👪

Inheritance

2

Autosomal dominant (DFNA22) HP:0000006

Autosomal dominant nonsyndromic hearing loss 22 (DFNA22) is caused by heterozygous pathogenic variants in MYO6. Progressive postlingual sensorineural hearing loss typically begins in childhood or adolescence and worsens with age.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:11468689 SUPPORT Human Clinical

"We describe the mapping of a new deafness locus, DFNA22, on chromosome 6q13 in a family affected by a nonsyndromic dominant form of deafness (NSAD), and the subsequent identification of a missense mutation in the MYO6 gene in all members of the family with hearing loss."

Original identification of DFNA22 locus with autosomal dominant inheritance linked to MYO6 mutation.

Autosomal recessive (DFNB37) HP:0000007

Autosomal recessive nonsyndromic hearing loss 37 (DFNB37) is caused by biallelic pathogenic variants in MYO6, resulting in congenital profound deafness.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:12687499 SUPPORT Human Clinical

"Cosegregation of profound, congenital deafness with markers on chromosome 6q13 in three Pakistani families defines a new recessive deafness locus, DFNB37."

Establishes DFNB37 as an autosomal recessive deafness locus mapping to MYO6 on chromosome 6q13.

◆

Subtypes

2

DFNA22 (Autosomal Dominant)

Autosomal dominant nonsyndromic hearing loss caused by heterozygous MYO6 mutations. Progressive postlingual sensorineural hearing loss, sometimes with hypertrophic cardiomyopathy.

DFNB37 (Autosomal Recessive)

Autosomal recessive nonsyndromic hearing loss caused by biallelic MYO6 mutations. Congenital profound deafness.

⚙

Pathophysiology

4

Stereocilia Dysfunction in Cochlear Hair Cells

MYO6 encodes myosin VI, the only known minus-end-directed actin-based motor protein. In cochlear hair cells, myosin VI is essential for anchoring the stereocilia plasma membrane to the actin core and for maintaining stereocilia structural integrity. Loss-of-function mutations lead to disorganized and malformed stereocilia, impairing mechanotransduction and causing sensorineural hearing loss.

Auditory hair cell link

MYO6 link

Actin cytoskeleton organization link Endocytosis link ⚠ ABNORMAL

microfilament motor activity link

Downstream

Inner Hair Cell Ribbon Synapse Exocytosis Defect MYO6 loss or deafness-inducing mutation reduces inner hair cell ribbon synapse vesicle release.

Progressive Sensorineural Hearing Loss

Show evidence (2 references)

PMID:32143290 SUPPORT Human Clinical

"In conclusion, the present data clearly showed that MYO6 is one of the genes to keep in mind with regard to ADSNHL, and the molecular characteristics of the identified gene variants suggest that a possible pathology seems to result from malformed stereocilia of the cochlear hair cells."

Links MYO6 variants to stereocilia malformation as the mechanism underlying hearing loss.

PMID:31103816 SUPPORT Model Organism

"We also observed disorganized stereocilia with irregular morphological features by immunohistochemistry and scanning electron microscopy."

Mouse model confirms that MYO6 mutation causes stereocilia disorganization in vivo.

Inner Hair Cell Ribbon Synapse Exocytosis Defect

MYO6 knockout and deafness-inducing MYO6 point mutation impair exocytosis at inner hair cell ribbon synapses, reducing readily releasable vesicle pool function and sustained synaptic release.

Cochlear inner hair cell link

Exocytosis link ↓ DECREASED

Downstream

Progressive Sensorineural Hearing Loss

Show evidence (2 references)

DOI:10.1038/s41420-023-01473-3 SUPPORT Model Organism

"In Myo6−/− cochleae of both before (P8-10) and after hearing onset (P18-20), exocytosis from IHCs, measured in whole-cell capacitance change (ΔCm), was significantly reduced"

Mouse knockout evidence directly supports reduced inner hair cell exocytosis at ribbon synapses downstream of MYO6 loss.

DOI:10.1038/s41420-023-01473-3 SUPPORT Model Organism

"it was likely due to smaller RRP and slower SRR in mature IHCs of both animal models."

Mouse knockout and p.C442Y models support impaired readily releasable vesicle pool and sustained release rate as synaptic mechanisms.

Progressive Sensorineural Hearing Loss

In DFNA22, heterozygous MYO6 mutations cause progressive sensorineural hearing loss typically beginning in childhood and accelerating after age 40. The progressive nature resembles presbyacusis. In DFNB37, biallelic MYO6 mutations cause congenital profound deafness.

Show evidence (3 references)

PMID:32143290 SUPPORT Human Clinical

"The present study clarified that most cases showed juvenile-onset progressive hearing loss and their hearing deteriorated markedly after 40 years of age."

Characterizes the progressive nature and age-dependent acceleration of MYO6-related hearing loss.

PMID:23340379 SUPPORT Human Clinical

"This missense mutation results in a flat configured audiogram with a mild hearing loss, which becomes severe to profound and gently to steeply downsloping later in life."

Further characterization of progressive hearing loss pattern in a DFNA22 family showing presbyacusis-like progression.

PMID:12687499 SUPPORT Human Clinical

"In families with recessively inherited deafness, DFNB37, our sequence analyses of MYO6 reveal a frameshift mutation (36-37insT), a nonsense mutation (R1166X), and a missense mutation (E216V)."

Documents the allelic spectrum in recessive DFNB37 including truncating and missense variants causing congenital deafness.

Cardiac Involvement

A subset of individuals with dominant MYO6 mutations develop hypertrophic cardiomyopathy with left ventricular hypertrophy. Myosin VI is expressed in cardiac tissue, predominantly in vascular endothelial cells, and loss of function leads to left ventricular hypertrophy with interstitial and perivascular fibrosis.

Show evidence (3 references)

PMID:26265212 SUPPORT Model Organism

"Sv/sv heart mass is significantly greater than that of sv/+ littermates, a result of left ventricle hypertrophy. The left ventricle of the sv/sv exhibits extensive fibrosis, both interstitial and perivascular"

Snell's waltzer mouse model demonstrates that MYO6 loss of function causes left ventricular hypertrophy and cardiac fibrosis.

PMID:26265212 SUPPORT Model Organism

"In mice and humans, loss of myosin VI (Myo6) function results in deafness, and certain Myo6 mutations also result in cardiomyopathies in humans."

Establishes the dual phenotype of deafness and cardiomyopathy associated with myosin VI dysfunction.

PMID:26265212 SUPPORT Human Clinical

"In addition to deafness, a kindred of patients has been identified with an autosomal dominant mutation in the motor domain of Myo6 who also present with familial hypertrophic cardiomyopathy"

The full-text introduction summarizes the previously reported human MYO6 kindred with deafness and familial hypertrophic cardiomyopathy, restoring direct human support for the cardiac claim when the primary PMID cache lacks abstract text.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

4

Cardiovascular 2

Hypertrophic cardiomyopathy Hypertrophic cardiomyopathy (HP:0001639)

Show evidence (2 references)

PMID:26265212 SUPPORT Model Organism

"In mice and humans, loss of myosin VI (Myo6) function results in deafness, and certain Myo6 mutations also result in cardiomyopathies in humans."

Confirms the association of MYO6 mutations with cardiomyopathy in humans and animal models.

PMID:26265212 SUPPORT Human Clinical

"In addition to deafness, a kindred of patients has been identified with an autosomal dominant mutation in the motor domain of Myo6 who also present with familial hypertrophic cardiomyopathy"

Restores human-kindred evidence for hypertrophic cardiomyopathy in MYO6-related disease after removal of the invalid PMID:15060111 title-as-snippet evidence.

Left ventricular hypertrophy Left ventricular hypertrophy (HP:0001712)

Show evidence (1 reference)

PMID:26265212 SUPPORT Model Organism

"Sv/sv heart mass is significantly greater than that of sv/+ littermates, a result of left ventricle hypertrophy."

Demonstrates left ventricular hypertrophy in the MYO6-null Snell's waltzer mouse model.

Ear 2

Sensorineural hearing impairment Sensorineural hearing impairment (HP:0000407)

Show evidence (1 reference)

PMID:32143290 SUPPORT Human Clinical

"most cases showed juvenile-onset progressive hearing loss and their hearing deteriorated markedly after 40 years of age"

Characterizes the progressive sensorineural hearing loss pattern in MYO6 DFNA22 patients.

