both kinase and motor activities.
  downstream:
  - target: Altered Myosin IIIa Function at Stereocilia Tips
    description: Variant-specific loss or alteration of myosin IIIa disrupts its regulation of stereocilia; the surviving protein and localization depend on the allele.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:12032315
    reference_title: "From flies' eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In an extended Israeli family, nonsyndromic progressive hearing loss is caused by three different recessive, loss-of-function mutations in myosin IIIA."
    explanation: Establishes loss of myosin IIIA function as the initiating lesion in humans.
  - reference: PMID:34423747
    reference_title: Molecular insights into MYO3A kinase domain variants explain variability in both severity and progression of DFNB30 hearing impairment.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    directness: INDIRECT
    snippet: "Our results suggest that KD mutations could either cause a congenital profound form of HI, when particularly affecting the kinase activity and preventing the auto-phosphorylation of the motor, or a late onset and progressive form, when partially or completely inactivating the MYO3A protein."
    explanation: >-
      Molecular-dynamics and structural modelling of kinase-domain variants; it proposes the
      allele-class split recorded in this node's description and is graded COMPUTATIONAL and
      INDIRECT because the phenotype claim follows from modelling rather than from measurement
      in patients.
  - reference: PMID:19287378
    reference_title: Myosin IIIa boosts elongation of stereocilia by transporting espin 1 to the plus ends of actin filaments.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Full-length myosin IIIa K50R localizes more efficiently to the tips of filopodia in COS-7 cells
    explanation: Engineered kinase-dead construct; kinase impairment does not necessarily eliminate motor function or tip localization.
  - reference: PMID:12032315
    reference_title: "From flies' eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: led to an unstable message, as revealed by the absence of message from this allele in persons who carried the mutation in their genomic DNA
    explanation: Allele-specific transcript loss was assayed in lymphoblasts; patient cochlear RNA was not studied.
- name: Altered Myosin IIIa Function at Stereocilia Tips
  description: >-
    Myosin IIIa regulates actin protrusions at stereocilia tips. Espin-1 binding and transport were demonstrated
    in COS-7 cells and organotypic hair-cell cultures. The roughly tenfold filopodial elongation used kinase-deleted
    MYO3A with espin-1; wild-type MYO3A and kinase-dead K50R produced smaller effects. These construct-dependent
    results do not establish obligatory espin-1 delivery failure in DFNB30. Espin-1 still localized to tips
    in constitutive Myo3a/Myo3b double-null mouse hair cells. In the nonsense knock-in, C-terminal myosin IIIa
    immunoreactivity was absent, but the antibody epitope lies beyond the truncation; this assay cannot exclude
    an N-terminal truncated protein or establish loss of localization for every disease allele.
  biological_scale: MOLECULAR
  cellular_components:
  - preferred_term: stereocilium tip
    term:
      id: GO:0032426
      label: stereocilium tip
  downstream:
  - target: Disordered Stereocilia and Hair Bundle Architecture
    description: Loss or alteration of class III myosin regulation can disrupt bundle architecture in mice; timing and severity depend on allele, paralogue and developmental stage.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Cochlear Hearing Dysfunction
    description: An early functional deficit is supported by abnormal ABR thresholds before visible degeneration in the nonsense knock-in. The intervening cellular defect was not measured directly.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Progressive Hair Cell Degeneration
    description: Impaired myosin IIIa function is followed by hair-cell degeneration in knock-in mice; the molecular steps causing cell death remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:19287378
    reference_title: Myosin IIIa boosts elongation of stereocilia by transporting espin 1 to the plus ends of actin filaments.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This extraordinary filopodia elongation results from the transport of espin 1 to the plus ends of F-actin by myosin IIIa and depends on espin 1 WH2 activity."
    explanation: >-
      Cargo binding and transport in experimental cells; the largest elongation effect used a kinase-deleted
      construct.
  - reference: PMID:21165622
    reference_title: A mouse model for human hearing loss DFNB30 due to loss of function of myosin IIIA.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Myosin IIIA, with a unique N-terminal kinase domain and a C-terminal actin-binding domain, localizes to the tips of stereocilia in wild-type mice but is absent in the mutant."
    explanation: >-
      The assay detects a C-terminal epitope lost by truncation; absence of staining does not establish absence
      of every truncated protein species.
  - reference: PMID:26754646
    reference_title: Class III myosins shape the auditory hair bundles by limiting microvilli and stereocilia growth.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Surprisingly, espin-1 is properly targeted to Myo3a(-/-)Myo3b(-/-) stereocilia tips."
    explanation: >-
      Preserved espin-1 targeting limits the obligatory cargo-delivery hypothesis; it does not refute altered
      myosin function.
  - reference: PMID:21165622
    reference_title: A mouse model for human hearing loss DFNB30 due to loss of function of myosin IIIA.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: against a synthetic peptide (NPYDYRRLLRKTSQRQR) that matches the C-terminus sequence of the mouse myosin IIIA.
    explanation: The methods identify the epitope and its relevance to interpreting negative staining.
- name: Disordered Stereocilia and Hair Bundle Architecture
  description: >-
    Constitutive deletion of both Myo3a and Myo3b causes embryonic and neonatal bundle abnormalities, including
    excess stereocilia length and number, altered height grading and bundle rounding or closure. This developmental
    double knockout is not equivalent to human single-gene DFNB30. The Y137C single-gene knock-in develops
    fused or shortened stereocilia and abnormal tips with age, whereas nonsense knock-in bundles appeared normal
    at P8, six months and 8.5 months despite earlier hearing deficits. In P7-P8 double-null apical hair cells
    selected initially for near-normal bundle shape, OHC peak mechanotransduction current was approximately
    halved and IHC/OHC response sensitivity was reduced; adaptation kinetics were preserved. Detectable currents
    therefore do not establish normal transduction across cells, ages or human alleles.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: auditory hair cell
    term:
      id: CL:0000202
      label: auditory hair cell
  cellular_components:
  - preferred_term: stereocilium
    term:
      id: GO:0032420
      label: stereocilium
  biological_processes:
  - preferred_term: auditory receptor cell stereocilium organization
    modifier: ABNORMAL
    term:
      id: GO:0060088
      label: auditory receptor cell stereocilium organization
  downstream:
  - target: Cochlear Hearing Dysfunction
    description: Abnormal bundle mechanics can impair sensory responses. Mouse double-null currents retain adaptation but show reduced amplitude or sensitivity; patient physiology has not established the same intermediate.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:26754646
    reference_title: Class III myosins shape the auditory hair bundles by limiting microvilli and stereocilia growth.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "These include abnormally tall and numerous microvilli or stereocilia, ungraded stereocilia bundles, and bundle rounding and closure."
    explanation: >-
      The bundle-architecture phenotype of the class III myosin double mutant; INDIRECT because
      it is a mouse double knockout, whereas DFNB30 is a single-gene human disease.
  - reference: PMID:30123247
    reference_title: Knock-In Mice with Myo3a Y137C Mutation Displayed Progressive Hearing Loss and Hair Cell Degeneration in the Inner Ear.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "We also found structural abnormality in the cochlear hair cell stereocilia."
    explanation: >-
      Age-dependent bundle abnormality in the Y137C knock-in; not evidence that bundle disorganization precedes
      hearing loss in all MYO3A models.
  - reference: PMID:26754646
    reference_title: Class III myosins shape the auditory hair bundles by limiting microvilli and stereocilia growth.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The sensitivity of the MET response, measured by determining the maximum slope of the MET current-deflection relationship, was lower than that in controls for both IHCs and OHCs
    explanation: P7-P8 apical double-null recordings; preserved adaptation did not imply normal response sensitivity.
- name: Progressive Hair Cell Degeneration
  description: >-
    Age-dependent cochlear hair-cell loss occurs in two Myo3a knock-in lines. In the nonsense model, ABR deficits
    were significant at 2.5 months, but bundles appeared normally shaped through 8.5 months and degeneration
    was described at ten and seventeen months. Thus degeneration can contribute to later deterioration but
    does not explain the earliest measured deficit. In the Y137C model, hearing was normal at two months; hearing
    deficits, stereocilia abnormalities and hair-cell degeneration were present at six months and worsened
    at twelve months. Human cochlear tissue has not established this sequence directly.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  downstream:
  - target: Cochlear Hearing Dysfunction
    description: Loss of cochlear hair cells reduces sensory capacity and can contribute to late hearing deterioration. It does not account for the earlier deficit in the nonsense knock-in.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:21165622
    reference_title: A mouse model for human hearing loss DFNB30 due to loss of function of myosin IIIA.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Outer hair cells of Myo3a(KI/KI) mice degenerate with age in a pattern consistent with their progressive hearing loss."
    explanation: >-
      Ties age-dependent outer hair cell loss to the progression of threshold elevation in the
      model carrying the human founding family's allele.
  - reference: PMID:30123247
    reference_title: Knock-In Mice with Myo3a Y137C Mutation Displayed Progressive Hearing Loss and Hair Cell Degeneration in the Inner Ear.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "We observed degeneration in the inner ear hair cells of 6-month-old Myo3a mutant mice, and the degeneration became more severe at the age of 12 months."
    explanation: Independent replication of age-dependent hair cell loss in a second knock-in line.
  - reference: PMID:21165622
    reference_title: A mouse model for human hearing loss DFNB30 due to loss of function of myosin IIIA.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: at 8 days, 6 months, and 8.5 months stereocilia hair bundles of mutant mice were shaped normally, with a well-organized stereocilia staircase, compared to wild-type littermates.
    explanation: Normal-appearing bundles at these ages limit a universal structural-disorganization-first sequence.
- name: Cochlear Hearing Dysfunction
  biological_scale: TISSUE
  description: Impaired cochlear function produces sensorineural hearing loss. Human audiometry establishes bilateral, often high-frequency and progressive loss, with congenital profound presentations in other families. Mouse ABR measures a functional deficit; it does not alone identify the defective cellular process.
  biological_processes:
  - preferred_term: sensory perception of sound
    modifier: DECREASED
    term:
      id: GO:0007605
      label: sensory perception of sound
  downstream:
  - target: Progressive Sensorineural Hearing Impairment
    description: Clinical expression of impaired auditory function; onset and course vary by family.
    causal_link_type: DIRECT
  - target: Bilateral Sensorineural Hearing Impairment
    description: Clinical expression of impaired auditory function; onset and course vary by family.
    causal_link_type: DIRECT
  - target: High-Frequency Predominant Audiometric Configuration
    description: Clinical expression of impaired auditory function; onset and course vary by family.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:12032315
    reference_title: "From flies' eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Members of three generations of Family N have experienced bilateral progressive hearing loss, which first affects the high frequencies.
    explanation: Direct human audiometric phenotype.
  - reference: PMID:21165622
    reference_title: A mouse model for human hearing loss DFNB30 due to loss of function of myosin IIIA.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In mutant mice, hearing loss is significant at 2.5 months and progresses first at high frequencies, then at all frequencies.
    explanation: Functional hearing deficit precedes visible degeneration.
phenotypes:
- name: Bilateral Sensorineural Hearing Impairment
  category: Auditory
  description: Bilateral hearing loss was explicitly reported in the founding family.
  phenotype_term:
    preferred_term: Bilateral sensorineural hearing impairment
    term:
      id: HP:0008619
      label: Bilateral sensorineural hearing impairment
  evidence:
  - reference: PMID:12032315
    reference_title: "From flies' eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Members of three generations of Family N have experienced bilateral progressive hearing loss, which first affects the high frequencies.
    explanation: Direct human audiometric phenotype.
- name: Progressive Sensorineural Hearing Impairment
  category: Auditory
  description: >-
    Progressive sensorineural hearing impairment is reported in the founding family and later series. Severe-to-profound
    loss can develop, but rate and final degree vary and cannot be predicted from the small cross-sectional
    Japanese series.
  phenotype_term:
    preferred_term: Progressive sensorineural hearing impairment
    term:
      id: HP:0000408
      label: Progressive sensorineural hearing impairment
    clinical_course: PROGRESSIVE
  notes: >-
    All eight clinically characterized Japanese probands reported progression. Two genotypes included a VUS
    and family segregation was unavailable. The age-threshold plot was cross-sectional rather than serial audiometry
