Aminoglycoside-Induced Hearing Loss

Mendelian MONDO:0010799 Pathograph 15 Show in embeddings browser Mitochondrial Disease Sensorineural Hearing Loss

Aminoglycoside-induced hearing loss in its Mendelian form is a gene-environment disease: a maternally inherited variant in the mitochondrial 12S rRNA gene MT-RNR1 - most often m.1555A>G, less often m.1494C>T - reshapes the decoding site of the mitochondrial small ribosomal subunit so that it resembles the bacterial 16S rRNA site that aminoglycosides were designed to bind. The variant is silent on its own. What converts it into deafness is exposure to the drug, and the resulting hearing loss is bilateral, severe to profound, irreversible, and idiosyncratic rather than dose-dependent: a single conventional dose is sufficient. That combination is what makes the disease unusual among Mendelian conditions - the genotype is common (roughly 1 in 385 in a UK birth cohort), the exposure is routine, and the outcome is entirely preventable if the two are kept apart. Because the variant is carried on mitochondrial DNA, transmission is maternal, so identifying one affected person places an entire matriline at risk. The clinical consequence is that this entry's most important treatment is not a drug but an avoidance: substituting a non-aminoglycoside antibiotic when the genotype is known. The practical obstacle has been time - aminoglycosides are first-line for suspected neonatal sepsis and are given within hours, while conventional genotyping takes days - which is why point-of-care testing that returns a result inside half an hour is curated here as the intervention that makes the avoidance actionable.

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1
Inheritance
7
Pathophys.
2
Phenotypes
3
Gaps
15
Pathograph
2
Genes
3
Variants
3
Medical Actions
7
References
1
Deep Research
👪

Inheritance

1
Mitochondrial (maternal) inheritance HP:0001427
MT-RNR1 is mitochondrially encoded, so the predisposing variant is transmitted only by mothers, to all of their children. A single index case therefore identifies a whole matriline whose members should be genotyped before any aminoglycoside is given.
Mitochondrial inheritance
Show evidence (1 reference)
PMID:20301595 SUPPORT Other
"is caused by pathogenic variants in mitochondrial DNA (mtDNA) and is transmitted by maternal inheritance"
GeneReviews Genetic Counseling states the mode of transmission.
?

Discussions and Knowledge Gaps

3
Does m.1555A>G cause hearing loss on its own, or only with exposure?
INTERPRETATION aihl_penetrance_without_exposure
Attached to
pathophysiology#MT-RNR1 12S rRNA Decoding-Site Variant phenotypes#Bilateral Sensorineural Hearing Loss
Family-based series report substantial penetrance of hearing loss in carrier matrilines even excluding aminoglycoside-exposed members - 14% on average across three Chinese pedigrees - which reads as evidence that the variant is independently pathogenic. An unbiased population cohort found the opposite: 19 carriers ascertained by genotyping the British 1958 birth cohort had hearing thresholds indistinguishable from non-carriers at 44-45 years. The discrepancy is most simply explained by ascertainment. Pedigrees come to attention because someone in them is deaf, so they are enriched for whatever modifiers or exposures made that happen; a birth cohort is not. Curated as an interpretation rather than a contradiction because both results can hold - the variant may be weakly penetrant in the presence of nuclear modifiers such as TRMU while contributing nothing detectable at population level. The practical consequence runs the other way from what "low penetrance" usually implies. If carriers keep normal hearing into middle age unless they are exposed, then the case for genotyping before prescribing gets stronger, not weaker: there is a long, entirely healthy window in which the disease is preventable.
Show evidence (3 references)
PMID:22223843 SUPPORT Human Clinical
"Unbiased ascertainment of mutation carriers provides no evidence that this mutation alone causes non-syndromic hearing impairment in the UK."
The population-level negative result, stated with its ascertainment caveat by the authors themselves.
PMID:22223843 SUPPORT Human Clinical
"The findings lend weight to arguments for genetic testing for this mutation prior to aminoglycoside administration, as hearing in susceptible individuals is expected to be preserved well into adult life."
The authors draw the same inference curated here - preserved baseline hearing strengthens rather than weakens the case for pre-emptive testing.
PMID:17698299 SUPPORT Human Clinical
"When the effect of aminoglycosides was excluded, the penetrances of hearing loss in these seven pedigrees were 21%, 13% and 8%, with an average of 14%."
The pedigree-based figure that the population study appears to contradict; PARTIAL because it supports one side of the interpretation rather than the whole.
Can the genotype-specific susceptibility be modelled in an animal at all?
HUMAN MODEL MISMATCH aihl_no_genotype_specific_animal_model
Attached to
pathophysiology#Bacterial-Like Conformation of the Mitoribosomal Decoding Site pathophysiology#Cochlear Hair Cell Death
This entry curates no animal model, and the reason is worth stating rather than leaving as a blank section. Animal work on aminoglycoside ototoxicity is extensive - zebrafish lateral-line hair cells resolve the death pathways, guinea pig cochlear explants rank congeners by toxicity - but it is done in wild-type animals and models the general drug-mitoribosome-hair-cell mechanism, not the human genetic susceptibility. The obstacle is intrinsic to the lesion. The disease is a single-nucleotide change that makes a human mitochondrial rRNA resemble a bacterial one, and species diverge at exactly that sequence, so an animal ribosome carrying the human substitution is not obviously the same object. A knock-in that reproduced the human hypersusceptibility would be the thing worth having, and the deep-research sweep for this entry did not surface a widely used line that does - stated that way because it is a limit of the search rather than a demonstrated absence. The consequence for reading the rest of the entry: every mechanistic step downstream of drug binding is supported by wild-type animal or in-vitro work plus human clinical observation, and none of it is supported by an animal that carries the variant.
Is there any way to protect a carrier who must receive an aminoglycoside?
KNOWLEDGE GAP aihl_otoprotection_when_avoidance_impossible
Attached to
treatments#
Avoidance fails when there is no adequate alternative - multidrug-resistant tuberculosis and some neonatal sepsis are the standing examples. No otoprotectant is approved for aminoglycoside ototoxicity. Sodium thiosulfate is approved for cisplatin ototoxicity in children, which is a different drug with a partly shared oxidative mechanism, and reduced-ototoxicity aminoglycosides such as apramycin remain preclinical. The entry therefore records no protective pharmacotherapy, and that absence is the gap rather than an omission.
⚙