Progressive hearing impairment Progressive hearing impairment (HP:0001730)

Show evidence (1 reference)

PMID:32143290 SUPPORT Human Clinical

"The estimated hearing deterioration was found to be 0.57 dB per year; when restricted to change after 40 years of age, the deterioration speed was accelerated to 1.07 dB per year."

Quantifies the progressive nature of MYO6-related hearing loss with age-dependent acceleration.

🧬

Genetic Associations

1

MYO6 pathogenic variants (Causative)

Autosomal dominant Autosomal recessive

Show evidence (3 references)

PMID:32451864 SUPPORT Other

"The evidence that pathogenic variants of human MYO3A, MYO6, MYO7A, MYO15A, MYH14 and MYH9 are associated with deafness ranges from moderate to definitive."

Review confirms definitive evidence for MYO6 as a deafness gene.

PMID:11468689 SUPPORT Human Clinical

"Mutations in the unconventional myosin VI gene, Myo6, are associated with deafness and vestibular dysfunction in the Snell's waltzer (sv) mouse. The corresponding human gene, MYO6, is located on chromosome 6q13."

First identification of MYO6 as the causative gene for DFNA22.

CGGV:assertion_50d408fe-e298-4683-985c-57a37b30e273-2018-02-20T170000.000Z SUPPORT Other

ClinGen classifies the MYO6-nonsyndromic genetic hearing loss gene-disease relationship as definitive with autosomal dominant inheritance.

💊

Treatments

2

Hearing aids

Action: hearing aid usage MAXO:0009030

Conventional amplification is considered for DFNA22 patients with progressive hearing loss when speech audiometry remains favorable.

Show evidence (1 reference)

DOI:10.1002/jgm.3019 SUPPORT Human Clinical

"Gradual progression with a good speech audiometry score could provide physicians with clinical insight with respect to advising patients to use hearing aids or consider middle ear implants"

DFNA22 cohort guidance explicitly supports hearing-aid use in appropriately selected MYO6-related hearing loss patients.

Cochlear implantation

Action: cochlear device implantation MAXO:0009025

Cochlear implantation may be considered in selected exceptional circumstances when MYO6-related hearing loss is severe enough that conventional amplification is inadequate.

Show evidence (1 reference)

DOI:10.1002/jgm.3019 SUPPORT Human Clinical

"in the case of certain exceptional circumstances, physicians could provide patients with the option to consider a cochlear implant."

DFNA22 clinical guidance supports cochlear implant consideration for selected MYO6-related hearing loss patients.