    of the same patients; no disease-wide frequency or annual rate follows from it.
  evidence:
  - reference: PMID:39858639
    reference_title: The Prevalence and Clinical Characteristics of MYO3A-Associated Hearing Loss in 15,684 Hearing Loss Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The severity of their HL varied from mild to profound, and all patients were aware of HL progression at the time of their genetic testing."
    explanation: Self-reported progression and prose severity range in a small candidate cohort; Table 2 lists moderate-to-profound loss in the eight characterized probands.
  - reference: PMID:12032315
    reference_title: "From flies' eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In an extended Israeli family, nonsyndromic progressive hearing loss is caused by three different recessive, loss-of-function mutations in myosin IIIA."
    explanation: The founding description of the phenotype as nonsyndromic and progressive.
- name: Postlingual Onset Hearing Loss
  category: Auditory
  description: >-
    Postlingual onset occurs in the founding family and Japanese series. Congenital presentations are also
    reported, so postlingual onset is not required for diagnosis.
  phenotype_term:
    preferred_term: Postlingual sensorineural hearing impairment
    term:
      id: HP:0008596
      label: Postlingual sensorineural hearing impairment
  notes: >-
    Eight characterized Japanese candidate probands reported onset at ages 10-30 years. These referral-cohort
    observations are not a population frequency.
  evidence:
  - reference: PMID:39858639
    reference_title: The Prevalence and Clinical Characteristics of MYO3A-Associated Hearing Loss in 15,684 Hearing Loss Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The onset age of their HL varied from 10 to 30 years old (mean age: 19.6 years old), and all of them presented with post-lingual deterioration in hearing."
    explanation: Numerator, onset range and post-lingual character in one sentence.
- name: Congenital Profound Sensorineural Hearing Loss
  category: Auditory
  description: >-
    Congenital profound nonsyndromic hearing loss segregated with homozygous p.Lys50Arg in a Tunisian family.
    A separate Kazakh family with homozygous p.Ser614Phe had congenital hearing loss, but the accessible abstract
    does not specify its severity.
  phenotype_term:
    preferred_term: Congenital profound sensorineural hearing impairment
    term:
      id: HP:0011476
      label: Profound sensorineural hearing impairment
    onset:
      onset_category: CONGENITAL
  notes: >-
    Profound hearing impairment is bound to HPO and congenital onset is represented separately. The Lys50Arg
    clinical segregation supports the combined phenotype; the Ser614Phe abstract supports congenital onset
    only. These families do not establish a frequency or a general kinase-domain genotype-phenotype rule.
  evidence:
  - reference: PMID:34423747
    reference_title: Molecular insights into MYO3A kinase domain variants explain variability in both severity and progression of DFNB30 hearing impairment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This Lys50Arg mutation segregated with congenital profound non-syndromic HI."
    explanation: >-
      The segregation observation in the reported family; graded HUMAN_CLINICAL because this
      sentence reports patients, unlike the same paper's modelling results.
  - reference: PMID:27063751
    reference_title: Identification of a novel homozygous mutation in MYO3A in a Chinese family with DFNB30 non-syndromic hearing impairment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, we characterized a consanguineous Kazakh family with congenital hearing loss."
    explanation: >-
      A second, independently reported congenital presentation. It supports the congenital onset
      only - this report does not grade the severity, so it is not a source for "profound".
- name: High-Frequency Predominant Audiometric Configuration
  category: Auditory
  description: >-
    High frequencies can be affected first. Down-sloping and flat audiograms have both been reported.
  phenotype_term:
    preferred_term: High-frequency sensorineural hearing impairment
    term:
      id: HP:0001757
      label: High-frequency sensorineural hearing impairment
  notes: >-
    The founding family had high-frequency loss initially. Six of eight characterized Japanese candidate probands
    had down-sloping audiograms and two had flat audiograms; this small series includes uncertain variants
    and is not a disease-wide frequency estimate.
  evidence:
  - reference: PMID:39858639
    reference_title: The Prevalence and Clinical Characteristics of MYO3A-Associated Hearing Loss in 15,684 Hearing Loss Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The types of HL were categorized as down-sloping in six, and flat in two patients."
    explanation: Numerator and denominator for the audiometric configuration.
  - reference: PMID:12032315
    reference_title: "From flies' eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Members of three generations of Family N have experienced bilateral progressive hearing loss, which first affects the high frequencies.
    explanation: Direct human audiometric phenotype.
- name: Vertigo
  category: Vestibular
  description: >-
    Vertigo was reported by two probands in the Japanese candidate series, but both carried a VUS and the symptoms
    were not characterized with vestibular tests. Its attribution to DFNB30 is unresolved.
  phenotype_term:
    preferred_term: Vertigo
    term:
      id: HP:0002321
      label: Vertigo
  notes: >-
    Table 2 identifies the symptomatic probands as Family 1 (p.Glu770Lys VUS with a likely pathogenic splice
    allele) and Family 4 (homozygous p.Ala238Thr VUS). The 2/8 proportion must not be treated as the frequency
    of vestibular disease in confirmed DFNB30. A 57-year-old man homozygous for the founding nonsense allele
    had normal formal ocular-motor and vestibular testing; normal findings in that individual do not refute
    symptoms in other genotypes.
  evidence:
  - reference: PMID:39858639
    reference_title: The Prevalence and Clinical Characteristics of MYO3A-Associated Hearing Loss in 15,684 Hearing Loss Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two individuals complained of vertigo, but the specifics are unknown."
    explanation: Reported symptoms in two uncertain genotypes; not proof of MYO3A-related vestibular dysfunction.
genetic:
- name: MYO3A
  notes: >-
    MYO3A encodes a class III myosin with kinase, motor and tail domains. In the founding family, a nonsense
    allele and two splice alleles segregated as recessive disease; lymphoblast transcript assays supported
    exon skipping or unstable message for the splice variants. Between ages 25 and 50, nonsense homozygotes
    had poorer hearing than nonsense/splice compound heterozygotes, with similarly severe loss later in life.
    This is a within-family association, not a universal prediction for all alleles. The Japanese series identified
    eight candidate variants, two classified as uncertain (p.Glu770Lys and p.Ala238Thr), and lacked familial
    segregation. Its failure to find a correlation does not negate the earlier family-specific observation.
    Dominant MYO3A alleles require separate assessment; simple heterozygosity for an established recessive
    allele is not itself diagnostic of dominant hearing loss.
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: MYO3A
    term:
      id: hgnc:7601
      label: MYO3A
  evidence:
  - reference: PMID:12032315
    reference_title: "From flies' eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we show that normal hearing in humans requires myosin IIIA, the human homolog of NINAC."
    explanation: The gene-disease assertion in its founding form.
  - reference: PMID:12032315
    reference_title: "From flies' eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Between ages 25 and 50, hearing across all frequencies was significantly poorer among individuals homozygous for the nonsense mutation
    explanation: Within-family genotype association, comparing nonsense homozygotes with nonsense/splice compound heterozygotes.
  - reference: PMID:39858639
    reference_title: "The Prevalence and Clinical Characteristics of MYO3A-Associated Hearing Loss in 15,684 Hearing Loss Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: As we were not able to conduct segregation analyses on the families of the probands due to a lack of peripheral blood samples, it is possible that the HL was due to other causes
    explanation: Authors explicitly acknowledge uncertain attribution in the Japanese candidate series.
prevalence:
- population: Japanese hearing-loss patients screened by massively parallel sequencing
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    Nine candidate probands were identified among 15,684 Japanese hearing-loss patients (reported 0.06%). Two
    genotypes included a VUS and familial segregation was unavailable, so this is a candidate detection proportion
    in a referral cohort, not confirmed diagnostic yield or population prevalence. Eight probands had clinical
    data. Literature case summaries cannot be treated as a complete count of affected individuals: the founding
    family alone contained eighteen affected relatives.
  evidence:
  - reference: PMID:39858639
    reference_title: The Prevalence and Clinical Characteristics of MYO3A-Associated Hearing Loss in 15,684 Hearing Loss Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MYO3A is a relatively rare causative gene, and the prevalence of MYO3A-associated HL among Japanese HL patients is 0.06% (9/15,684)."
    explanation: Numerator, denominator and proportion in one sentence.
  - reference: PMID:39858639
    reference_title: "The Prevalence and Clinical Characteristics of MYO3A-Associated Hearing Loss in 15,684 Hearing Loss Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: As we were not able to conduct segregation analyses on the families of the probands due to a lack of peripheral blood samples, it is possible that the HL was due to other causes
    explanation: Authors explicitly acknowledge uncertain attribution in the Japanese candidate series.
progression:
- phase: Onset
  age_range: congenital to third decade
  notes: >-
    Reported onset spans congenital hearing loss and postlingual onset. The Japanese candidate series reported
    10-30 years; small selected families do not demonstrate a bimodal population distribution.
  evidence:
  - reference: PMID:39858639
    reference_title: The Prevalence and Clinical Characteristics of MYO3A-Associated Hearing Loss in 15,684 Hearing Loss Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The onset age of their HL varied from 10 to 30 years old (mean age: 19.6 years old), and all of them presented with post-lingual deterioration in hearing."
    explanation: The late-onset arm of the range.
  - reference: PMID:34423747
    reference_title: Molecular insights into MYO3A kinase domain variants explain variability in both severity and progression of DFNB30 hearing impairment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This Lys50Arg mutation segregated with congenital profound non-syndromic HI."
    explanation: The congenital arm of the range.
- phase: Deterioration
  age_range: adulthood
  notes: >-
    Progression to severe or profound loss was observed in reported families and described in the Japanese
    series. Its cross-sectional age-threshold relationship and self-reported progression do not establish an
    individual deterioration rate or an inevitable outcome for every allele.
  evidence:
  - reference: PMID:39858639
    reference_title: The Prevalence and Clinical Characteristics of MYO3A-Associated Hearing Loss in 15,684 Hearing Loss Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In particular, most of the cases identified in this study and previous reports showed progressive HL, eventually progressing to severe-to-profound HL."
    explanation: States the trajectory across this series and prior reports.
treatments:
- name: Hearing Aid Amplification
  description: >-
    Hearing aids can improve access to sound when appropriate for measured hearing levels and communication
    goals. Acoustic amplification uses residual auditory function; it does not bypass hair cells or correct
    MYO3A dysfunction. The Japanese series recommends rehabilitation but does not measure DFNB30-specific hearing-aid
    outcomes.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: hearing aid amplification
    term:
      id: NCIT:C15315
      label: Rehabilitation
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: hearing aid
        term:
          id: NCIT:C183182
          label: Hearing Aid
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: "Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: customized by an audiologist to the degree and frequency of hearing loss, can be used in individuals with mild-to-severe hearing loss.
    explanation: General hereditary-hearing-loss guidance, not a DFNB30 outcome study.
- name: Cochlear Implantation
  description: >-
    Cochlear implantation may be considered for severe-to-profound hearing loss after specialist assessment
    of candidacy and aided benefit. It electrically stimulates the auditory pathway, bypassing hair-cell transduction.
    The Japanese DFNB30 study recommends considering implantation but does not provide implant outcomes or
    prove preserved auditory-nerve function in every patient.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cochlear device implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: cochlear implant
        term:
          id: NCIT:C157820
          label: Cochlear Implant
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: "Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months.
    explanation: General GeneReviews guidance; eligibility depends on individual clinical assessment.
  - reference: PMID:39858639
    reference_title: "The Prevalence and Clinical Characteristics of MYO3A-Associated Hearing Loss in 15,684 Hearing Loss Patients."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: In addition, the evaluation of the outcomes of hearing aids or cochlear implantation will also be useful.
    explanation: The authors identify treatment outcome measurement as future work.
- name: Genetic Counselling
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  description: >-
    Provide nondirective counseling after molecular confirmation. Recurrence risk is conditional on established
    parental pathogenic genotypes, and testing relatives requires identification of the familial variants.
    Distinguish recessive DFNB30 from allele-specific dominant MYO3A-associated hearing loss.