Pathophysiology

7
MT-RNR1 12S rRNA Decoding-Site Variant
A homoplasmic or near-homoplasmic substitution in the mitochondrially encoded 12S rRNA, most commonly m.1555A>G and less commonly m.1494C>T, both of which fall in the decoding region of the small subunit.
Downstream
Bacterial-Like Conformation of the Mitoribosomal Decoding Site
Show evidence (1 reference)
PMID:17698299 SUPPORT Human Clinical
"Sequence analysis of the complete mitochondrial genomes in these pedigrees showed the presence of the deafness-associated 12S rRNA C1494T mutation"
Identifies the second recurrent 12S rRNA decoding-site variant in maternally transmitted aminoglycoside-induced deafness.
Bacterial-Like Conformation of the Mitoribosomal Decoding Site
The variant remodels the 12S rRNA decoding site so that it more closely resembles the bacterial 16S rRNA A site. This is the whole mechanism in one step: aminoglycosides are selective antibacterials only because the human mitoribosome normally differs from the bacterial ribosome at this position, and the variant erases that difference.
Downstream
Aminoglycoside Binding to the Mitochondrial Ribosome The altered site is necessary but not sufficient - binding additionally requires that the drug be administered.
Show evidence (1 reference)
PMID:20301595 SUPPORT Other
"Pathogenic variants in MT-RNR1 can be associated with predisposition to aminoglycoside ototoxicity"
PARTIAL because the chapter states the predisposition without describing the structural basis; the 16S-mimicry step is the mechanistic reading.
Aminoglycoside Binding to the Mitochondrial Ribosome
Drug occupies the altered decoding site. This node is the point at which the environmental exposure enters the pathograph, and nothing downstream of it happens in an unexposed carrier.
Downstream
Impaired Mitochondrial Translation
Impaired Mitochondrial Translation
Drug occupancy of the decoding site inhibits and misdirects synthesis of the mitochondrially encoded oxidative phosphorylation subunits, in the same way aminoglycosides act on the bacterial ribosome.
mitochondrial translation GO:0032543 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitochondrial translation (GO:0032543). GO:0032543 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Cochlear Hair Cell Mitochondrial Injury and Oxidative Stress
Cochlear Hair Cell Mitochondrial Injury and Oxidative Stress
Loss of OXPHOS subunit synthesis collapses mitochondrial function in hair cells and generates reactive oxygen species. Hair cells are the vulnerable population because of their high and sustained metabolic demand.
cochlear outer hair cell CL:0000601 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear outer hair cell (CL:0000601). CL:0000601 is a cell type from the Cell Ontology. cochlear inner hair cell CL:0000589 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear inner hair cell (CL:0000589). CL:0000589 is a cell type from the Cell Ontology.
cellular response to oxidative stress GO:0034599 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cellular response to oxidative stress (GO:0034599). GO:0034599 is a biological process from the Gene Ontology. ↑ INCREASED
spiral organ of cochlea (organ of Corti) UBERON:0002227 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in spiral organ of cochlea (organ of Corti), annotated with spiral organ of cochlea (UBERON:0002227). UBERON:0002227 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Cochlear Hair Cell Death
Cochlear Hair Cell Death
Hair cells die by intrinsic apoptosis with a contribution from regulated necrosis. Loss follows a base-to-apex gradient, so the high-frequency-encoding basal turn goes first - which is what gives the audiogram its characteristic downward-sloping shape before speech frequencies are involved. Mammalian cochlear hair cells do not regenerate, which is why the deficit is permanent.
intrinsic apoptotic signaling pathway GO:0097193 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased intrinsic apoptotic signaling pathway (GO:0097193). GO:0097193 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Irreversible Bilateral Sensorineural Hearing Loss
Irreversible Bilateral Sensorineural Hearing Loss
Bilateral, severe-to-profound, permanent sensorineural loss appearing days to weeks after exposure.
Show evidence (1 reference)
PMID:20301595 SUPPORT Other
"Hearing loss associated with aminoglycoside ototoxicity is bilateral and severe to profound, occurring within a few days to weeks after administration of any amount (even a single dose) of an aminoglycoside antibiotic"
GeneReviews Clinical Characteristics gives the laterality, severity, latency, and the dose-independence that defines this presentation.
⬡