{ }

Source YAML

click to show

name: MYO6_Hearing_Loss
creation_date: '2026-04-04T00:00:00Z'
updated_date: '2026-04-24T00:00:00Z'
category: Mendelian
description: >
  MYO6-related hearing loss encompasses autosomal dominant nonsyndromic hearing loss 22
  (DFNA22) and autosomal recessive nonsyndromic hearing loss 37 (DFNB37), both caused
  by pathogenic variants in MYO6 encoding the unconventional myosin VI motor protein.
  Myosin VI is unique among myosins in moving toward the minus end of actin filaments
  and is essential for stereocilia maintenance in cochlear hair cells. Dominant (DFNA22)
  mutations typically cause progressive postlingual sensorineural hearing loss with
  juvenile onset that accelerates after age 40, while recessive (DFNB37) mutations
  cause congenital profound deafness. A subset of families with dominant MYO6 mutations
  also present with hypertrophic cardiomyopathy featuring left ventricular hypertrophy,
  reflecting the role of myosin VI in cardiac tissue. MYO6 accounts for approximately
  2.4% of autosomal dominant sensorineural hearing loss.
disease_term:
  preferred_term: MYO6-related hearing loss
  term:
    id: MONDO:0019497
    label: nonsyndromic genetic hearing loss
parents:
- Nonsyndromic Hearing Loss
- Inner Ear Disorder
inheritance:
- name: Autosomal dominant (DFNA22)
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >
    Autosomal dominant nonsyndromic hearing loss 22 (DFNA22) is caused by heterozygous
    pathogenic variants in MYO6. Progressive postlingual sensorineural hearing loss
    typically begins in childhood or adolescence and worsens with age.
  evidence:
  - reference: PMID:11468689
    reference_title: "MYO6, the human homologue of the gene responsible for deafness in Snell's waltzer mice, is mutated in autosomal dominant nonsyndromic hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe the mapping of a new deafness locus, DFNA22, on chromosome 6q13 in a family affected by a nonsyndromic dominant form of deafness (NSAD), and the subsequent identification of a missense mutation in the MYO6 gene in all members of the family with hearing loss."
    explanation: Original identification of DFNA22 locus with autosomal dominant inheritance linked to MYO6 mutation.
- name: Autosomal recessive (DFNB37)
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    Autosomal recessive nonsyndromic hearing loss 37 (DFNB37) is caused by biallelic
    pathogenic variants in MYO6, resulting in congenital profound deafness.
  evidence:
  - reference: PMID:12687499
    reference_title: "Mutations of MYO6 are associated with recessive deafness, DFNB37."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cosegregation of profound, congenital deafness with markers on chromosome 6q13 in three Pakistani families defines a new recessive deafness locus, DFNB37."
    explanation: Establishes DFNB37 as an autosomal recessive deafness locus mapping to MYO6 on chromosome 6q13.
prevalence:
- population: Japanese ADSNHL families
  percentage: '2.4'
  notes: >-
    MYO6 mutations accounted for 2.40% of autosomal dominant sensorineural hearing
    loss in a large Japanese cohort of 1336 ADSNHL families.
  evidence:
  - reference: PMID:32143290
    reference_title: "Clinical Characteristics and In Vitro Analysis of MYO6 Variants Causing Late-Onset Progressive Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In total, 2.40% of autosomal dominant sensorineural hearing loss (ADSNHL) in families in this study (32 out of 1336) was found to be caused by MYO6 mutations."
    explanation: Large-scale genetic screening of Japanese hearing loss patients establishes MYO6 mutation frequency among ADSNHL families.
pathophysiology:
- name: Stereocilia Dysfunction in Cochlear Hair Cells
  description: >
    MYO6 encodes myosin VI, the only known minus-end-directed actin-based motor
    protein. In cochlear hair cells, myosin VI is essential for anchoring the
    stereocilia plasma membrane to the actin core and for maintaining stereocilia
    structural integrity. Loss-of-function mutations lead to disorganized and
    malformed stereocilia, impairing mechanotransduction and causing sensorineural
    hearing loss.
  genes:
  - preferred_term: MYO6
    term:
      id: hgnc:7605
      label: MYO6
  molecular_functions:
  - preferred_term: microfilament motor activity
    term:
      id: GO:0000146
      label: microfilament motor activity
  cell_types:
  - preferred_term: Auditory hair cell
    term:
      id: CL:0000202
      label: auditory hair cell
  biological_processes:
  - preferred_term: Actin cytoskeleton organization
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
  - preferred_term: Endocytosis
    modifier: ABNORMAL
    term:
      id: GO:0006897
      label: endocytosis
  evidence:
  - reference: PMID:32143290
    reference_title: "Clinical Characteristics and In Vitro Analysis of MYO6 Variants Causing Late-Onset Progressive Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion, the present data clearly showed that MYO6 is one of the genes to keep in mind with regard to ADSNHL, and the molecular characteristics of the identified gene variants suggest that a possible pathology seems to result from malformed stereocilia of the cochlear hair cells."
    explanation: Links MYO6 variants to stereocilia malformation as the mechanism underlying hearing loss.
  - reference: PMID:31103816
    reference_title: "A humanized mouse model, demonstrating progressive hearing loss caused by MYO6 p.C442Y, is inherited in a semi-dominant pattern."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We also observed disorganized stereocilia with irregular morphological features by immunohistochemistry and scanning electron microscopy."
    explanation: Mouse model confirms that MYO6 mutation causes stereocilia disorganization in vivo.
  downstream:
  - target: Inner Hair Cell Ribbon Synapse Exocytosis Defect
    description: MYO6 loss or deafness-inducing mutation reduces inner hair cell ribbon synapse vesicle release.
  - target: Progressive Sensorineural Hearing Loss
- name: Inner Hair Cell Ribbon Synapse Exocytosis Defect
  description: >
    MYO6 knockout and deafness-inducing MYO6 point mutation impair exocytosis at
    inner hair cell ribbon synapses, reducing readily releasable vesicle pool
    function and sustained synaptic release.
  cell_types:
  - preferred_term: Cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  biological_processes:
  - preferred_term: Exocytosis
    modifier: DECREASED
    term:
      id: GO:0006887
      label: exocytosis
  evidence:
  - reference: DOI:10.1038/s41420-023-01473-3
    reference_title: "Functional and developmental changes in the inner hair cell ribbon synapses caused by Myosin VI knockout and deafness-inducing point mutation"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In Myo6−/− cochleae of both before (P8-10) and after hearing onset (P18-20), exocytosis from IHCs, measured in whole-cell capacitance change (ΔCm), was significantly reduced"
    explanation: Mouse knockout evidence directly supports reduced inner hair cell exocytosis at ribbon synapses downstream of MYO6 loss.
  - reference: DOI:10.1038/s41420-023-01473-3
    reference_title: "Functional and developmental changes in the inner hair cell ribbon synapses caused by Myosin VI knockout and deafness-inducing point mutation"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "it was likely due to smaller RRP and slower SRR in mature IHCs of both animal models."
    explanation: Mouse knockout and p.C442Y models support impaired readily releasable vesicle pool and sustained release rate as synaptic mechanisms.
  downstream:
  - target: Progressive Sensorineural Hearing Loss
- name: Progressive Sensorineural Hearing Loss
  description: >
    In DFNA22, heterozygous MYO6 mutations cause progressive sensorineural hearing
    loss typically beginning in childhood and accelerating after age 40. The progressive
    nature resembles presbyacusis. In DFNB37, biallelic MYO6 mutations cause congenital
    profound deafness.
  evidence:
  - reference: PMID:32143290
    reference_title: "Clinical Characteristics and In Vitro Analysis of MYO6 Variants Causing Late-Onset Progressive Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The present study clarified that most cases showed juvenile-onset progressive hearing loss and their hearing deteriorated markedly after 40 years of age."
    explanation: Characterizes the progressive nature and age-dependent acceleration of MYO6-related hearing loss.
  - reference: PMID:23340379
    reference_title: "Progressive hereditary hearing impairment caused by a MYO6 mutation resembles presbyacusis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This missense mutation results in a flat configured audiogram with a mild hearing loss, which becomes severe to profound and gently to steeply downsloping later in life."
    explanation: Further characterization of progressive hearing loss pattern in a DFNA22 family showing presbyacusis-like progression.
  - reference: PMID:12687499
    reference_title: "Mutations of MYO6 are associated with recessive deafness, DFNB37."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In families with recessively inherited deafness, DFNB37, our sequence analyses of MYO6 reveal a frameshift mutation (36-37insT), a nonsense mutation (R1166X), and a missense mutation (E216V)."
    explanation: Documents the allelic spectrum in recessive DFNB37 including truncating and missense variants causing congenital deafness.
- name: Cardiac Involvement
  description: >
    A subset of individuals with dominant MYO6 mutations develop hypertrophic
    cardiomyopathy with left ventricular hypertrophy. Myosin VI is expressed in
    cardiac tissue, predominantly in vascular endothelial cells, and loss of function
    leads to left ventricular hypertrophy with interstitial and perivascular fibrosis.
  evidence:
  - reference: PMID:26265212
    reference_title: "Myosin VI and cardiomyopathy: Left ventricular hypertrophy, fibrosis, and both cardiac and pulmonary vascular endothelial cell defects in the Snell's waltzer mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Sv/sv heart mass is significantly greater than that of sv/+ littermates, a result of left ventricle hypertrophy. The left ventricle of the sv/sv exhibits extensive fibrosis, both interstitial and perivascular"
    explanation: Snell's waltzer mouse model demonstrates that MYO6 loss of function causes left ventricular hypertrophy and cardiac fibrosis.
  - reference: PMID:26265212
    reference_title: "Myosin VI and cardiomyopathy: Left ventricular hypertrophy, fibrosis, and both cardiac and pulmonary vascular endothelial cell defects in the Snell's waltzer mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In mice and humans, loss of myosin VI (Myo6) function results in deafness, and certain Myo6 mutations also result in cardiomyopathies in humans."
    explanation: Establishes the dual phenotype of deafness and cardiomyopathy associated with myosin VI dysfunction.
  - reference: PMID:26265212
    reference_title: "Myosin VI and cardiomyopathy: Left ventricular hypertrophy, fibrosis, and both cardiac and pulmonary vascular endothelial cell defects in the Snell's waltzer mouse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to deafness, a kindred of patients has been identified with an autosomal dominant mutation in the motor domain of Myo6 who also present with familial hypertrophic cardiomyopathy"
    explanation: The full-text introduction summarizes the previously reported human MYO6 kindred with deafness and familial hypertrophic cardiomyopathy, restoring direct human support for the cardiac claim when the primary PMID cache lacks abstract text.
phenotypes:
- category: Clinical
  name: Sensorineural hearing impairment
  description: >
    Progressive sensorineural hearing loss is the hallmark feature. In DFNA22,
    onset is typically juvenile with accelerating deterioration after age 40.
    In DFNB37, hearing loss is congenital and profound.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:32143290
    reference_title: "Clinical Characteristics and In Vitro Analysis of MYO6 Variants Causing Late-Onset Progressive Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "most cases showed juvenile-onset progressive hearing loss and their hearing deteriorated markedly after 40 years of age"
    explanation: Characterizes the progressive sensorineural hearing loss pattern in MYO6 DFNA22 patients.
- category: Clinical
  name: Progressive hearing impairment
  description: >
    Hearing deterioration is progressive, estimated at 0.57 dB per year overall,
    accelerating to 1.07 dB per year after age 40.
  phenotype_term:
    preferred_term: Progressive hearing impairment
    term:
      id: HP:0001730
      label: Progressive hearing impairment
  evidence:
  - reference: PMID:32143290
    reference_title: "Clinical Characteristics and In Vitro Analysis of MYO6 Variants Causing Late-Onset Progressive Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The estimated hearing deterioration was found to be 0.57 dB per year; when restricted to change after 40 years of age, the deterioration speed was accelerated to 1.07 dB per year."
    explanation: Quantifies the progressive nature of MYO6-related hearing loss with age-dependent acceleration.
- category: Clinical
  name: Hypertrophic cardiomyopathy
  description: >
    A subset of families with dominant MYO6 mutations present with hypertrophic
    cardiomyopathy, particularly left ventricular hypertrophy. This was first
    described in association with the H246R mutation.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:26265212
    reference_title: "Myosin VI and cardiomyopathy: Left ventricular hypertrophy, fibrosis, and both cardiac and pulmonary vascular endothelial cell defects in the Snell's waltzer mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In mice and humans, loss of myosin VI (Myo6) function results in deafness, and certain Myo6 mutations also result in cardiomyopathies in humans."
    explanation: Confirms the association of MYO6 mutations with cardiomyopathy in humans and animal models.
  - reference: PMID:26265212
    reference_title: "Myosin VI and cardiomyopathy: Left ventricular hypertrophy, fibrosis, and both cardiac and pulmonary vascular endothelial cell defects in the Snell's waltzer mouse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to deafness, a kindred of patients has been identified with an autosomal dominant mutation in the motor domain of Myo6 who also present with familial hypertrophic cardiomyopathy"
    explanation: Restores human-kindred evidence for hypertrophic cardiomyopathy in MYO6-related disease after removal of the invalid PMID:15060111 title-as-snippet evidence.
- category: Clinical
  name: Left ventricular hypertrophy
  description: >
    Left ventricular hypertrophy with fibrosis has been documented in MYO6
    loss-of-function contexts, both in human kindreds and in the Snell's waltzer
    mouse model.
  phenotype_term:
    preferred_term: Left ventricular hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
  evidence:
  - reference: PMID:26265212
    reference_title: "Myosin VI and cardiomyopathy: Left ventricular hypertrophy, fibrosis, and both cardiac and pulmonary vascular endothelial cell defects in the Snell's waltzer mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Sv/sv heart mass is significantly greater than that of sv/+ littermates, a result of left ventricle hypertrophy."
    explanation: Demonstrates left ventricular hypertrophy in the MYO6-null Snell's waltzer mouse model.
genetic:
- name: MYO6 pathogenic variants
  gene_term:
    preferred_term: MYO6
    term:
      id: hgnc:7605
      label: MYO6
  association: Causative
  features: 'MYO6 encodes unconventional myosin VI, the only known minus-end-directed actin-based motor. Pathogenic variants include missense mutations causing dominant progressive hearing loss (DFNA22), and frameshift, nonsense, and missense mutations causing recessive congenital deafness (DFNB37). Specific mutations such as H246R have been associated with both hearing loss and hypertrophic cardiomyopathy.'
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  variants:
  - name: c.737A>G (p.His246Arg)
    description: Missense mutation associated with both sensorineural hearing loss and hypertrophic cardiomyopathy in a large kindred.
    evidence:
    - reference: PMID:26265212
      reference_title: "Myosin VI and cardiomyopathy: Left ventricular hypertrophy, fibrosis, and both cardiac and pulmonary vascular endothelial cell defects in the Snell's waltzer mouse."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "a kindred of patients has been identified with an autosomal dominant mutation in the motor domain of Myo6 who also present with familial hypertrophic cardiomyopathy"
      explanation: The cited full text summarizes the human MYO6 motor-domain kindred with familial hypertrophic cardiomyopathy; it supports the variant-associated phenotype claim, though the exact cDNA/protein notation is not present in this cached passage.
  - name: c.36-37insT (frameshift)
    description: Frameshift mutation causing recessive congenital profound deafness (DFNB37).
    evidence:
    - reference: PMID:12687499
      reference_title: "Mutations of MYO6 are associated with recessive deafness, DFNB37."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "our sequence analyses of MYO6 reveal a frameshift mutation (36-37insT), a nonsense mutation (R1166X), and a missense mutation (E216V)"
      explanation: Documents truncating and missense MYO6 variants in DFNB37 families with congenital deafness.
  evidence:
  - reference: PMID:32451864
    reference_title: "Myosins and Hearing."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The evidence that pathogenic variants of human MYO3A, MYO6, MYO7A, MYO15A, MYH14 and MYH9 are associated with deafness ranges from moderate to definitive."
    explanation: Review confirms definitive evidence for MYO6 as a deafness gene.
  - reference: PMID:11468689
    reference_title: "MYO6, the human homologue of the gene responsible for deafness in Snell's waltzer mice, is mutated in autosomal dominant nonsyndromic hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in the unconventional myosin VI gene, Myo6, are associated with deafness and vestibular dysfunction in the Snell's waltzer (sv) mouse. The corresponding human gene, MYO6, is located on chromosome 6q13."
    explanation: First identification of MYO6 as the causative gene for DFNA22.
  - reference: CGGV:assertion_50d408fe-e298-4683-985c-57a37b30e273-2018-02-20T170000.000Z
    reference_title: "MYO6 / nonsyndromic genetic hearing loss (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYO6 | HGNC:7605 | nonsyndromic genetic hearing loss | MONDO:0019497 | AD | Definitive"
    explanation: ClinGen classifies the MYO6-nonsyndromic genetic hearing loss gene-disease relationship as definitive with autosomal dominant inheritance.
treatments:
- name: Hearing aids
  description: >
    Conventional amplification is considered for DFNA22 patients with progressive
    hearing loss when speech audiometry remains favorable.
  treatment_term:
    preferred_term: hearing aid usage
    term:
      id: MAXO:0009030
      label: hearing aid usage
  evidence:
  - reference: DOI:10.1002/jgm.3019
    reference_title: "A clinical guidance to DFNA22 drawn from a Korean cohort study with an autosomal dominant deaf population: A retrospective cohort study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gradual progression with a good speech audiometry score could provide physicians with clinical insight with respect to advising patients to use hearing aids or consider middle ear implants"
    explanation: DFNA22 cohort guidance explicitly supports hearing-aid use in appropriately selected MYO6-related hearing loss patients.
- name: Cochlear implantation
  description: >
    Cochlear implantation may be considered in selected exceptional circumstances
    when MYO6-related hearing loss is severe enough that conventional amplification
    is inadequate.
  treatment_term:
    preferred_term: cochlear device implantation
    term:
      id: MAXO:0009025
      label: cochlear device implantation
  evidence:
  - reference: DOI:10.1002/jgm.3019
    reference_title: "A clinical guidance to DFNA22 drawn from a Korean cohort study with an autosomal dominant deaf population: A retrospective cohort study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in the case of certain exceptional circumstances, physicians could provide patients with the option to consider a cochlear implant."
    explanation: DFNA22 clinical guidance supports cochlear implant consideration for selected MYO6-related hearing loss patients.
animal_models:
- species: Mouse
  genotype: Snell's waltzer (sv/sv) - Myo6 functional null
  description: >
    The Snell's waltzer mouse carries a spontaneous null mutation in Myo6 and exhibits
    deafness, vestibular dysfunction, and cardiac defects including left ventricular
    hypertrophy with extensive fibrosis.
  evidence:
  - reference: PMID:26265212
    reference_title: "Myosin VI and cardiomyopathy: Left ventricular hypertrophy, fibrosis, and both cardiac and pulmonary vascular endothelial cell defects in the Snell's waltzer mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The current studies have utilized the Snell's waltzer (sv) mouse (a functional null mutation for Myo6) to determine if this mouse also exhibits cardiac defects"
    explanation: Characterization of the Snell's waltzer mouse as a model for MYO6-related cardiac and hearing phenotypes.
- species: Mouse
  genotype: Myo6-C442Y knock-in
  description: >
    Humanized knock-in mouse model mimicking the p.C442Y DFNA22 variant. Both
    homozygous and heterozygous mice exhibit progressive hearing loss from three
    weeks after birth, with semi-dominant inheritance pattern.
  evidence:
  - reference: PMID:31103816
    reference_title: "A humanized mouse model, demonstrating progressive hearing loss caused by MYO6 p.C442Y, is inherited in a semi-dominant pattern."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Heterozygous Myo6-C442Y mice recapitulated the progressive postlingual sensorineural deafness in human, thus providing a useful model for elucidating the role myosin VI plays in the mammalian auditory system."
    explanation: Humanized mouse model recapitulates the progressive hearing loss seen in human DFNA22 patients.
has_subtypes:
- name: DFNA22
  display_name: DFNA22 (Autosomal Dominant)
  description: >
    Autosomal dominant nonsyndromic hearing loss caused by heterozygous MYO6 mutations.
    Progressive postlingual sensorineural hearing loss, sometimes with hypertrophic
    cardiomyopathy.
- name: DFNB37
  display_name: DFNB37 (Autosomal Recessive)
  description: >-
    Autosomal recessive nonsyndromic hearing loss caused by biallelic MYO6 mutations.
    Congenital profound deafness.