  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: "Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: If both parents are known to be heterozygous for an autosomal recessive hearing loss-related pathogenic variant, each sib of the proband has at conception a 25% chance of having hearing loss, a 50% chance of having no hearing loss and being a carrier, and a 25% chance of having no hearing loss and not being a carrier.
    explanation: General recessive recurrence risk, conditional on established parental pathogenic variants.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: "Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Carrier testing for relatives who may have a hearing loss-related pathogenic variant requires prior identification of the pathogenic variants in the family.
    explanation: Prerequisite for informative family testing.
- name: Communication and language support
  description: Establish communication goals and provide appropriate language access, speech-language services and educational support. These are general measures for hearing loss, not evidence of a primary neurodevelopmental syndrome caused by MYO3A.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: "Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: On initial evaluation of individuals with hearing loss, the goals for communication must be established with a focus on equipping individuals with language and appropriate access to language.
    explanation: General hearing-loss management.
diagnosis:
- name: Age-appropriate audiometry
  description: >-
    Age-appropriate audiometry characterizes degree, configuration and sensorineural status. The Japanese cohort
    used pure-tone audiometry from age five and behavioral or evoked-response approaches in younger children.
    Audiogram shape alone does not establish MYO3A causation.
  diagnosis_term:
    preferred_term: audiometric assessment
    term:
      id: NCIT:C38036
      label: Audiometric Test
  results: Sensorineural loss, mild to profound, usually down-sloping.
  evidence:
  - reference: PMID:39858639
    reference_title: The Prevalence and Clinical Characteristics of MYO3A-Associated Hearing Loss in 15,684 Hearing Loss Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pure-tone audiometry was used to assess hearing thresholds for patients aged 5 years and above, whereas auditory steady state response (ASSR), conditioned orientation response audiometry (COR: one type of the behavioral audiometry), or play audiometry were used for individuals under 5 years old."
    explanation: >-
      The audiometric methods used in the largest series, including the age threshold at which
      they switch.
- name: Serial audiometric follow-up
  description: >-
    Repeated audiometry documents change and guides rehabilitation. It is useful for monitoring suspected or
    confirmed progressive hearing loss, but serial deterioration is not a prerequisite for molecular diagnosis
    and congenital presentations occur.
  diagnosis_term:
    preferred_term: serial audiometric follow-up
    term:
      id: NCIT:C38036
      label: Audiometric Test
  results: Individual trajectory assessed over time; no validated DFNB30-specific deterioration rate.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: "Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'Regular follow up is recommended for all individuals with genetic hearing loss in order to:'
    explanation: General management guidance supports continued audiologic assessment.
  - reference: PMID:39858639
    reference_title: The Prevalence and Clinical Characteristics of MYO3A-Associated Hearing Loss in 15,684 Hearing Loss Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A further prospective study will be useful in evaluating hearing deterioration through the use of the serial audiometric testing results from the same patient."
    explanation: >-
      The Japanese study lacked same-patient longitudinal audiometry; it recommends prospective measurement.
- name: Massively parallel sequencing of a hearing-loss gene panel
  description: >-
    A hearing-loss multigene panel or genomic testing can assess MYO3A alongside other hearing-loss genes.
    The Japanese study used a 158-gene panel and read-depth copy-number analysis. Interpretation requires pathogenicity
    assessment and, where possible, confirmation that two variants are in trans. MYO3A need not be tested only
    after excluding each more common gene.
  diagnosis_term:
    preferred_term: massively parallel sequencing of a targeted hearing-loss gene panel
    term:
      id: NCIT:C101293
      label: Next Generation Sequencing
  results: Biallelic pathogenic or likely pathogenic MYO3A variants consistent with recessive inheritance support DFNB30; unresolved variants or phase require further assessment.
  evidence:
  - reference: PMID:39858639
    reference_title: The Prevalence and Clinical Characteristics of MYO3A-Associated Hearing Loss in 15,684 Hearing Loss Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among these subjects, we selected patients with biallelic MYO3A variants through MPS of 158 target genes."
    explanation: The testing modality and the biallelic requirement in one sentence.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: "Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: can often identify the cause of genetic hearing loss while limiting identification of pathogenic variants and variants of uncertain significance in genes that are irrelevant to the underlying phenotype.
    explanation: General guidance for hearing-loss panels.
- name: Variant interpretation under the ClinGen hearing-loss specification
  description: >-
    Variant classification, segregation and phase distinguish a molecular diagnosis from an uncertain candidate
    genotype. The Japanese series used ACMG/AMP criteria with hearing-loss specifications, but p.Glu770Lys
    and p.Ala238Thr remained uncertain and family segregation was unavailable. A VUS does not establish or
    exclude DFNB30; dominant MYO3A-associated hearing loss must also be considered for appropriate alleles
    and pedigrees.
  diagnosis_term:
    preferred_term: variant classification
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  results: Allele-specific classification and inheritance assessment; uncertain genotypes remain unresolved.
  evidence:
  - reference: PMID:39858639
    reference_title: The Prevalence and Clinical Characteristics of MYO3A-Associated Hearing Loss in 15,684 Hearing Loss Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pathogenicity of identified variants was evaluated according to the American College of Medical Genetics (ACMG) standards and guidelines"
    explanation: >-
      Study classification framework; Table 1 and segregation limitations must accompany its interpretation.
  - reference: PMID:39858639
    reference_title: "The Prevalence and Clinical Characteristics of MYO3A-Associated Hearing Loss in 15,684 Hearing Loss Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: As we were not able to conduct segregation analyses on the families of the probands due to a lack of peripheral blood samples, it is possible that the HL was due to other causes
    explanation: Authors explicitly acknowledge uncertain attribution in the Japanese candidate series.
differential_diagnoses:
- name: Age-related hearing loss (presbycusis)
  description: >-
    Age-related hearing loss can overlap with later-recognized progressive sensorineural impairment. Age at
    onset, family history and molecular findings help distinguish inherited disease; the cited paper does not
    establish presbycusis as the main cause of DFNB30 underdiagnosis.
  distinguishing_features:
  - Onset in the second or third decade rather than in late middle age
  - Biallelic MYO3A variants on panel or exome testing
  evidence:
  - reference: PMID:39858639
    reference_title: The Prevalence and Clinical Characteristics of MYO3A-Associated Hearing Loss in 15,684 Hearing Loss Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, the elucidation of HL causation becomes more challenging when related to late-onset HL, as multiple factors, such as presbycusis, idiopathic sudden SNHL, environmental risk factors, etc., can be involved."
    explanation: >-
      Names presbycusis and idiopathic sudden sensorineural hearing loss as the confounders for
      exactly the presentation DFNB30 produces.
- name: Idiopathic sudden sensorineural hearing loss
  description: >-
    The Japanese study lists idiopathic sudden sensorineural hearing loss among competing explanations for
    later-onset hearing loss. Clinical chronology helps distinguish abrupt loss from a progressive inherited
    course.
  distinguishing_features:
  - Abrupt onset over hours to days rather than progressive deterioration over years
  evidence:
  - reference: PMID:39858639
    reference_title: The Prevalence and Clinical Characteristics of MYO3A-Associated Hearing Loss in 15,684 Hearing Loss Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, the elucidation of HL causation becomes more challenging when related to late-onset HL, as multiple factors, such as presbycusis, idiopathic sudden SNHL, environmental risk factors, etc., can be involved."
    explanation: The same sentence names it as a competing explanation for late-onset hearing loss.
- name: Other autosomal recessive nonsyndromic hearing loss, principally GJB2, SLC26A4 and CDH23
  description: >-
    Other hearing-loss genes can produce overlapping nonsyndromic presentations. Multigene testing evaluates
    these alternatives together; DFNB30 is not a diagnosis of exclusion after each common gene is tested.
  distinguishing_features:
  - Pathogenic variants and appropriate segregation in the causative gene
  - Onset and audiometric configuration overlap and cannot by themselves assign the gene
  evidence:
  - reference: PMID:39858639
    reference_title: The Prevalence and Clinical Characteristics of MYO3A-Associated Hearing Loss in 15,684 Hearing Loss Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The major causative genes of ARSNHL in Japanese patients are GJB2 (16%), SLC26A4 (5%) and CDH23 (4%), and the detection of causative genes for HL has become significantly more achievable through the introduction of massively parallel DNA sequencing (MPS) analysis [5]."
    explanation: >-
      Cohort-specific contributions motivate multigene assessment, not a required sequence of gene exclusions.
- name: Autosomal dominant MYO3A-related hearing loss
  description: >-
    The same gene, a different disease. A motor-domain missense allele segregates as an autosomal
    dominant trait, so a MYO3A variant report does not by itself establish DFNB30 - the zygosity
    and the segregation do.
  distinguishing_features:
  - A variant with evidence supporting a dominant effect, rather than any heterozygous MYO3A finding
  - Segregation and allele-specific functional evidence supporting dominant inheritance
  evidence:
  - reference: PMID:26841241
    reference_title: MYO3A Causes Human Dominant Deafness and Interacts with Protocadherin 15-CD2 Isoform.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In a family with post-lingual progressive non-syndromic deafness, whole-exome sequencing of genomic DNA from five hearing-impaired relatives revealed a single variant, p.Gly488Glu (rs145970949:G>A) in MYO3A, co-segregating with HL as an autosomal dominant trait.
    explanation: Primary dominant-family report, distinct from recessive DFNB30.
animal_models:
- name: Myo3a knock-in mouse (human nonsense allele equivalent)