Pathograph

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

Phenotypes

2
Bilateral Sensorineural Hearing Loss VERY_FREQUENT Auditory HP:0008619 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral sensorineural hearing impairment (HP:0008619), qualified as severity severe. HP:0008619 is a phenotype from the Human Phenotype Ontology.
Severity: SEVERE
Show evidence (1 reference)
PMID:20301595 SUPPORT Other
"Hearing loss associated with aminoglycoside ototoxicity is bilateral and severe to profound"
States laterality and severity directly.
High-Frequency Predominant Loss FREQUENT Auditory HP:0001757 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High-frequency sensorineural hearing impairment (HP:0001757). HP:0001757 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17698299 SUPPORT Human Clinical
"Clinical evaluation revealed the wide range of severity, age-at-onset and audiometric configuration of hearing impairment in matrilineal relatives in these families"
PARTIAL because the paper documents variable audiometric configuration across carriers rather than establishing a high-frequency-first pattern specifically.
🧬

Genetic Associations

2
MT-RNR1
Gene: MT-RNR1 hgnc:7470 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MT-RNR1 (hgnc:7470). hgnc:7470 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:37314952 SUPPORT Other
"Aminoglycoside antibiotic exposure can result in ototoxicity and irreversible hearing loss among individuals that harbor the m.1555A>G variant in the mitochondrial 12S rRNA gene, MT-RNR1"
Names the gene, the variant, and the exposure dependency together.
Variants (3)
m.1555A>G
The most common and first-identified predisposing variant, in a highly conserved region of the 12S rRNA. CPIC-actionable.
Show evidence (1 reference)
PMID:34032273 SUPPORT Other
"Some MT-RNR1 variants (i.e., m.1095T>C; m.1494C>T; m.1555A>G) more closely resemble the bacterial 16s rRNA subunit and result in increased risk of aminoglycoside-induced hearing loss."
CPIC names the three actionable variants and states the structural basis they share.
m.1494C>T
The second decoding-site variant, documented in maternally transmitted pedigrees. CPIC-actionable.
Show evidence (1 reference)
PMID:34032273 SUPPORT Other
"additional variants with sufficient evidence to support a drug-variant interaction are m.1095T>C and m.1494C>T"
CPIC states the evidence basis for treating this variant as actionable alongside m.1555A>G.
m.1095T>C
The third CPIC-actionable variant. Carriers receive the same avoidance recommendation as the other two, so an actionable-variant list that omits it is incomplete for prescribing purposes.
Show evidence (1 reference)
PMID:34032273 SUPPORT Other
"additional variants with sufficient evidence to support a drug-variant interaction are m.1095T>C and m.1494C>T"
Establishes m.1095T>C as carrying sufficient evidence for prescribing guidance.
TRMU
Gene: TRMU hgnc:25481 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TRMU (hgnc:25481). hgnc:25481 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: MODIFIER
Show evidence (1 reference)
PMID:17698299 SUPPORT Human Clinical
"aminoglycosides and other nuclear modifier genes play a modifying role in the phenotypic manifestation of the C1494T mutation in these Chinese families"
Establishes that nuclear modifiers act on penetrance alongside the drug.
💊