📚

References & Deep Research

Deep Research

1

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Disease Characteristics Research Template

Edison Scientific Literature 34 citations 2026-04-04T12:49:22.510845

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: MYO6 Hearing Loss
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on MYO6 Hearing Loss 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

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:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

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, MAXO, 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 (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive Research Report: MYO6 Hearing Loss (DFNA22 / DFNB37)

Executive summary

MYO6-related hearing loss comprises non-syndromic sensorineural hearing loss (SNHL) caused by pathogenic variants in MYO6 (myosin VI). Two canonical Mendelian entities are recognized in the literature: DFNA22 (autosomal dominant NSHL) and DFNB37 (autosomal recessive NSHL). Clinical presentation is typically postlingual and progressive in DFNA22, with variable onset and severity; DFNB37 represents recessive disease reported in prior families and summarized in later cohorts and reviews. Quantitative cohort data indicate MYO6 is a non-trivial contributor to autosomal dominant SNHL (e.g., ~2.4% in a large Japanese ADSNHL cohort), with measurable progression rates and characteristic hair-cell structural/synaptic mechanisms. Recent 2024 studies expand variant spectrum and provide functional validation in zebrafish and mouse models, while a 2022 gene-editing study demonstrates preclinical therapeutic rescue in a semi-dominant mouse model. (oka2020clinicalcharacteristicsand pages 1-3, kim2018aclinicalguidance pages 5-8, miyoshi2024pathophysiologyofhuman pages 1-2, yin2023functionalanddevelopmental pages 1-2, buonfiglio2024insilicoand pages 2-4, xue2022geneeditingin pages 1-2)