  species: Mouse
  genotype: Myo3a(KI/KI), knock-in of the mouse equivalent of the human MYO3A nonsense allele
  publication: PMID:21165622
  description: >-
    C57BL/6 knock-in of the human founding nonsense allele equivalent, compared with wild-type littermates.
    ABR deficits begin at 2.5 months and progress; bundles appear normally shaped through 8.5 months, followed
    by hair-cell degeneration at ten and seventeen months. Vestibular reaching and forced-swim tests were normal.
  modeled_mechanisms:
  - target: Progressive Hair Cell Degeneration
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Later outer-hair-cell loss recapitulates a plausible contributor to progressive cochlear dysfunction;
      human tissue pathology is not available.
    limitations: >-
      The model carries one nonsense allele on a mouse background. Early hearing loss precedes visible degeneration,
      and mouse ages do not predict human onset. Outer-hair-cell counts used three animals per genotype; inner
      hair cells could not be counted consistently.
    readouts:
    - name: Outer hair cell survival
      target: Progressive Hair Cell Degeneration
      direction: DECREASED
      interpretation: Structural correlate of the degeneration node in this model.
      evidence:
      - reference: PMID:21165622
        reference_title: A mouse model for human hearing loss DFNB30 due to loss of function of myosin IIIA.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Outer hair cells of Myo3a(KI/KI) mice degenerate with age in a pattern consistent with their progressive hearing loss."
        explanation: The histological measurement behind this readout.
    evidence:
    - reference: PMID:21165622
      reference_title: A mouse model for human hearing loss DFNB30 due to loss of function of myosin IIIA.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The phenotype of the Myo3a(KI/KI) mouse parallels the phenotype of human DFNB30."
      explanation: The authors' own assessment that this model is informative for the human disease.
  - target: Altered Myosin IIIa Function at Stereocilia Tips
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Loss of C-terminal myosin IIIa staining after truncation.
    limitations: >-
      The antibody recognizes the C-terminal epitope removed by the mutation; it cannot exclude residual N-terminal
      protein.
    readouts:
    - name: C-terminal myosin IIIa immunoreactivity at stereocilia tips
      target: Altered Myosin IIIa Function at Stereocilia Tips
      direction: ABOLISHED
      interpretation: C-terminal staining is absent; complete absence or failed targeting of every mutant protein species is not demonstrated.
      evidence:
      - reference: PMID:21165622
        reference_title: A mouse model for human hearing loss DFNB30 due to loss of function of myosin IIIA.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Myosin IIIA, with a unique N-terminal kinase domain and a C-terminal actin-binding domain, localizes to the tips of stereocilia in wild-type mice but is absent in the mutant."
        explanation: Epitope-dependent localization assay; interpreted with the methods.
    evidence:
    - reference: PMID:21165622
      reference_title: A mouse model for human hearing loss DFNB30 due to loss of function of myosin IIIA.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: against a synthetic peptide (NPYDYRRLLRKTSQRQR) that matches the C-terminus sequence of the mouse myosin IIIA.
      explanation: The methods identify the epitope and its relevance to interpreting negative staining.
  - target: Cochlear Hearing Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Progressive functional hearing deficit with a human disease-allele equivalent.
    limitations: ABR is not a direct assay of the cellular cause of the early deficit.
    readouts:
    - name: Auditory brainstem response threshold
      target: Cochlear Hearing Dysfunction
      direction: INCREASED
      interpretation: >-
        ABR thresholds rise from 2.5 months, before visible hair-cell degeneration.
      evidence:
      - reference: PMID:21165622
        reference_title: A mouse model for human hearing loss DFNB30 due to loss of function of myosin IIIA.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: In mutant mice, hearing loss is significant at 2.5 months and progresses first at high frequencies, then at all frequencies.
        explanation: Functional hearing deficit precedes visible degeneration.
- name: Myo3a Y137C knock-in mouse
  species: Mouse
  genotype: Myo3a Y137C kinase-domain missense knock-in, generated by CRISPR/Cas9
  publication: PMID:30123247
  description: >-
    CBA/CaJ kinase-domain Y137C knock-in made by CRISPR/Cas9. ABR thresholds were normal at two months and
    elevated at six and twelve months, when stereocilia abnormalities and hair-cell loss were present. A noise
    challenge at 4.5 months showed no significant genotype difference in threshold shifts under that protocol,
    so it does not establish increased noise susceptibility.
  modeled_mechanisms:
  - target: Disordered Stereocilia and Hair Bundle Architecture
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Structural abnormality of cochlear hair cell stereocilia in a single-gene Myo3a mutant.
    limitations: >-
      The CBA/CaJ mouse Y137C substitution was designed to model human Y129C, but the human family data were
      not shown in this paper. Stereocilia were intact at two months and abnormal at six and twelve months.
      Positive FM1-43 uptake is a proxy, not proof of normal mechanotransduction currents across age. The paper
      did not directly measure mutant kinase activity.
    readouts:
    - name: Cochlear hair cell stereocilia structure
      target: Disordered Stereocilia and Hair Bundle Architecture
      direction: ALTERED
      interpretation: Structural correlate of the bundle-architecture node.
      evidence:
      - reference: PMID:30123247
        reference_title: Knock-In Mice with Myo3a Y137C Mutation Displayed Progressive Hearing Loss and Hair Cell Degeneration in the Inner Ear.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "We also found structural abnormality in the cochlear hair cell stereocilia."
        explanation: The structural measurement behind this readout.
    evidence:
    - reference: PMID:30123247
      reference_title: Knock-In Mice with Myo3a Y137C Mutation Displayed Progressive Hearing Loss and Hair Cell Degeneration in the Inner Ear.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our results showed that Myo3a is essential for normal hearing by maintaining the intact structure of hair cell stereocilia, and the kinase domain plays a critical role in the normal functions of Myo3a."
      explanation: The authors' statement of what the model establishes about the mechanism.
- name: Myo3a/Myo3b double knockout mouse
  species: Mouse
  genotype: Myo3a(-/-)Myo3b(-/-) double knockout
  publication: PMID:26754646
  description: >-
    Not a model of DFNB30 but of class III myosin function generally: removing both paralogues
    produces profound deafness and a grossly abnormal hair bundle, and it is the source of the
    finding that these motors limit rather than only promote stereocilia elongation.
  modeled_mechanisms:
  - target: Disordered Stereocilia and Hair Bundle Architecture
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Reproduces disordered bundle architecture, but only when both class III myosins are
      removed - so it speaks to the pathway rather than to the human single-gene disease.
    limitations: >-
      Constitutive deletion of both paralogues causes a developmental phenotype distinct from human single-gene
      DFNB30. In the same study, Myo3a deletion beginning postnatally on a Myo3b-null background left ABR and
      DPOAE normal through six months, while postnatal Myo3a loss with Myo3b intact raised ABR thresholds.
      Timing and paralogue context therefore preclude a simple lifelong protective-compensation model.
    readouts:
    - name: Hair bundle morphology
      target: Disordered Stereocilia and Hair Bundle Architecture
      direction: ALTERED
      interpretation: >-
        Abnormally tall and numerous stereocilia with loss of height grading, in the double
        mutant.
      evidence:
      - reference: PMID:26754646
        reference_title: Class III myosins shape the auditory hair bundles by limiting microvilli and stereocilia growth.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "These include abnormally tall and numerous microvilli or stereocilia, ungraded stereocilia bundles, and bundle rounding and closure."
        explanation: The morphological measurement behind this readout.
    evidence:
    - reference: PMID:26754646
      reference_title: Class III myosins shape the auditory hair bundles by limiting microvilli and stereocilia growth.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We show that Myo3a(-/-)Myo3b(-/-) mice lacking myosin IIIa and myosin IIIb are profoundly deaf, whereas Myo3a-cKO Myo3b(-/-) mice lacking myosin IIIb and losing myosin IIIa postnatally have normal hearing."
      explanation: >-
        The comparison that both establishes the double mutant's deafness and limits how far it
        can be read as a MYO3A model.
discussions:
- discussion_id: dfnb30_longitudinal_retinal_assessment
  kind: KNOWLEDGE_GAP
  prompt: >-
    How well has long-term retinal function been assessed in DFNB30?
  attaches_to:
  - phenotypes#
  rationale: >-
    The founding study explicitly reported normal vision and balance in affected relatives, and the Lys50Arg
    family report also described normal ocular and vestibular findings. These are positive reports of assessment,
    not merely absence of volunteered complaints. They do not establish systematic longitudinal electroretinography
    or lifelong absence of retinal disease; retinal expression alone does not establish a clinical retinal
    phenotype.
- discussion_id: dfnb30_espin1_transport_model_mismatch
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Is the espin-1 cargo-transport model the mechanism of DFNB30, given that espin-1 still
    reaches stereocilia tips in mice lacking both class III myosins?
  attaches_to:
  - pathophysiology#Altered Myosin IIIa Function at Stereocilia Tips
  rationale: >-
    COS-7 and organotypic experiments demonstrate MYO3A/espin-1 interaction and construct-dependent protrusion
    elongation; the roughly tenfold effect used kinase-deleted MYO3A in COS-7 cells. Constitutive double-null
    mouse hair cells retained espin-1 tip localization and developed excessively long, poorly organized bundles.
    These model-to-model differences limit obligatory cargo-delivery failure as the mechanism in patients.
- discussion_id: dfnb30_kinase_domain_genotype_phenotype
  kind: KNOWLEDGE_GAP
  prompt: >-
    Do MYO3A kinase-domain alleles really separate congenital profound from late-onset
    progressive hearing loss?
  attaches_to:
  - pathophysiology#MYO3A Loss of Function
  rationale: >-
    Structural modelling proposes different consequences for kinase-specific impairment and wider protein dysfunction.
    The founding family showed a narrower genotype association between nonsense homozygotes and nonsense/splice
    compound heterozygotes, while the Japanese candidate series did not detect a correlation. These small and
    differently ascertained datasets neither validate a universal allele-domain rule nor establish a bimodal
    population onset distribution. Direct allele-resolved functional and longitudinal clinical evidence is
    needed.
📚