Medical Actions

3
Avoidance of Aminoglycoside Antibiotics
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Substituting a non-aminoglycoside agent in a known carrier. This is the only intervention that prevents the disease rather than managing its result, and it is the reason genotype matters clinically. Noise exposure is avoided on the same grounds.
Mechanism Target:
INHIBITS Aminoglycoside Binding to the Mitochondrial Ribosome — Withholding the drug removes the ligand, so the pathway is never entered. It does nothing to the underlying variant.
Show evidence (3 references)
PMID:20301595 SUPPORT Other
"Agents/circumstances to avoid: Aminoglycosides and noise exposure, especially in those with normal hearing who have the m.1555A>G or m.1494C>T MT-RNR1 pathogenic variants."
GeneReviews names both the drug class and noise as exposures to avoid, and singles out the still-normal-hearing carrier as the person to protect.
PMID:34032273 SUPPORT Other
"Use of aminoglycosides should be avoided in individuals with an MT-RNR1 variant associated with an increased risk of aminoglycoside-induced hearing loss unless the high risk of permanent hearing loss is outweighed by the severity of infection and safe or effective alternative therapies are not available"
The CPIC prescribing recommendation itself, including the exception that makes it a risk-benefit judgement rather than an absolute bar.
PMID:34032273 SUPPORT Other
"the advice to avoid aminoglycosides should be cascaded to the relevant individuals within the family"
CPIC extends the avoidance from the individual to the matriline, which is what makes cascade testing a preventive act rather than bookkeeping.
Hearing Amplification and Cochlear Implantation
Action: hearing amplification and cochlear implantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hearing amplification and cochlear implantation, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Rehabilitation once loss has occurred. Nothing restores dead hair cells, so this is compensation rather than treatment of the mechanism.
Mechanism Target:
MODULATES Irreversible Bilateral Sensorineural Hearing Loss — Compensates for the sensory deficit; it does not act on hair cell survival.
Show evidence (1 reference)
PMID:20301595 SUPPORT Other
"Treatment of manifestations: Appropriate rehabilitation (hearing aids, speech therapy, culturally appropriate language training, cochlear implantation, educational programs for the hearing impaired)."
GeneReviews Management lists the rehabilitative options.
Genetic Counseling and Matrilineal Cascade Testing
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Because transmission is maternal, testing the proband's maternal relatives converts one diagnosis into protection for a whole matriline of people who are still normal-hearing.
Mechanism Target:
INHIBITS Aminoglycoside Binding to the Mitochondrial Ribosome — Identifies at-risk relatives before any exposure occurs.
Show evidence (1 reference)
PMID:20301595 SUPPORT Other
"Evaluation of relatives at risk: Molecular genetic testing of at-risk maternal relatives allows for early detection of those who have inherited the mtDNA pathogenic variant and would benefit from avoiding aminoglycosides"
GeneReviews Evaluation of relatives states the cascade-testing rationale.
🌍

Environmental Factors

1
Systemic aminoglycoside antibiotic administration
exposure to aminoglycoside antibiotic Relation: this environmental factor is this exposure This environmental factor is exposure to aminoglycoside antibiotic.
Therapeutic exposure to gentamicin, tobramycin, amikacin, kanamycin or streptomycin. In a carrier this is not a dose-related risk but a threshold event, which is why ordinary therapeutic drug monitoring does not protect against it.
Show evidence (1 reference)
PMID:34015383 SUPPORT Human Clinical
"aminoglycoside use results in high prevalence of ototoxic hearing loss"
Establishes the exposure as the operative risk factor at population scale.
Mechanism Target:
TRIGGERS Aminoglycoside Binding to the Mitochondrial Ribosome — The exposure supplies the ligand for the altered decoding site. It is the second of the two hits, and the only one that is modifiable.
Show evidence (1 reference)
PMID:20301595 SUPPORT Other
"occurring within a few days to weeks after administration of any amount (even a single dose) of an aminoglycoside antibiotic such as gentamycin, tobramycin, amikacin, kanamycin, or streptomycin"
Names the triggering exposure and the drugs that carry it, and states that any amount suffices.
🔬