Disease / scope	Inheritance	Key cohort / clinical statistics	Representative variant(s)	Study (year, journal)	URL	Key mechanistic note	Evidence
DFNA22 (MYO6-related dominant nonsyndromic hearing loss)	Autosomal dominant	In a Japanese cohort, MYO6 variants explained 2.40% of autosomal dominant sensorineural hearing loss (32/1336 families); overall deterioration estimated at 0.57 dB/year, accelerating to 1.07 dB/year after age 40	Multiple truncating, splice, missense variants; recurrent p.R1166X noted across families	Oka et al. 2020, Genes	https://doi.org/10.3390/genes11030273	Mutant MYO6 shortened espin1-induced microvilli in CL4 cells, supporting malformed stereocilia as a disease mechanism	(oka2020clinicalcharacteristicsand pages 1-3, oka2020clinicalcharacteristicsand pages 3-5)
DFNA22 (Korean ADNSHL cohort guidance)	Autosomal dominant	DFNA22 frequency 6.2% (5/81) in one Korean ADNSHL cohort; combined Korean cohorts 6.7% (9/134); most cases moderate, gradually progressive, often with preserved speech scores	p.R205X recurrent in 3/5 MYO6 families (~60%); novel p.G223R, p.T158R	Kim et al. 2018, The Journal of Gene Medicine	https://doi.org/10.1002/jgm.3019	MYO6 is concentrated in the actin-rich cuticular plate and helps anchor/stabilize stereocilia; clinical profile supports hearing aids or middle-ear implants, CI in selected cases	(kim2018aclinicalguidance pages 1-5, kim2018aclinicalguidance pages 5-8)
Foundational DFNA22 family	Autosomal dominant	Childhood/postlingual onset with first audiometric abnormalities at 6–8 years, symptoms at 8–10 years; by ~50 years, affected individuals typically had profound sensorineural deafness	p.C442Y	Melchionda et al. 2001, American Journal of Human Genetics	https://doi.org/10.1086/323156	First human MYO6 deafness report; mapped DFNA22 to 6q13 and linked MYO6 motor-domain dysfunction to progressive hearing loss	(melchionda2001myo6thehuman pages 1-3)
DFNA22 semi-dominant therapeutic model	Semi-dominant mouse model of dominant MYO6 disease	In vivo allele-selective editing efficiency of mutant allele averaged 4.05%; rescue of ABR, DPOAE, hair-bundle morphology, and calcium homeostasis observed up to 5 months after treatment	p.C442Y	Xue et al. 2022, Molecular Therapy	https://doi.org/10.1016/j.ymthe.2021.06.015	Supports dominant-negative / toxic mutant allele targeting as a plausible therapeutic strategy; MYO6 is localized near stereocilia base/cuticular plate	(xue2022geneeditingin pages 1-2)
DFNA22 / early-onset Chinese family	Autosomal dominant presentation reported for cis MYO6 alleles	Progressive sensorineural hearing loss with onset around 8–10 years; severe, progressive course	cis p.Trp793Gly + p.Lys794Asn	Ji et al. 2024, Frontiers in Genetics	https://doi.org/10.3389/fgene.2023.1275633	MYO6 is essential for stereocilia bundle organization, mechanotransduction, endocytosis, ion-channel regulation, anchoring of stereocilia, and vesicle movement	(ji2024novelciscompound pages 1-2, ji2024novelciscompound pages 2-3)
Dominant Argentine family with functional validation	Autosomal dominant	Postlingual progressive hearing loss with variable expressivity; affected relatives had onset in their 30s; mild-moderate to severe/profound HL reported; one family member received CI	p.Arg925Ser	Buonfiglio et al. 2024, NAR Genomics and Bioinformatics	https://doi.org/10.1093/nargab/lqae162	Structural modeling showed altered electrostatic charge in the SAH region; zebrafish rescue assays supported reduced MYO6 function in auditory hair-cell biology	(buonfiglio2024insilicoand pages 1-2, buonfiglio2024insilicoand pages 2-4, buonfiglio2024insilicoand media e17c45f9, buonfiglio2024insilicoand media 24cec060)
DFNB37 / recessive MYO6-related hearing loss	Autosomal recessive	MYO6 is established as a cause of recessive nonsyndromic hearing loss; specific prevalence is less well quantified than DFNA22 in available excerpts	Recessive MYO6 variants including nonsense, frameshift, missense reported in prior literature	Ahmed et al. 2003 and summarized in later reviews/cohorts	Not available in retrieved full text; summarized in later studies	Loss of MYO6 function disrupts stereocilia maintenance and can produce fused/branched stereocilia, consistent with loss-of-function pathogenesis	(kim2018aclinicalguidance pages 1-5, hilgert2008asplicesitemutation pages 1-2, oka2020clinicalcharacteristicsand pages 12-13)
Inner-hair-cell synaptic pathophysiology	Model-organism mechanistic evidence relevant to DFNA22/DFNB37	In Myo6 knockout mice, exocytosis from IHCs was significantly reduced before and after hearing onset; mature p.C442Y/C442Y IHCs also showed reduced exocytosis and calcium current	knockout Myo6−/−; p.C442Y	Yin et al. 2023, Cell Death Discovery	https://doi.org/10.1038/s41420-023-01473-3	Demonstrates ribbon-synapse dysfunction downstream of MYO6 defects: smaller readily releasable pool and slower sustained release contribute to hearing loss	(yin2023functionalanddevelopmental pages 1-2)
MYO6 function in hair cells (review synthesis)	Dominant and recessive forms summarized	Review-level synthesis, not a prevalence study	Multiple ClinVar/pathogenic MYO6 variants	Miyoshi et al. 2024, Frontiers in Physiology	https://doi.org/10.3389/fphys.2024.1374901	MYO6 uniquely moves toward the pointed end of F-actin and “tethers plasma membrane to the F-actin core, keeps stereocilia in place and mediates vesicle transport including endocytosis”	(miyoshi2024pathophysiologyofhuman pages 5-6, miyoshi2024pathophysiologyofhuman pages 1-2)

Table: This table condenses key disease-entity, genotype, clinical, and mechanistic facts for MYO6-related hearing loss into a knowledge-base-ready format. It emphasizes dominant DFNA22, recessive DFNB37, quantitative cohort data, representative variants, and recent mechanistic studies.

1. Disease information

1.1 What is the disease?

MYO6 hearing loss refers to hereditary non-syndromic sensorineural hearing loss caused by pathogenic variants in MYO6, encoding the unconventional actin motor myosin VI expressed in cochlear hair cells. Dominant disease is historically mapped as DFNA22, and recessive disease is referred to as DFNB37 in the hearing-loss locus nomenclature. (alde2023autosomaldominantnonsyndromic pages 10-11, kim2018aclinicalguidance pages 1-5, melchionda2001myo6thehuman pages 1-3)

1.2 Key identifiers (available from retrieved sources)

Gene: MYO6 (myosin VI)
OMIM Gene (MIM): 600970 (reported in the foundational DFNA22 mapping report) (melchionda2001myo6thehuman pages 1-3)
Locus / disease designations: DFNA22 (autosomal dominant NSHL), DFNB37 (autosomal recessive NSHL) (kim2018aclinicalguidance pages 1-5, hilgert2008asplicesitemutation pages 1-2, melchionda2001myo6thehuman pages 1-3)
Cytogenetic locus: reported as 6q13 in early mapping and many clinical series; later papers also cite 6q14.1 for MYO6 (melchionda2001myo6thehuman pages 1-3, ji2024novelciscompound pages 1-2)

Not retrievable from the currently accessed full texts: MONDO disease ID for “MYO6 hearing loss”, Orphanet ID, MeSH identifier, and ICD-10/ICD-11 code mapping. These should be filled by direct queries to OMIM/Orphanet/MONDO/MeSH/ICD resources in a subsequent curation pass.

1.3 Synonyms / alternative names

DFNA22 hearing loss; MYO6-related autosomal dominant non-syndromic hearing loss (ADNSHL) (kim2018aclinicalguidance pages 1-5, melchionda2001myo6thehuman pages 1-3)
DFNB37 hearing loss; MYO6-related autosomal recessive non-syndromic hearing loss (ARNSHL) (kim2018aclinicalguidance pages 1-5, hilgert2008asplicesitemutation pages 1-2)
Non-syndromic sensorineural hearing loss due to MYO6 variants (oka2020clinicalcharacteristicsand pages 1-3)

1.4 Evidence source type

Evidence summarized here is primarily from aggregated cohort studies and primary family studies (human genetics/audiology), complemented by mouse and zebrafish functional studies and mechanistic review synthesis. (oka2020clinicalcharacteristicsand pages 1-3, yin2023functionalanddevelopmental pages 1-2, buonfiglio2024insilicoand pages 2-4, xue2022geneeditingin pages 1-2)

2. Etiology

2.1 Disease causal factors

Primary cause: pathogenic germline variants in MYO6, producing altered myosin VI function in hair cells, which disrupts stereocilia architecture, membrane–actin tethering/endocytic trafficking, and/or inner hair cell synaptic physiology. (oka2020clinicalcharacteristicsand pages 1-3, miyoshi2024pathophysiologyofhuman pages 5-6, yin2023functionalanddevelopmental pages 1-2)

2.2 Risk factors

Genetic: family history consistent with autosomal dominant (DFNA22) or autosomal recessive (DFNB37) inheritance; specific variants including truncating, splice, and missense variants in MYO6. (oka2020clinicalcharacteristicsand pages 1-3, kim2018aclinicalguidance pages 1-5, hilgert2008asplicesitemutation pages 1-2)
Environmental: For the Argentine family report, common environmental causes (ototoxic drugs, infection, acoustic trauma) were explicitly ruled out during clinical assessment, supporting a genetic etiology. (buonfiglio2024insilicoand pages 2-4)

2.3 Protective factors / gene–environment interaction

No MYO6-specific protective variants or gene–environment interaction evidence was identified in the retrieved texts.