References & Deep Research

References

10
PMID:12032315
From flies' eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30.
No top-level findings curated for this source.
PMID:27063751
Identification of a novel homozygous mutation in MYO3A in a Chinese family with DFNB30 non-syndromic hearing impairment.
No top-level findings curated for this source.
PMID:34423747
Molecular insights into MYO3A kinase domain variants explain variability in both severity and progression of DFNB30 hearing impairment.
No top-level findings curated for this source.
PMID:39858639
The Prevalence and Clinical Characteristics of MYO3A-Associated Hearing Loss in 15,684 Hearing Loss Patients.
No top-level findings curated for this source.
PMID:19287378
Myosin IIIa boosts elongation of stereocilia by transporting espin 1 to the plus ends of actin filaments.
No top-level findings curated for this source.
PMID:26754646
Class III myosins shape the auditory hair bundles by limiting microvilli and stereocilia growth.
No top-level findings curated for this source.
PMID:21165622
A mouse model for human hearing loss DFNB30 due to loss of function of myosin IIIA.
No top-level findings curated for this source.
PMID:30123247
Knock-In Mice with Myo3a Y137C Mutation Displayed Progressive Hearing Loss and Hair Cell Degeneration in the Inner Ear.
No top-level findings curated for this source.
PMID:26841241
MYO3A Causes Human Dominant Deafness and Interacts with Protocadherin 15-CD2 Isoform.
No top-level findings curated for this source.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Autosomal Recessive Nonsyndromic Hearing Loss 30 (DFNB30) · 2026-09-04T20:43:18Z · View source

De-novo curation of DFNB30 (MONDO:0011774), biallelic MYO3A. Four-node pathograph: MYO3A loss of function -> failure of myosin IIIa delivery to stereocilia tips -> disordered stereocilia and hair bundle architecture -> progressive hair cell degeneration, feeding five wired phenotypes (progressive SNHL, postlingual onset, congenital profound, high-frequency-predominant configuration, vertigo). Nine PMIDs cited, 41/41 snippets verified against the local cache, no DOI-only citations. Human evidence is three reports totalling ~30 patients, so every frequency band carries its numerator/denominator in notes. Mechanism evidence is mouse and cell culture and is graded MODEL_ORGANISM/IN_VITRO with directness INDIRECT where it supports a human claim. Three negative or contradicting results are curated as REFUTE items rather than dropped: espin-1 still reaches stereocilia tips in the class III myosin double knockout, congenital onset refutes obligate postlingual onset, and both a formally examined DFNB30 patient and the knock-in mouse have normal vestibular function against the reported vertigo. Three discussions record the open questions (unassessed retinal involvement despite strong retinal MYO3A expression, the in-vitro/in-vivo mismatch in the espin-1 transport model, and the unresolved kinase-domain genotype-phenotype proposal). A Falcon deep-research report is committed alongside; preflight-dr PASS with MYO3A mentioned 52 times, reference validation 8/8 verified with 0 confabulation.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 26 citations 2026-09-04T13:36:35.744714

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Autosomal Recessive Nonsyndromic Hearing Loss 30
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Autosomal Recessive Nonsyndromic Hearing Loss 30 covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
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Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Autosomal Recessive Nonsyndromic Hearing Loss 30 (DFNB30)

Executive summary

Autosomal recessive nonsyndromic hearing loss 30 (DFNB30) is a very rare Mendelian sensorineural hearing-loss disorder caused by biallelic pathogenic variants in MYO3A, encoding the actin-based motor myosin IIIA. Its defining phenotype is bilateral, progressive hearing loss without a consistent extra-auditory syndrome. Onset is variable—from congenital hearing loss to the second decade—and progression can culminate in severe-to-profound loss. MYO3A dysfunction compromises the dimensions and maintenance of cochlear hair-cell stereocilia, probably through impaired motor activity, kinase regulation, actin interaction, and transport/regulation of stereociliary cargoes such as espin-1 and espin-like. The phenotype is distinct from autosomal-dominant MYO3A-associated hearing loss produced by particular heterozygous dominant-negative alleles. (OpenTargets Search: autosomal recessive nonsyndromic hearing loss 30-MYO3A, doll2020anovelmissense pages 1-2, dantas2018characterizationofa pages 1-2, maekawa2025theprevalenceand pages 1-2)

Domain Established finding Evidence type Ontology/identifier suggestions
Disease identity Autosomal recessive nonsyndromic hearing loss 30 (DFNB30), a Mendelian nonsyndromic sensorineural hearing-loss disorder Aggregated disease-resource association plus human molecular genetics (OpenTargets Search: autosomal recessive nonsyndromic hearing loss 30-MYO3A) MONDO:0011774; synonym: DFNB30
Causal gene Biallelic loss-of-function or damaging variants in MYO3A (myosin IIIA) cause DFNB30; heterozygous dominant MYO3A disease is a distinct allelic disorder (OpenTargets Search: autosomal recessive nonsyndromic hearing loss 30-MYO3A, doll2020anovelmissense pages 1-2, dantas2018characterizationofa pages 1-2) Human pedigrees, sequencing, segregation, functional studies MYO3A; OMIM gene 606808; Ensembl ENSG00000095777
Inheritance Autosomal recessive; affected individuals are homozygous or compound heterozygous, whereas heterozygous relatives are generally carriers unless they harbor a distinct dominant-acting allele Human family segregation (doll2020anovelmissense pages 1-2, dantas2018characterizationofa pages 1-2) Autosomal recessive inheritance; germline variant
Core phenotype Bilateral, nonsyndromic, progressive sensorineural hearing loss, often initially affecting high frequencies; reported onset ranges from congenital to the second decade and may ultimately reach severe-to-profound levels (maekawa2025theprevalenceand pages 6-8, doll2020anovelmissense pages 1-2, maekawa2025theprevalenceand pages 1-2) Human clinical audiology and cohorts Sensorineural hearing impairment; bilateral hearing impairment; progressive hearing impairment; high-frequency hearing impairment; profound hearing impairment
Anatomy and mechanism MYO3A localizes near the tips of cochlear and vestibular hair-cell stereocilia. Impaired actin-based motor/cargo regulation disrupts stereocilia length, spacing, staircase organization, and consequently mechanotransduction (dantas2018characterizationofa pages 1-2, maekawa2025theprevalenceand pages 2-4, maekawa2025theprevalenceand pages 1-2) Hair-cell studies, biochemical/cellular assays, mouse models; final mechanotransduction link partly inferred Cochlea; organ of Corti; inner and outer hair cell; stereocilium; actin cytoskeleton; sensory perception of sound
Epidemiology Nine candidate individuals were found among 15,684 Japanese hearing-loss referrals—0.06% of that referral cohort, not population prevalence (maekawa2025theprevalenceand pages 1-2, maekawa2025theprevalenceand pages 6-8) 2025 multicenter referral-cohort sequencing study Rare disease; prevalence among hearing-loss referrals
Diagnosis Confirm sensorineural loss and progression with age-appropriate audiometry, otoacoustic emissions and/or auditory brainstem response, then identify pathogenic/likely pathogenic variants on both MYO3A alleles using a comprehensive hearing-loss panel, exome, or genome sequencing with segregation and copy-number analysis as appropriate (maekawa2025theprevalenceand pages 2-4, maekawa2025theprevalenceand pages 12-13) Clinical audiology plus molecular diagnosis; general hereditary-hearing-loss practice Pure-tone audiometry; auditory brainstem response; otoacoustic emission; molecular genetic testing; biallelic genotype
Current management No disease-modifying MYO3A-specific treatment is established. Management follows hearing-loss severity and communication needs: serial audiology, hearing aids, cochlear implantation when indicated, and speech/language, auditory, educational, or sign-language support Standard-of-care extrapolation from nonsyndromic sensorineural hearing loss; not tested specifically in DFNB30 Hearing aid; cochlear implantation; audiologic rehabilitation; speech-language therapy
Experimental therapy No MYO3A-targeted gene, RNA, cell, or pharmacologic therapy trial was identified; current hereditary-hearing-loss gene-therapy trials target other genes and should not be represented as DFNB30 trials Clinical-trial search and literature review Gene therapy—investigational; no DFNB30-specific intervention
Model organisms MYO3A loss-of-function mouse models develop progressive hearing loss beginning at high frequencies and later involving broader frequencies, with abnormal stereocilia; combined Myo3a/Myo3b loss produces a stronger phenotype, indicating partial redundancy (doll2020anovelmissense pages 1-2, dantas2018characterizationofa pages 1-2, maekawa2025theprevalenceand pages 2-4) Knock-in/knockout mouse models Mus musculus; Myo3a knock-in/knockout; auditory hair cell; abnormal stereocilium morphology

Table: Concise evidence-based summary of DFNB30 identity, phenotype, mechanism, frequency, diagnosis, management, and models. It separates established disease-specific findings from standard-care extrapolation and investigational gaps.