Diagnosis

3
MT-RNR1 Genotyping
Targeted testing for m.1555A>G and m.1494C>T. Diagnostic after the fact, but the reason to do it is pre-emptive.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:20301595 SUPPORT Other
"is established in a proband with hearing loss and identification of a pathogenic variant in MT-RNR1 or MT-TS1"
GeneReviews Diagnosis states the molecular basis of diagnosis.
Point-of-Care m.1555A>G Genotyping Before Antibiotic Choice
A rapid bedside assay returning a genotype in about 26 minutes, fast enough to sit inside the window in which empirical antibiotics for suspected neonatal sepsis must be started. This is the step that turns a known risk into an avoided one: conventional genotyping takes days and therefore cannot inform the prescription it is meant to change.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:35311942 SUPPORT Human Clinical
"The MT-RNR1 POCT was able to genotype the m.1555A>G variant in 26 minutes."
Gives the turnaround time that makes pre-prescription genotyping feasible.
PMID:35311942 SUPPORT Human Clinical
"Three participants with the m.1555A>G variant were identified, all of whom avoided aminoglycoside antibiotics."
Demonstrates the test changing prescribing in carriers, which is the clinical endpoint that matters.
Audiometric Surveillance
Annual audiometry in known carriers and after any exposure.
audiometric test NCIT:C38036 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:20301595 SUPPORT Other
"Surveillance: Annual audiometric assessment to evaluate stability/progression of hearing loss."
GeneReviews Surveillance sets the interval.
📊

Prevalence

2
United Kingdom, British 1958 birth cohort (m.1555A>G carriers)
Carrier Frequency 260.0 per 100,000 >1 in 1,000
Carrier frequency of the predisposing genotype, not of hearing loss. Unbiased population ascertainment rather than referral-based, which matters because family-based series over-represent penetrant matrilines.
Show evidence (1 reference)
PMID:22223843 SUPPORT Human Clinical
"19 of 7350 individuals successfully genotyped had the m.1555A>G mutation, giving a prevalence of 0.26% (95% CI 0.14% to 0.38%) or 1 in 385"
Gives the carrier frequency with its confidence interval in an unselected birth cohort.
Drug-resistant tuberculosis patients treated with aminoglycosides (pooled, 10 countries)
Period Prevalence 40620.0 per 100,000 >1 in 1,000
Occurrence of ototoxic hearing loss among exposed patients, most of whom will not carry an MT-RNR1 variant - this is the dose-dependent toxicity of the drug class rather than the Mendelian susceptibility this entry curates. Recorded to keep the two apart.
Show evidence (1 reference)
PMID:34015383 SUPPORT Human Clinical
"Pooled prevalence of ototoxic hearing loss and the corresponding 95% confidence interval (CI) was 40.62% CI [32.77- 66.61%] for all drugs"
Meta-analytic prevalence of hearing loss among aminoglycoside-exposed DR-TB patients.
{ }

Source YAML

click to show 
name: Aminoglycoside-Induced Hearing Loss
creation_date: "2026-08-27T06:05:00Z"
category: Mendelian
description: >-
  Aminoglycoside-induced hearing loss in its Mendelian form is a gene-environment
  disease: a maternally inherited variant in the mitochondrial 12S rRNA gene MT-RNR1
  - most often m.1555A>G, less often m.1494C>T - reshapes the decoding site of the
  mitochondrial small ribosomal subunit so that it resembles the bacterial 16S rRNA
  site that aminoglycosides were designed to bind. The variant is silent on its own.
  What converts it into deafness is exposure to the drug, and the resulting hearing
  loss is bilateral, severe to profound, irreversible, and idiosyncratic rather than
  dose-dependent: a single conventional dose is sufficient. That combination is what
  makes the disease unusual among Mendelian conditions - the genotype is common
  (roughly 1 in 385 in a UK birth cohort), the exposure is routine, and the outcome
  is entirely preventable if the two are kept apart.