3. Phenotypes (clinical presentation)

3.1 Core phenotype

Sensorineural hearing loss that is frequently postlingual and progressive in DFNA22, with variable severity (mild to profound) and variable audiogram configurations reported across families and cohorts. (kim2018aclinicalguidance pages 5-8, melchionda2001myo6thehuman pages 1-3)

3.2 Age of onset, severity, progression (quantitative where available)

In the foundational DFNA22 Italian family (MYO6 missense p.C442Y), onset occurred in childhood (symptoms ~8–10 years; first audiometric abnormalities ~6–8 years) and individuals “invariably have profound sensorineural deafness” by ~50 years. (melchionda2001myo6thehuman pages 1-3)
In a large Japanese cohort study (8074 families), most MYO6-associated cases were juvenile-onset, progressive, and deterioration accelerated after age 40; estimated progression 0.57 dB/year overall and 1.07 dB/year after age 40. (oka2020clinicalcharacteristicsand pages 1-3)
In a Korean DFNA22 cohort, onset ranged from perilingual to late-forties and the severity was often moderate with gradual progression and relatively preserved speech scores (≥60% reported in their summary of cohort phenotype). (kim2018aclinicalguidance pages 5-8)
In a 2024 Chinese family report, affected relatives had progressive SNHL with onset around 8–10 years, described as severe and progressive. (ji2024novelciscompound pages 1-2)
In a 2024 Argentine family report, multiple affected members had postlingual progressive HL; mild–moderate cases were described in several individuals and severe–profound in one; onset in their thirties is described for affected women in the figure caption text, and hearing aids were used by most affected individuals, with one cochlear implant recipient. (buonfiglio2024insilicoand pages 2-4, buonfiglio2024insilicoand media e17c45f9)

3.3 HPO term suggestions (non-exhaustive)

Based on reported phenotypes: - Hearing impairment: HP:0000365 (supported by general association context) (miyoshi2024pathophysiologyofhuman pages 1-2) - Sensorineural hearing impairment: HP:0000407 (implied across cohorts describing SNHL) (oka2020clinicalcharacteristicsand pages 1-3, ji2024novelciscompound pages 1-2) - Progressive hearing impairment: HP:0001733 (progression described across families/cohorts) (oka2020clinicalcharacteristicsand pages 1-3, melchionda2001myo6thehuman pages 1-3) - Postlingual onset hearing impairment: HP:0008554 (postlingual described) (melchionda2001myo6thehuman pages 1-3)

3.4 Quality of life impact

No disease-specific QoL instruments (e.g., EQ-5D/SF-36) were reported in the retrieved texts; functional impact is inferred from the need for hearing aids and occasional cochlear implantation. (kim2018aclinicalguidance pages 5-8, buonfiglio2024insilicoand media e17c45f9)

4. Genetic / molecular information

4.1 Causal gene

MYO6 encodes myosin VI, an unconventional actin motor. (kim2018aclinicalguidance pages 1-5, melchionda2001myo6thehuman pages 1-3)

4.2 Pathogenic variants and classes

Cohorts demonstrate a broad variant spectrum including nonsense, frameshift, splice-site, and missense variants: - Japanese cohort: 27 variants across 33 families (including nonsense, frameshift, splicing, and missense); ACMG classification included pathogenic/likely pathogenic/VUS calls. (oka2020clinicalcharacteristicsand pages 3-5) - Korean cohort: recurrent truncation p.R205X and novel missense p.G223R and p.T158R (motor domain). (kim2018aclinicalguidance pages 5-8) - Foundational DFNA22: missense p.C442Y segregating in an Italian family. (melchionda2001myo6thehuman pages 1-3) - 2024 Chinese family: cis compound heterozygous variants p.Trp793Gly and p.Lys794Asn associated with early-onset progressive SNHL. (ji2024novelciscompound pages 1-2) - 2024 Argentine family: novel c.2775G>C (p.Arg925Ser) classified as likely pathogenic using ACMG/AMP and ClinGen hearing-loss gene-specific criteria; functional validation in zebrafish supported reduced function. (buonfiglio2024insilicoand pages 2-4)

Allele frequency: Buonfiglio et al. describe filtering for variants <0.1% in 1000 Genomes and gnomAD during WES analysis, but the specific numeric allele frequency for p.Arg925Ser was not captured in the retrieved text excerpt. (buonfiglio2024insilicoand pages 2-4)

4.3 Functional consequence (current understanding)

Evidence supports that MYO6 variants can lead to loss of normal hair-cell structural/synaptic function. - In vitro: multiple patient-derived MYO6 variants caused severely shortened espin1-induced microvilli in an epithelial cell model, consistent with stereocilia structural pathology. (oka2020clinicalcharacteristicsand pages 1-3) - In vivo: MYO6 loss-of-function is associated with profound hearing loss and stereocilia fusion/bifurcation in animal models (review synthesis). (miyoshi2024pathophysiologyofhuman pages 5-6)

4.4 Modifier genes, epigenetics, chromosomal abnormalities

No MYO6-specific modifier genes, epigenetic mechanisms, or recurrent chromosomal abnormalities were identified in the retrieved texts.

5. Environmental information

The retrieved evidence focuses on Mendelian genetic causation. Environmental etiologies were explicitly excluded in at least one family workup (ototoxic drugs, infections, acoustic trauma). (buonfiglio2024insilicoand pages 2-4)

6. Mechanism / pathophysiology

6.1 Key mechanistic concepts (current understanding)

Stereocilia biology: Stereocilia are actin-rich mechanosensors required for hearing. Unconventional myosins (including MYO6) are essential for developing and maintaining stereocilia. (miyoshi2024pathophysiologyofhuman pages 1-2)
MYO6 functional roles (review synthesis): MYO6 “tethers plasma membrane to the F-actin core, keeps stereocilia in place and mediates vesicle transport including endocytosis.” (miyoshi2024pathophysiologyofhuman pages 5-6)

6.2 Causal chain (example synthesis)

1) Pathogenic MYO6 variant → 2) altered myosin VI motor/structural function and/or altered dosage → 3) impaired stereocilia anchoring/maintenance and/or vesicle trafficking; plus downstream inner hair cell synaptic dysfunction → 4) progressive loss of mechanoelectrical transduction efficiency and synaptic output → 5) progressive SNHL and worsening audiometric thresholds. This chain is supported by cellular microvilli defects and mouse synaptic physiology data. (oka2020clinicalcharacteristicsand pages 1-3, yin2023functionalanddevelopmental pages 1-2)

6.3 Cellular processes and pathways (GO term suggestions)

Actin cytoskeleton organization (GO:0030036) (supported conceptually by stereocilia actin core dependence) (miyoshi2024pathophysiologyofhuman pages 1-2)
Endocytosis (GO:0006897) (MYO6 mediates vesicle transport including endocytosis) (miyoshi2024pathophysiologyofhuman pages 5-6)
Synaptic vesicle exocytosis (GO:0016079) / regulated exocytosis (GO:0045055) (reduced exocytosis in Myo6 knockout IHCs) (yin2023functionalanddevelopmental pages 1-2)

6.4 Cell types (CL suggestions)

Cochlear inner hair cell: CL:0000601 (IHC physiology studies) (yin2023functionalanddevelopmental pages 1-2)
Cochlear outer hair cell: CL:0000602 (MYO6 is expressed in inner and outer hair cells per review) (alde2023autosomaldominantnonsyndromic pages 10-11)