1. Disease information

Definition and identifiers

DFNB30 is an inherited, usually bilateral, progressive nonsyndromic sensorineural hearing loss caused by pathogenic variants affecting both MYO3A alleles. “Nonsyndromic” means that hearing impairment is the primary consistent clinical manifestation; it does not imply that every reported patient is free of coincidental symptoms such as vertigo. Open Targets identifies one associated target, MYO3A, for this disease. (OpenTargets Search: autosomal recessive nonsyndromic hearing loss 30-MYO3A)

Field Entry
Preferred name Autosomal recessive nonsyndromic hearing loss 30
Common synonyms DFNB30; deafness, autosomal recessive 30; MYO3A-related autosomal recessive hearing loss; MYO3A-related DFNB30
MONDO MONDO:0011774
Causal gene MYO3A, myosin IIIA; Ensembl ENSG00000095777
Gene OMIM 606808
Disease OMIM Commonly represented as 607101; users should verify against the current OMIM release before database ingestion
Orphanet No confidently disease-specific ORPHA identifier was recovered; it may be nested under genetic nonsyndromic deafness classifications
ICD-10-CM No DFNB30-specific code; use phenotype codes such as H90.3 for bilateral sensorineural hearing loss as clinically appropriate
ICD-11 No known gene-specific DFNB30 code; classify under sensorineural hearing loss
MeSH No DFNB30-specific descriptor; relevant headings include Hearing Loss, Sensorineural and Hearing Loss, Genetic

The original disease evidence was patient-level pedigree and molecular-genetic evidence. Modern MONDO/Open Targets entries and review resources are aggregated disease-level representations of those cases—not individual EHR records. Open Targets cites literature including PMIDs 12032315, 21165622, 26841241, 29880844, and 33078831 in support of the MYO3A association. (OpenTargets Search: autosomal recessive nonsyndromic hearing loss 30-MYO3A)

The landmark report was Walsh et al., PNAS, published 28 May 2002, DOI 10.1073/pnas.102091699, PMID 12032315. Its abstract states: “In an extended Israeli family, nonsyndromic progressive hearing loss is caused by three different recessive, loss-of-function mutations in myosin IIIA.” It further reports that, among 18 affected relatives, seven were homozygous and 11 compound heterozygous. (souissi2022molecularinsightsinto pages 12-13)

2. Etiology

Causal and genetic factors

The primary cause is germline biallelic MYO3A dysfunction. Established disease alleles include nonsense, frameshift, splice-disrupting, and damaging missense variants in the kinase, motor, and tail regions. The 2002 Family N carried three recessive loss-of-function alleles; later families expanded the spectrum and demonstrated congenital as well as delayed-onset disease. (doll2020anovelmissense pages 1-2, maekawa2025theprevalenceand pages 2-4)

Representative reported variants include:

  • p.Ser614Phe, a recessive motor-domain variant reported in a consanguineous Kazakh family with congenital hearing loss. (dantas2018characterizationofa pages 1-2)
  • p.Lys50Arg, a kinase-domain variant segregating with congenital profound nonsyndromic hearing loss; computational and previous in-vitro evidence supported a “kinase-dead” effect. DOI 10.1080/07391102.2021.1953600, published in final form in 2022. (souissi2022molecularinsightsinto pages 12-13)
  • Recent Japanese candidates included c.893dupA (p.Gln300Thrfs*21), c.991C>T (p.Arg331Ter), c.1450T>C (p.Ser484Pro), c.1464del (p.Lys489Asnfs*3), and c.4164dup (p.Asn1389Lysfs*4). Two reported missense candidates, p.Ala238Thr and p.Glu770Lys, remained VUS in that study and should not independently establish diagnosis. (maekawa2025theprevalenceand pages 4-6)

Allele frequencies in the recent Japanese series were below 0.0007. Exact gnomAD frequencies must be retrieved by transcript/build and variant; rarity alone is not evidence of pathogenicity. Variants are germline, not somatic. (maekawa2025theprevalenceand pages 6-8)

Risk, protective factors, and gene–environment interaction

  • Risk: two pathogenic alleles in trans; parental consanguinity increases the probability that a rare allele is inherited homozygously. Family history may be absent because carriers are generally unaffected and onset can be delayed.
  • Modifiers: no replicated DFNB30 modifier gene has been established. Partial functional redundancy with MYO3B is biologically important, but a clinically validated human MYO3B modifier effect has not been demonstrated. (maekawa2025theprevalenceand pages 2-4)
  • Protective alleles: none established.
  • Environmental causes: noise, aminoglycosides, cisplatin, and other ototoxic exposures can independently worsen hearing, but no DFNB30-specific gene–environment interaction has been demonstrated.
  • Lifestyle, infection, sex, diet: no evidence that these initiate the Mendelian disorder. Avoiding excessive noise and unnecessary ototoxins protects residual hearing generally but does not prevent inheritance or molecular onset.

3. Phenotypes

Phenotype Characterization Suggested HPO annotation
Sensorineural hearing impairment Defining manifestation; usually bilateral and nonsyndromic Sensorineural hearing impairment; Bilateral sensorineural hearing impairment
Progressive hearing impairment Common defining course; all eight clinically characterized individuals in the 2025 Japanese series recognized progression Progressive hearing impairment
High-frequency-predominant loss Characteristic in original Family N and mouse model; six of eight recent audiograms were down-sloping High-frequency hearing impairment
Severe/profound hearing loss May be congenital for severe alleles or arise after progression Severe hearing impairment; Profound hearing impairment
Postlingual hearing impairment Common in later-onset disease; recent cohort onset usually 10–30 years Postlingual hearing impairment
Congenital hearing impairment Documented with some kinase/motor-domain alleles Congenital sensorineural hearing impairment
Vertigo/vestibular symptom Reported in two recent subjects, but not sufficiently consistent to redefine DFNB30 as syndromic Vertigo, if clinically documented

In the 2025 Japanese referral cohort, clinical data from eight patients showed onset at 10–30 years (mean 19.6 years), mild-to-profound severity, six down-sloping and two flat audiograms, and recognized progression in all eight. Two reported vertigo. The broader literature supports onset from birth through the second decade and eventual severe-to-profound loss. (maekawa2025theprevalenceand pages 6-8, maekawa2025theprevalenceand pages 1-2)

Phenotype frequencies cannot be generalized reliably because published cases are few and ascertainment is biased. The strongest qualitative conclusions are bilateral sensorineural loss, progression, and frequent early high-frequency involvement. There is no validated DFNB30-specific EQ-5D, SF-36, PROMIS, behavioral, or laboratory phenotype. Expected consequences of inadequately treated hearing loss include impaired speech perception, communication, education, employment, and social participation, especially when onset occurs before or during language acquisition; these are general hearing-loss consequences rather than quantified DFNB30-specific outcomes.

4. Genetic and molecular information

MYO3A lies at chromosome 10p12.1, has 33 exons, and encodes myosin IIIA. Its architecture comprises an N-terminal serine/threonine kinase region, an actin-activated ATPase motor/head, a neck containing three IQ/calmodulin-binding motifs, and a specialized C-terminal tail with actin- and cargo-interaction functions. (doll2020anovelmissense pages 1-2)

Pathogenic mechanisms are principally loss of function or severe functional impairment. Truncating and canonical splice variants may cause absent/truncated protein or nonsense-mediated decay. Missense variants can disrupt ATP binding, kinase autophosphorylation, actin binding, ATPase cycling, motility, or tip localization. Both intact motor and tail domains are needed for normal tip localization and actin-protrusion regulation. (maekawa2025theprevalenceand pages 2-4)

Variant interpretation should use ACMG/AMP criteria with hearing-loss specifications, population frequency, phase, segregation, phenotype consistency, and functional evidence. A VUS must not be used alone for predictive testing or reproductive decision-making. No recurrent large chromosomal abnormality, repeat expansion, mitochondrial lesion, or somatic event defines DFNB30. No clinically established DNA-methylation, histone, or other epigenetic signature is known.

Particular heterozygous MYO3A motor/kinase variants cause a distinct autosomal-dominant allelic disorder. For example, p.Leu697Trp reduces ATPase activity and motility, increases actin affinity, displaces wild-type MYO3A at stereocilia tips, and acts dominantly negatively. It must not be conflated with recessive DFNB30. (dantas2018characterizationofa pages 1-2, dantas2018characterizationofa pages 10-11, dantas2018characterizationofa pages 2-3)

5. Environmental information

DFNB30 is not an infectious, toxic, nutritional, occupational, or lifestyle-induced disease. No pathogen, immune trigger, smoking effect, dietary factor, radiation exposure, or pollution exposure has been shown to cause it. General cochlear hazards—intense noise, aminoglycosides, platinum chemotherapy, and other ototoxic agents—may add acquired injury to genetically vulnerable hearing but have not been shown to interact specifically with MYO3A. Such exposures should be documented as comorbidity or possible aggravators, not disease causes.