  Because the variant is carried on mitochondrial DNA, transmission is maternal, so
  identifying one affected person places an entire matriline at risk. The clinical
  consequence is that this entry's most important treatment is not a drug but an
  avoidance: substituting a non-aminoglycoside antibiotic when the genotype is known.
  The practical obstacle has been time - aminoglycosides are first-line for suspected
  neonatal sepsis and are given within hours, while conventional genotyping takes
  days - which is why point-of-care testing that returns a result inside half an hour
  is curated here as the intervention that makes the avoidance actionable.
disease_term:
  preferred_term: deafness, aminoglycoside-induced
  term:
    id: MONDO:0010799
    label: deafness, aminoglycoside-induced
synonyms:
- aminoglycoside-induced deafness
- maternally inherited aminoglycoside-induced deafness
- mitochondrial isolated sensorineural deafness with susceptibility to aminoglycoside exposure
parents:
- Mitochondrial Disease
- Sensorineural Hearing Loss
inheritance:
- name: Mitochondrial (maternal) inheritance
  inheritance_term:
    preferred_term: Mitochondrial inheritance
    term:
      id: HP:0001427
      label: Mitochondrial inheritance
  description: >-
    MT-RNR1 is mitochondrially encoded, so the predisposing variant is transmitted
    only by mothers, to all of their children. A single index case therefore identifies
    a whole matriline whose members should be genotyped before any aminoglycoside is
    given.
  evidence:
  - reference: PMID:20301595
    reference_title: Nonsyndromic Hearing Loss and Deafness, Mitochondrial.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: is caused by pathogenic variants in mitochondrial DNA (mtDNA) and is transmitted
      by maternal inheritance
    explanation: GeneReviews Genetic Counseling states the mode of transmission.
pathophysiology:
- name: MT-RNR1 12S rRNA Decoding-Site Variant
  biological_scale: MOLECULAR
  description: >-
    A homoplasmic or near-homoplasmic substitution in the mitochondrially encoded 12S
    rRNA, most commonly m.1555A>G and less commonly m.1494C>T, both of which fall in
    the decoding region of the small subunit.
  mechanism_confidence: ESTABLISHED
  downstream:
  - target: Bacterial-Like Conformation of the Mitoribosomal Decoding Site
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:17698299
    reference_title: Maternally inherited aminoglycoside-induced and nonsyndromic hearing
      loss is associated with the 12S rRNA C1494T mutation in three Han Chinese pedigrees.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sequence analysis of the complete mitochondrial genomes in these pedigrees
      showed the presence of the deafness-associated 12S rRNA C1494T mutation
    explanation: Identifies the second recurrent 12S rRNA decoding-site variant in
      maternally transmitted aminoglycoside-induced deafness.
- name: Bacterial-Like Conformation of the Mitoribosomal Decoding Site
  biological_scale: MOLECULAR
  description: >-
    The variant remodels the 12S rRNA decoding site so that it more closely resembles
    the bacterial 16S rRNA A site. This is the whole mechanism in one step: aminoglycosides
    are selective antibacterials only because the human mitoribosome normally differs
    from the bacterial ribosome at this position, and the variant erases that difference.
  mechanism_confidence: ESTABLISHED
  downstream:
  - target: Aminoglycoside Binding to the Mitochondrial Ribosome
    causal_link_type: DIRECT
    description: >-
      The altered site is necessary but not sufficient - binding additionally requires
      that the drug be administered.
  evidence:
  - reference: PMID:20301595
    reference_title: Nonsyndromic Hearing Loss and Deafness, Mitochondrial.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Pathogenic variants in MT-RNR1 can be associated with predisposition to
      aminoglycoside ototoxicity
    explanation: PARTIAL because the chapter states the predisposition without describing
      the structural basis; the 16S-mimicry step is the mechanistic reading.
- name: Aminoglycoside Binding to the Mitochondrial Ribosome
  biological_scale: MOLECULAR
  description: >-
    Drug occupies the altered decoding site. This node is the point at which the
    environmental exposure enters the pathograph, and nothing downstream of it happens
    in an unexposed carrier.
  mechanism_confidence: ESTABLISHED
  downstream:
  - target: Impaired Mitochondrial Translation
    causal_link_type: DIRECT
- name: Impaired Mitochondrial Translation
  biological_scale: MOLECULAR
  description: >-
    Drug occupancy of the decoding site inhibits and misdirects synthesis of the