6.5 Anatomical structures (UBERON suggestions)

Cochlea: UBERON:0001768 (general locus of pathology in studies) (yin2023functionalanddevelopmental pages 1-2)
Organ of Corti: UBERON:0002470 (MYO6 expression/role in hair cells of organ of Corti) (alde2023autosomaldominantnonsyndromic pages 10-11)
Stereocilium: UBERON:0002302 (core affected structure) (miyoshi2024pathophysiologyofhuman pages 1-2)

6.6 Recent developments (2023–2024)

2023 mouse synapse physiology: Myo6 knockout and deafness-inducing point mutation altered IHC ribbon synapse exocytosis kinetics and vesicle pool properties, providing downstream synaptic mechanism detail. (yin2023functionalanddevelopmental pages 1-2)
2024 mechanistic review: comprehensive synthesis of myosin-linked hearing loss, emphasizing stereocilia trafficking uncertainties and variant–phenotype correlations. (miyoshi2024pathophysiologyofhuman pages 1-2)
2024 functional validation of novel human variant: zebrafish knockdown/rescue assays and structural modeling supported pathogenicity of p.Arg925Ser in MYO6. (buonfiglio2024insilicoand pages 2-4)

7. Anatomical structures affected

7.1 Primary organ/system

Auditory system, specifically the inner ear cochlea and hair-cell stereocilia. (miyoshi2024pathophysiologyofhuman pages 1-2, yin2023functionalanddevelopmental pages 1-2)

7.2 Tissue/cellular/subcellular localization

MYO6 is reported localized to basal regions of stereocilia and cuticular plate regions in hair cells; disruption leads to stereocilia abnormalities. (xue2022geneeditingin pages 1-2, kim2018aclinicalguidance pages 1-5)

8. Temporal development

8.1 Onset

Postlingual childhood onset is common in DFNA22 families, but onset can be variable including adult-onset. (kim2018aclinicalguidance pages 5-8, melchionda2001myo6thehuman pages 1-3)

8.2 Progression

Progressive course is typical, with some cohorts noting acceleration after age 40. (oka2020clinicalcharacteristicsand pages 1-3)

9. Inheritance and population

9.1 Inheritance

DFNA22: autosomal dominant MYO6-related NSHL (kim2018aclinicalguidance pages 1-5, melchionda2001myo6thehuman pages 1-3)
DFNB37: autosomal recessive MYO6-related NSHL (kim2018aclinicalguidance pages 1-5, hilgert2008asplicesitemutation pages 1-2)

9.2 Epidemiology / contribution to hereditary hearing loss (statistics)

2.40% of Japanese ADSNHL in one large cohort was attributed to MYO6 variants (32/1336 ADSNHL families). (oka2020clinicalcharacteristicsand pages 1-3)
6.2% DFNA22 frequency in one Korean autosomal-dominant NSHL cohort (5/81 families) and 6.7% in combined Korean cohorts (9/134). (kim2018aclinicalguidance pages 5-8)

Population prevalence/incidence for MYO6 hearing loss as a standalone entity was not identified in the retrieved texts; most literature reports are family-based or cohort contribution estimates.

10. Diagnostics

10.1 Clinical tests

Common audiology evaluations described include: - Pure-tone audiometry and PTA (0.5, 1, 2, 4 kHz) (buonfiglio2024insilicoand pages 2-4) - Auditory brainstem response (ABR), tympanometry, and speech audiometry in family studies (buonfiglio2024insilicoand pages 2-4)

10.2 Genetic testing

Targeted gene panels, massively parallel sequencing, and WES are used to identify MYO6 variants, followed by Sanger segregation confirmation and ACMG/AMP classification. (oka2020clinicalcharacteristicsand pages 3-5, buonfiglio2024insilicoand pages 2-4, ji2024novelciscompound pages 1-2)
Buonfiglio et al. explicitly reference ClinGen hearing-loss gene-specific criteria (HL-EP) in variant interpretation. (buonfiglio2024insilicoand pages 2-4)

10.3 Differential diagnosis

Not explicitly detailed in retrieved texts; in practice, differential includes other genetic SNHL etiologies and non-genetic causes. Environmental causes were excluded in at least one family evaluation. (buonfiglio2024insilicoand pages 2-4)

11. Outcome / prognosis

11.1 Hearing trajectory

Longitudinal progression can be substantial: the foundational DFNA22 family demonstrated profound deafness by ~50 years. (melchionda2001myo6thehuman pages 1-3)
Cohort-estimated progression rates: 0.57 dB/year overall and 1.07 dB/year after age 40 in a Japanese series. (oka2020clinicalcharacteristicsand pages 1-3)
Many DFNA22 cases may remain moderate with preserved speech scores in certain cohorts, supporting prolonged benefit from amplification. (kim2018aclinicalguidance pages 5-8)

11.2 Mortality

No disease-specific mortality signal reported for non-syndromic MYO6 hearing loss in retrieved texts.

12. Treatment

12.1 Current clinical management (real-world implementation)

Hearing aids are commonly used in affected individuals in reported families; a 2024 Argentine family report notes multiple relatives equipped with hearing aids. (buonfiglio2024insilicoand media e17c45f9)
Cochlear implantation (CI): considered in select DFNA22 cases; the Argentine family figure notes one CI recipient, and a DFNA review notes favorable outcomes in DFNA22 patients in literature. (buonfiglio2024insilicoand media e17c45f9, alde2023autosomaldominantnonsyndromic pages 10-11)

MAXO term suggestions (illustrative): - Hearing aid therapy (MAXO term not retrieved in texts; suggested for ontology mapping) - Cochlear implantation (MAXO term not retrieved in texts; suggested for ontology mapping)

12.2 Emerging / experimental therapeutics

Preclinical allele-selective gene editing: AAV-PHP.eB–mediated delivery of SaCas9/sgRNA to target the mutant Myo6C442Y allele showed allele-biased editing and rescued multiple auditory outcomes up to 5 months in a semi-dominant mouse model, supporting genome editing as a candidate strategy for semi-dominant MYO6 deafness. (xue2022geneeditingin pages 1-2)

12.3 Clinical trials

No MYO6 hearing-loss interventional clinical trials were identified in the retrieved clinical trial set. The retrieved NCT record pertains to a breast-cancer observational study involving nuclear myosin VI and is not applicable to MYO6 hearing loss.

13. Prevention

No MYO6-specific primary prevention interventions are established in the retrieved literature. Secondary prevention includes early genetic diagnosis and audiologic monitoring, consistent with progressive courses and possible acceleration after midlife. (oka2020clinicalcharacteristicsand pages 1-3)

14. Other species / natural disease

Mouse models (e.g., Snell’s waltzer; Myo6 knockout; Myo6 point mutation models) demonstrate deafness/vestibular phenotypes and provide mechanistic support for MYO6 function in hair cells. (yin2023functionalanddevelopmental pages 1-2, melchionda2001myo6thehuman pages 1-3)
Zebrafish assays (myo6b knockdown/rescue) were used to assess functional impact of a novel human MYO6 variant. (buonfiglio2024insilicoand pages 2-4)

15. Model organisms

15.1 Mouse models

Myo6−/− knockout mice used to study IHC ribbon synapse physiology (reduced exocytosis). (yin2023functionalanddevelopmental pages 1-2)
Myo6C442Y point mutation models (including semi-dominant models) used for mechanistic and gene-editing rescue studies. (yin2023functionalanddevelopmental pages 1-2, xue2022geneeditingin pages 1-2)

15.2 Zebrafish

myo6b is expressed in lateral line hair cells; morpholino knockdown with rescue by wild-type vs mutant human MYO6 RNA provides an in vivo functional assay for variant interpretation. (buonfiglio2024insilicoand pages 2-4)

Visual evidence (figure/table)

Pedigree and audiograms for a MYO6 p.Arg925Ser family and ACMG/HL-EP evidence table for variant classification are available from Buonfiglio et al. 2024 (Figure 1; Table 1). (buonfiglio2024insilicoand media e17c45f9, buonfiglio2024insilicoand media 24cec060)

Expert opinion / authoritative synthesis (2024)

A 2024 NIH-authored review emphasizes that while stereocilia biology and the roles of unconventional myosins (including MYO6) are well-established, “less is known about how myosins traffic in a stereocilium using their motor function, and how each variant correlates with a clinical condition,” highlighting ongoing uncertainty in variant-to-phenotype prediction and the need for functional assays and longitudinal clinical data. (miyoshi2024pathophysiologyofhuman pages 1-2)

URLs and publication dates (as available in retrieved sources)