6. Mechanism and pathophysiology

Ordered causal chain

  1. Biallelic pathogenic MYO3A variants lead to absent, unstable, truncated, kinase-impaired, or motor-impaired myosin IIIA.
  2. MYO3A dysfunction leads to reduced actin-plus-end motility and/or abnormal kinase autophosphorylation, actin binding, and stereociliary tip localization.
  3. Impaired tip-directed function leads to abnormal delivery or regulation of actin-associated cargoes, especially espin-1 and espin-like; a role in PCDH15-CD2 trafficking is supported experimentally but its contribution to human DFNB30 remains partly inferred. (dantas2018characterizationofa pages 1-2, dantas2018characterizationofa pages 10-11)
  4. Abnormal motor/cargo regulation results in disturbed actin-protrusion growth, stereocilia length, width, spacing, and staircase organization; MYO3B partially compensates, producing variable onset and progression. (maekawa2025theprevalenceand pages 2-4, maekawa2025theprevalenceand pages 1-2)
  5. Disordered stereociliary architecture leads to inefficient hair-bundle deflection and impaired mechanoelectrical transduction; this final connection is strongly biologically supported but not directly measured in living DFNB30 patients.
  6. Chronic hair-cell dysfunction and probable degeneration result in high-frequency sensorineural hearing loss that progressively spreads to additional frequencies and may become severe-to-profound. (doll2020anovelmissense pages 1-2, dantas2018characterizationofa pages 1-2)

This is primarily a cytoskeletal mechanotransduction disorder, not a canonical Wnt, MAPK, PI3K–AKT, immune, inflammatory, or metabolic disease. Relevant processes include actin-filament organization, actin-dependent motor activity, protein transport along actin, stereocilium organization, sensory perception of sound, and auditory receptor-cell development/maintenance. Suggested GO concepts are actin filament organization, actin-dependent ATPase activity, microfilament motor activity, stereocilium organization, protein localization to stereocilium, and sensory perception of sound.

The principal cells are cochlear inner and outer hair cells—suggested CL concepts: auditory hair cell, inner hair cell, and outer hair cell. Vestibular hair-cell expression is documented, although clinically important vestibular disease is inconsistent. MYO3A localizes at the stereociliary tip and associates with the F-actin cytoskeleton and plasma-membrane-adjacent tip complex. (maekawa2025theprevalenceand pages 1-2, doll2020anovelmissense pages 1-2)

No validated DFNB30 patient transcriptomic, proteomic, metabolomic, lipidomic, spatial-transcriptomic, or single-cell disease signature was found. Available molecular profiling is principally expression/localization, biochemical motor assays, structural modeling, cultured-cell protrusion assays, and animal hair-bundle morphology.

7. Anatomical structures affected

  • Organ/system: inner ear; auditory system.
  • Primary site: cochlea and organ of Corti.
  • Tissue: sensory neuroepithelium.
  • Cells: inner and outer cochlear hair cells; vestibular hair cells express MYO3A but are not consistently clinically impaired.
  • Subcellular site: actin-rich stereocilia, especially distal tips; F-actin core and associated cargo complex.
  • Laterality: usually bilateral.
  • Suggested UBERON terms: inner ear, cochlea, organ of Corti, cochlear hair cell, hair-cell stereocilium; vestibular sensory epithelium may be recorded as an expression site rather than a universally diseased structure.
  • Suggested GO cellular components: stereocilium, stereocilium tip, actin cytoskeleton, actin filament bundle.

No consistent secondary-organ disease is established despite MYO3A expression in retina; the human DFNB30 phenotype remains nonsyndromic. (doll2020anovelmissense pages 1-2)

8. Temporal development

Onset varies from congenital to the second decade. Classic Family N developed bilateral high-frequency loss beginning in the second decade, whereas some later kinase- or motor-domain genotypes caused congenital profound loss. The condition is chronic and lifelong. Progression is generally insidious rather than episodic, initially affecting higher frequencies and later broader frequencies. (doll2020anovelmissense pages 1-2, maekawa2025theprevalenceand pages 1-2)

No formal staging system or genotype-specific annual dB progression rate exists. Practical stages are: detectable high-frequency loss; broader speech-frequency involvement; severe-to-profound hearing loss requiring increasingly intensive rehabilitation. Spontaneous remission is not expected. Critical intervention periods include infancy and early childhood for congenital cases and the interval before speech-frequency deterioration in later-onset cases.

9. Inheritance and population

Inheritance is autosomal recessive. When both parents are heterozygous carriers, each pregnancy has a 25% probability of an affected child, 50% probability of an unaffected carrier, and 25% probability of inheriting neither familial allele. Both sexes should be affected equally. Penetrance appears high for clearly pathogenic biallelic genotypes but may be age-dependent; exact penetrance estimates are unavailable. Expressivity is variable in onset and severity. Anticipation has not been reported. Germline mosaicism is theoretically possible but not established as a recurrent feature.

The original extended Israeli Jewish family and subsequent Kazakh, Chinese, Tunisian/North African, Cameroonian, and Japanese cases demonstrate broad geographic distribution. Consanguinity has facilitated discovery, but DFNB30 is not limited to consanguineous families. No universally important founder allele or reliable global carrier frequency has been established. (doll2020anovelmissense pages 1-2, dantas2018characterizationofa pages 1-2, maekawa2025theprevalenceand pages 12-13)

In the largest recent study, nine candidates were detected among 15,684 Japanese hearing-loss referrals, or 0.06%. This is a clinic-based proportion—not population prevalence or annual incidence. Before that study, only 13 cases had reportedly been published. Disease-specific prevalence per 100,000 and incidence are unknown. (maekawa2025theprevalenceand pages 1-2, maekawa2025theprevalenceand pages 6-8, maekawa2025theprevalenceand pages 2-4)

10. Diagnostics

Clinical evaluation

Diagnosis starts with otoscopy and age-appropriate audiology: pure-tone and speech audiometry, tympanometry, otoacoustic emissions, and auditory brainstem response when behavioral testing is unreliable. Serial audiograms are important because progression is central to DFNB30. Vestibular testing is appropriate when vertigo or imbalance is present. CT/MRI is not diagnostic of DFNB30 and should be reserved for cochlear-implant planning, asymmetric findings, or suspected structural disease.

There is no characteristic blood, urine, enzyme, metabolite, biopsy, or circulating biomarker. The molecular biomarker is a pathogenic/likely pathogenic biallelic MYO3A genotype in trans consistent with phenotype and inheritance.

Genetic-testing strategy

  1. Use a comprehensive hereditary-hearing-loss panel that includes MYO3A, with deletion/duplication analysis.
  2. If nondiagnostic, use exome or genome sequencing, ideally trio/family based; genome sequencing can better detect noncoding and structural variants.
  3. Confirm candidate variants and phase by parental/relative testing.
  4. Apply hearing-loss-specific ACMG/AMP interpretation and periodically reanalyze negative or VUS results.
  5. Single-gene testing is efficient only when familial MYO3A variants are already known.

The 2025 multicenter study used massively parallel sequencing of 158 hearing-loss genes, illustrating current real-world implementation and why a panel is preferable to sequential single-gene testing in this genetically heterogeneous phenotype. (maekawa2025theprevalenceand pages 2-4)

CMA, karyotyping, FISH, mitochondrial DNA testing, and repeat-expansion testing are not first-line DFNB30 tests unless other clinical findings suggest an alternative diagnosis. Differential diagnoses include other progressive nonsyndromic hearing-loss genes—such as TMC1, TMPRSS3, MYO15A, POU4F3, ACTG1, and dominant MYO3A alleles—plus congenital CMV, noise/ototoxic injury, auditory neuropathy, and syndromic hearing loss.

Newborn physiologic hearing screening remains essential but may miss delayed-onset DFNB30. Once a familial genotype is known, cascade testing can identify siblings or relatives requiring prospective audiologic surveillance.

11. Outcome and prognosis

DFNB30 does not appear to shorten life expectancy or directly increase mortality. Its burden is auditory disability rather than systemic organ failure. Untreated progression can substantially impair speech understanding, communication, education, employment, safety, and social participation. Congenital profound loss poses the greatest risk to spoken-language development if access to communication and rehabilitation is delayed.

Hearing recovery is not expected spontaneously. Functional prognosis depends on age at onset, rate and severity of progression, timing and consistency of amplification, communication access, and candidacy for cochlear implantation. No validated molecular prognostic biomarker exists, although genotype/domain and residual MYO3A function may partly explain congenital-profound versus later-progressive phenotypes. The 2025 study concluded that genetic identification can help anticipate progression and enable timely intervention. (maekawa2025theprevalenceand pages 1-2)

12. Treatment

There is no approved MYO3A-restoring drug, RNA therapy, cell therapy, or gene therapy. Pharmacogenomic guidance specific to DFNB30 is unavailable.

Current management is individualized:

  • Hearing aids for aidable mild-to-severe loss; suggested NCIt concept: Hearing Aid.
  • Cochlear implantation for severe-to-profound loss with insufficient aided speech recognition; suggested NCIt concept: Cochlear Implantation.
  • Audiologic rehabilitation, auditory-verbal or speech-language therapy, educational accommodations, assistive listening technology, captioning, and/or sign-language access according to patient goals.
  • Serial audiometry, because thresholds may deteriorate after a normal newborn screen or initial mild high-frequency loss.
  • Vestibular rehabilitation only for documented vestibular dysfunction.

A ClinicalTrials.gov search found gene-therapy studies for other genetic hearing losses—including OTOF and GJB2—and general human auditory-cell transduction research, but no MYO3A/DFNB30-specific interventional trial. Those studies should not be entered as DFNB30 treatments.

Gene replacement is conceptually attractive because recessive disease is usually loss-of-function, but challenges include MYO3A coding size, delivery to the correct mature hair cells, dosage, developmental timing, and whether abnormal/degenerating stereocilia remain rescuable. Thus, gene therapy is preclinical speculation, not present clinical care.

13. Prevention

The inherited genotype cannot be prevented by lifestyle modification.

  • Primary prevention/reproductive options: genetic counseling, partner testing when appropriate, prenatal diagnosis, and preimplantation genetic testing for monogenic disease after familial variants are established. These are optional, values-sensitive choices—not requirements.
  • Secondary prevention: newborn hearing screening, cascade genetic testing, and periodic audiology for genetically at-risk relatives, including those who initially pass newborn screening.
  • Tertiary prevention: early amplification or implantation, communication access, education support, and avoidance of unnecessary cochlear hazards to preserve residual hearing.
  • Vaccination: no DFNB30-specific vaccine; routine immunization can prevent some acquired infectious causes of hearing loss but not MYO3A disease.
  • Counseling: clearly distinguish recessive carrier status from dominant MYO3A alleles and explain age-dependent manifestation.

14. Other species and natural disease

No well-established naturally occurring companion-animal or livestock disorder directly equivalent to human MYO3A-DFNB30 was identified. There is no zoonotic potential or cross-species transmission because this is a germline genetic disease.

The human MYO3A protein is evolutionarily related to Drosophila NINAC, a class III myosin required in photoreceptors. The original paper described this as an evolutionary connection between visual and auditory sensory systems, but NINAC retinal degeneration is not a literal fly model of human cochlear disease. (souissi2022molecularinsightsinto pages 12-13)

Suggested taxonomy annotations include Homo sapiens (NCBI Taxon 9606), Mus musculus (10090), and Drosophila melanogaster (7227). Ortholog identifiers should be taken from the current NCBI Gene/Alliance release at ingestion.

15. Model organisms

The most disease-relevant model is the mouse carrying a human DFNB30-associated MYO3A loss-of-function allele. These mice developed significant hearing loss by approximately 2.5 months, first at high frequencies and subsequently across all tested frequencies, recapitulating the progressive human course. DOI 10.1007/s00335-010-9310-6, PMID 21165622. (doll2020anovelmissense pages 1-2, dantas2018characterizationofa pages 1-2)

Myo3a-deficient mice show abnormal stereocilia dimensions and spacing. Combined Myo3a/Myo3b deficiency produces a more severe or profound phenotype than MYO3A loss alone, demonstrating partial redundancy between class III myosins. These models are useful for longitudinal auditory brainstem response testing, otoacoustic emissions, ultrastructural analysis, actin/cargo trafficking, and preclinical rescue studies. (maekawa2025theprevalenceand pages 1-2, maekawa2025theprevalenceand pages 2-4)

Limitations include interspecies differences in cochlear maturation and frequency range, redundancy between Myo3a and Myo3b, and the inability of a single engineered allele to represent the full human genotype–phenotype spectrum. COS-7 filopodia and epithelial microvilli are useful reductionist systems for motor and actin-protrusion assays but are not auditory hair cells. Patient-derived iPSC hair-cell or organoid models would be valuable, but no validated DFNB30 clinical platform was identified.

Recent developments and evidence appraisal

A 2024 authoritative review of hearing-loss-associated myosins emphasized that MYO3A, MYO6, MYO7A, and MYO15A are essential to developing and maintaining functional hair-cell stereocilia, while also noting that variant-level clinical correlations and in-stereocilium trafficking remain incompletely understood. Miyoshi et al., Frontiers in Physiology, published March 2024, DOI 10.3389/fphys.2024.1374901. This is expert synthesis rather than new DFNB30 patient evidence. (elbagoury2025wholeexomesequencing pages 10-11)

The strongest new disease-specific clinical evidence is the study published 16 January 2025, just outside the requested 2023–2024 priority window. It supplied the largest unrelated MYO3A series, eight candidate causal variants—six novel—and the 0.06% estimate among Japanese hearing-loss referrals. Its abstract states: “Our findings confirmed that MYO3A variants cause progressive hearing loss, with its onset varying from birth to the second decade, eventually leading to severe-to-profound hearing loss.” Maekawa et al., Genes 2025;16:92, DOI 10.3390/genes16010092. (maekawa2025theprevalenceand pages 1-2)

Overall certainty is high for MYO3A causality, autosomal-recessive inheritance, sensorineural pathology, and progression; moderate for domain-specific genotype–phenotype correlations and individual cargo contributions; and low or absent for population prevalence, penetrance estimates, modifiers, environmental interaction, epigenetics, patient omics, disease-specific quality-of-life statistics, and MYO3A-targeted treatment outcomes.

References

  1. (OpenTargets Search: autosomal recessive nonsyndromic hearing loss 30-MYO3A): Open Targets Query (autosomal recessive nonsyndromic hearing loss 30-MYO3A, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  2. (doll2020anovelmissense pages 1-2): Julia Doll, Michaela A. H. Hofrichter, Paulina Bahena, Alfred Heihoff, Dennis Segebarth, Tobias Müller, Marcus Dittrich, Thomas Haaf, and Barbara Vona. A novel missense variant in myo3a is associated with autosomal dominant high‐frequency hearing loss in a german family. Molecular Genetics & Genomic Medicine, Jun 2020. URL: https://doi.org/10.1002/mgg3.1343, doi:10.1002/mgg3.1343. This article has 17 citations and is from a peer-reviewed journal.

  3. (dantas2018characterizationofa pages 1-2): Vitor G. L. Dantas, Manmeet H. Raval, Angela Ballesteros, Runjia Cui, Laura K. Gunther, Guilherme L. Yamamoto, Leandro Ucela Alves, André Silva Bueno, Karina Lezirovitz, Sulene Pirana, Beatriz C. A. Mendes, Christopher M. Yengo, Bechara Kachar, and Regina C. Mingroni-Netto. Characterization of a novel myo3a missense mutation associated with a dominant form of late onset hearing loss. Scientific Reports, Jun 2018. URL: https://doi.org/10.1038/s41598-018-26818-2, doi:10.1038/s41598-018-26818-2. This article has 32 citations and is from a peer-reviewed journal.

  4. (maekawa2025theprevalenceand pages 1-2): Karuna Maekawa, Shin-ya Nishio, Hiromitsu Miyazaki, Yoko Ohta, Naoki Oishi, Misato Kasai, Ai Yamamoto, Mayuri Okami, Koichiro Wasano, Akihiro Sakai, and Shin-ichi Usami. The prevalence and clinical characteristics of myo3a-associated hearing loss in 15,684 hearing loss patients. Jan 2025. URL: https://doi.org/10.3390/genes16010092, doi:10.3390/genes16010092. This article has 1 citations.

  5. (maekawa2025theprevalenceand pages 6-8): Karuna Maekawa, Shin-ya Nishio, Hiromitsu Miyazaki, Yoko Ohta, Naoki Oishi, Misato Kasai, Ai Yamamoto, Mayuri Okami, Koichiro Wasano, Akihiro Sakai, and Shin-ichi Usami. The prevalence and clinical characteristics of myo3a-associated hearing loss in 15,684 hearing loss patients. Jan 2025. URL: https://doi.org/10.3390/genes16010092, doi:10.3390/genes16010092. This article has 1 citations.

  6. (maekawa2025theprevalenceand pages 2-4): Karuna Maekawa, Shin-ya Nishio, Hiromitsu Miyazaki, Yoko Ohta, Naoki Oishi, Misato Kasai, Ai Yamamoto, Mayuri Okami, Koichiro Wasano, Akihiro Sakai, and Shin-ichi Usami. The prevalence and clinical characteristics of myo3a-associated hearing loss in 15,684 hearing loss patients. Jan 2025. URL: https://doi.org/10.3390/genes16010092, doi:10.3390/genes16010092. This article has 1 citations.

  7. (maekawa2025theprevalenceand pages 12-13): Karuna Maekawa, Shin-ya Nishio, Hiromitsu Miyazaki, Yoko Ohta, Naoki Oishi, Misato Kasai, Ai Yamamoto, Mayuri Okami, Koichiro Wasano, Akihiro Sakai, and Shin-ichi Usami. The prevalence and clinical characteristics of myo3a-associated hearing loss in 15,684 hearing loss patients. Jan 2025. URL: https://doi.org/10.3390/genes16010092, doi:10.3390/genes16010092. This article has 1 citations.

  8. (souissi2022molecularinsightsinto pages 12-13): Amal Souissi, Dorra Abdelmalek Driss, Imen Chakchouk, Mariem Ben Said, Ikhlas Ben Ayed, Mohamed Ali Mosrati, Ines Elloumi, Abdelaziz Tlili, Sami Aifa, and Saber Masmoudi. Molecular insights into myo3a kinase domain variants explain variability in both severity and progression of dfnb30 hearing impairment. Journal of Biomolecular Structure and Dynamics, 40:10940-10951, Aug 2022. URL: https://doi.org/10.1080/07391102.2021.1953600, doi:10.1080/07391102.2021.1953600. This article has 4 citations and is from a peer-reviewed journal.

  9. (maekawa2025theprevalenceand pages 4-6): Karuna Maekawa, Shin-ya Nishio, Hiromitsu Miyazaki, Yoko Ohta, Naoki Oishi, Misato Kasai, Ai Yamamoto, Mayuri Okami, Koichiro Wasano, Akihiro Sakai, and Shin-ichi Usami. The prevalence and clinical characteristics of myo3a-associated hearing loss in 15,684 hearing loss patients. Jan 2025. URL: https://doi.org/10.3390/genes16010092, doi:10.3390/genes16010092. This article has 1 citations.

  10. (dantas2018characterizationofa pages 10-11): Vitor G. L. Dantas, Manmeet H. Raval, Angela Ballesteros, Runjia Cui, Laura K. Gunther, Guilherme L. Yamamoto, Leandro Ucela Alves, André Silva Bueno, Karina Lezirovitz, Sulene Pirana, Beatriz C. A. Mendes, Christopher M. Yengo, Bechara Kachar, and Regina C. Mingroni-Netto. Characterization of a novel myo3a missense mutation associated with a dominant form of late onset hearing loss. Scientific Reports, Jun 2018. URL: https://doi.org/10.1038/s41598-018-26818-2, doi:10.1038/s41598-018-26818-2. This article has 32 citations and is from a peer-reviewed journal.

  11. (dantas2018characterizationofa pages 2-3): Vitor G. L. Dantas, Manmeet H. Raval, Angela Ballesteros, Runjia Cui, Laura K. Gunther, Guilherme L. Yamamoto, Leandro Ucela Alves, André Silva Bueno, Karina Lezirovitz, Sulene Pirana, Beatriz C. A. Mendes, Christopher M. Yengo, Bechara Kachar, and Regina C. Mingroni-Netto. Characterization of a novel myo3a missense mutation associated with a dominant form of late onset hearing loss. Scientific Reports, Jun 2018. URL: https://doi.org/10.1038/s41598-018-26818-2, doi:10.1038/s41598-018-26818-2. This article has 32 citations and is from a peer-reviewed journal.

  12. (elbagoury2025wholeexomesequencing pages 10-11): Nagham M. Elbagoury, Engy A. Ashaat, Mona K. Mekkawy, Ragaey Y. Mohamed, Anas M. Askoura, Peter M. Milad, and Mona L. Essawi. Whole exome sequencing diagnosing syndromic and non-syndromic hearing loss with expansion of the phenotypic spectrum related to tmc1 variants. European Journal of Pediatrics, Mar 2025. URL: https://doi.org/10.1007/s00431-025-06052-5, doi:10.1007/s00431-025-06052-5. This article has 2 citations and is from a peer-reviewed journal.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 8
Resolved 8
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 8
On topic 5
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 1
Resolved 1
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 1
Terms named correctly 0
Terms named as a different term 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0011774 (2 mentions) - the report calls it "MONDO"; MONDO calls it autosomal recessive nonsyndromic hearing loss 30