Miyoshi et al., Frontiers in Physiology — Published 18 Mar 2024 — https://doi.org/10.3389/fphys.2024.1374901 (miyoshi2024pathophysiologyofhuman pages 1-2)
Buonfiglio et al., NAR Genomics and Bioinformatics — Advance access date noted as 11 Dec 2024 — https://doi.org/10.1093/nargab/lqae162 (buonfiglio2024insilicoand pages 1-2)
Ji et al., Frontiers in Genetics — Published 11 Jan 2024 — https://doi.org/10.3389/fgene.2023.1275633 (ji2024novelciscompound pages 1-2)
Yin et al., Cell Death Discovery — 2023 — https://doi.org/10.1038/s41420-023-01473-3 (yin2023functionalanddevelopmental pages 1-2)
Aldè et al., Biomedicines — Jun 2023 — https://doi.org/10.3390/biomedicines11061616 (alde2023autosomaldominantnonsyndromic pages 10-11)
Oka et al., Genes — Mar 2020 — https://doi.org/10.3390/genes11030273 (oka2020clinicalcharacteristicsand pages 1-3)
Kim et al., Journal of Gene Medicine — Apr 2018 — https://doi.org/10.1002/jgm.3019 (kim2018aclinicalguidance pages 1-5)
Melchionda et al., American Journal of Human Genetics — 2001 (electronically published Jul 20, 2001 noted) — https://doi.org/10.1086/323156 (melchionda2001myo6thehuman pages 1-3)
Xue et al., Molecular Therapy — 2022 (article in press text shows 2021 DOI acceptance; published in journal volume later) — https://doi.org/10.1016/j.ymthe.2021.06.015 (xue2022geneeditingin pages 1-2)

Limitations / gaps for knowledge-base completion

1) Disease-level identifiers (MONDO, Orphanet, ICD-10/11, MeSH) were not present in the retrieved full texts and require direct database lookup. 2) Variant allele frequencies (exact gnomAD values) and ClinVar/ClinGen assertions were not fully extractable from the accessed excerpts; Buonfiglio 2024 provides methodology and classification framework but not all numerical frequencies in the excerpted text. 3) Population prevalence/incidence for MYO6 hearing loss as a distinct entity remains sparsely reported in the retrieved materials; available statistics are mainly cohort contribution rates.

References

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(oka2020clinicalcharacteristicsand pages 3-5): Shin-ichiro Oka, Timothy F. Day, Shin-ya Nishio, Hideaki Moteki, Maiko Miyagawa, Shinya Morita, Shuji Izumi, Tetsuo Ikezono, Satoko Abe, Jun Nakayama, Misako Hyogo, Nobuhiko Okamoto, Natsumi Uehara, Chie Oshikawa, Shin-ichiro Kitajiri, and Shin-ichi Usami. Clinical characteristics and in vitro analysis of myo6 variants causing late-onset progressive hearing loss. Genes, 11:273, Mar 2020. URL: https://doi.org/10.3390/genes11030273, doi:10.3390/genes11030273. This article has 29 citations.
(kim2018aclinicalguidance pages 1-5): Bong Jik Kim, Jin Hee Han, Hye‐Rim Park, Min Young Kim, Ah Reum Kim, Seung‐Ha Oh, Woong‐Yang Park, Doo Yi Oh, Seungmin Lee, and Byung Yoon Choi. A clinical guidance to dfna22 drawn from a korean cohort study with an autosomal dominant deaf population: a retrospective cohort study. The Journal of Gene Medicine, Apr 2018. URL: https://doi.org/10.1002/jgm.3019, doi:10.1002/jgm.3019. This article has 10 citations.
(melchionda2001myo6thehuman pages 1-3): Salvatore Melchionda, Nadav Ahituv, Luigi Bisceglia, Tama Sobe, Fabian Glaser, Raquel Rabionet, Maria Lourdes Arbones, Angelo Notarangelo, Enzo Di Iorio, Massimo Carella, Leopoldo Zelante, Xavier Estivill, Karen B. Avraham, and Paolo Gasparini. Myo6, the human homologue of the gene responsible for deafness in snell's waltzer mice, is mutated in autosomal dominant nonsyndromic hearing loss. American journal of human genetics, 69 3:635-40, Sep 2001. URL: https://doi.org/10.1086/323156, doi:10.1086/323156. This article has 294 citations and is from a highest quality peer-reviewed journal.
(ji2024novelciscompound pages 1-2): Haiting Ji, Lichun Zhang, Hafiz Muhammad Jafar Hussain, Ayesha Aftab, Huiqian Yu, and Min Xiao. Novel cis compound heterozygous variants in myo6 causes early onset of non-syndromic hearing loss in a chinese family. Frontiers in Genetics, Jan 2024. URL: https://doi.org/10.3389/fgene.2023.1275633, doi:10.3389/fgene.2023.1275633. This article has 1 citations and is from a peer-reviewed journal.
(ji2024novelciscompound pages 2-3): Haiting Ji, Lichun Zhang, Hafiz Muhammad Jafar Hussain, Ayesha Aftab, Huiqian Yu, and Min Xiao. Novel cis compound heterozygous variants in myo6 causes early onset of non-syndromic hearing loss in a chinese family. Frontiers in Genetics, Jan 2024. URL: https://doi.org/10.3389/fgene.2023.1275633, doi:10.3389/fgene.2023.1275633. This article has 1 citations and is from a peer-reviewed journal.
(buonfiglio2024insilicoand pages 1-2): Paula I Buonfiglio, Carlos D Bruque, Lucía Salatino, Vanesa Lotersztein, Mariela Pace, Sofia Grinberg, Ana B Elgoyhen, Paola V Plazas, and Viviana Dalamón. In silico and in vivo analyses of a novel variant in myo6 identified in a family with postlingual non-syndromic hearing loss from argentina. NAR Genomics and Bioinformatics, Sep 2024. URL: https://doi.org/10.1093/nargab/lqae162, doi:10.1093/nargab/lqae162. This article has 0 citations and is from a peer-reviewed journal.
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(oka2020clinicalcharacteristicsand pages 12-13): Shin-ichiro Oka, Timothy F. Day, Shin-ya Nishio, Hideaki Moteki, Maiko Miyagawa, Shinya Morita, Shuji Izumi, Tetsuo Ikezono, Satoko Abe, Jun Nakayama, Misako Hyogo, Nobuhiko Okamoto, Natsumi Uehara, Chie Oshikawa, Shin-ichiro Kitajiri, and Shin-ichi Usami. Clinical characteristics and in vitro analysis of myo6 variants causing late-onset progressive hearing loss. Genes, 11:273, Mar 2020. URL: https://doi.org/10.3390/genes11030273, doi:10.3390/genes11030273. This article has 29 citations.
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OpenScientist Report

Inheritance

Subtypes

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Treatments

Source YAML

References & Deep Research

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Comprehensive Research Report: MYO6 Hearing Loss (DFNA22 / DFNB37)

Executive summary

1. Disease information

1.1 What is the disease?

1.2 Key identifiers (available from retrieved sources)

1.3 Synonyms / alternative names

1.4 Evidence source type

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors / gene–environment interaction

3. Phenotypes (clinical presentation)

3.1 Core phenotype

3.2 Age of onset, severity, progression (quantitative where available)

3.3 HPO term suggestions (non-exhaustive)

3.4 Quality of life impact

4. Genetic / molecular information

4.1 Causal gene

4.2 Pathogenic variants and classes

4.3 Functional consequence (current understanding)

4.4 Modifier genes, epigenetics, chromosomal abnormalities

5. Environmental information

6. Mechanism / pathophysiology

6.1 Key mechanistic concepts (current understanding)

6.2 Causal chain (example synthesis)

6.3 Cellular processes and pathways (GO term suggestions)

6.4 Cell types (CL suggestions)

6.5 Anatomical structures (UBERON suggestions)

6.6 Recent developments (2023–2024)

7. Anatomical structures affected

7.1 Primary organ/system

7.2 Tissue/cellular/subcellular localization

8. Temporal development

8.1 Onset

8.2 Progression

9. Inheritance and population

9.1 Inheritance

9.2 Epidemiology / contribution to hereditary hearing loss (statistics)

10. Diagnostics

10.1 Clinical tests

10.2 Genetic testing

10.3 Differential diagnosis

11. Outcome / prognosis

11.1 Hearing trajectory

11.2 Mortality

12. Treatment

12.1 Current clinical management (real-world implementation)

12.2 Emerging / experimental therapeutics