    mitochondrially encoded oxidative phosphorylation subunits, in the same way
    aminoglycosides act on the bacterial ribosome.
  mechanism_confidence: ESTABLISHED
  biological_processes:
  - preferred_term: mitochondrial translation
    modifier: DECREASED
    term:
      id: GO:0032543
      label: mitochondrial translation
  downstream:
  - target: Cochlear Hair Cell Mitochondrial Injury and Oxidative Stress
    causal_link_type: DIRECT
- name: Cochlear Hair Cell Mitochondrial Injury and Oxidative Stress
  biological_scale: CELLULAR
  description: >-
    Loss of OXPHOS subunit synthesis collapses mitochondrial function in hair cells
    and generates reactive oxygen species. Hair cells are the vulnerable population
    because of their high and sustained metabolic demand.
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  biological_processes:
  - preferred_term: cellular response to oxidative stress
    modifier: INCREASED
    term:
      id: GO:0034599
      label: cellular response to oxidative stress
  locations:
  - preferred_term: spiral organ of cochlea (organ of Corti)
    term:
      id: UBERON:0002227
      label: spiral organ of cochlea
  downstream:
  - target: Cochlear Hair Cell Death
    causal_link_type: DIRECT
- name: Cochlear Hair Cell Death
  biological_scale: CELLULAR
  description: >-
    Hair cells die by intrinsic apoptosis with a contribution from regulated necrosis.
    Loss follows a base-to-apex gradient, so the high-frequency-encoding basal turn
    goes first - which is what gives the audiogram its characteristic downward-sloping
    shape before speech frequencies are involved. Mammalian cochlear hair cells do
    not regenerate, which is why the deficit is permanent.
  mechanism_confidence: ESTABLISHED
  biological_processes:
  - preferred_term: intrinsic apoptotic signaling pathway
    modifier: INCREASED
    term:
      id: GO:0097193
      label: intrinsic apoptotic signaling pathway
  downstream:
  - target: Irreversible Bilateral Sensorineural Hearing Loss
    causal_link_type: DIRECT
- name: Irreversible Bilateral Sensorineural Hearing Loss
  biological_scale: ORGANISM
  description: >-
    Bilateral, severe-to-profound, permanent sensorineural loss appearing days to weeks
    after exposure.
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:20301595
    reference_title: Nonsyndromic Hearing Loss and Deafness, Mitochondrial.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Hearing loss associated with aminoglycoside ototoxicity is bilateral and
      severe to profound, occurring within a few days to weeks after administration
      of any amount (even a single dose) of an aminoglycoside antibiotic
    explanation: GeneReviews Clinical Characteristics gives the laterality, severity,
      latency, and the dose-independence that defines this presentation.
environmental:
- name: Systemic aminoglycoside antibiotic administration
  description: >-
    Therapeutic exposure to gentamicin, tobramycin, amikacin, kanamycin or streptomycin.
    In a carrier this is not a dose-related risk but a threshold event, which is why
    ordinary therapeutic drug monitoring does not protect against it.
  exposure_term:
    preferred_term: exposure to aminoglycoside antibiotic
  influences_mechanisms:
  - target: Aminoglycoside Binding to the Mitochondrial Ribosome
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      The exposure supplies the ligand for the altered decoding site. It is the second
      of the two hits, and the only one that is modifiable.
    evidence:
    - reference: PMID:20301595
      reference_title: Nonsyndromic Hearing Loss and Deafness, Mitochondrial.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: occurring within a few days to weeks after administration of any amount
        (even a single dose) of an aminoglycoside antibiotic such as gentamycin, tobramycin,
        amikacin, kanamycin, or streptomycin
      explanation: Names the triggering exposure and the drugs that carry it, and states
        that any amount suffices.
  evidence:
  - reference: PMID:34015383
    reference_title: 'Prevalence of aminoglycoside-induced hearing loss in drug-resistant
      tuberculosis patients: A systematic review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: aminoglycoside use results in high prevalence of ototoxic hearing loss
    explanation: Establishes the exposure as the operative risk factor at population
      scale.
phenotypes:
- category: Auditory
  name: Bilateral Sensorineural Hearing Loss
  frequency: VERY_FREQUENT
  description: >-
    The defining feature: bilateral, severe to profound, and permanent.
  phenotype_term:
    preferred_term: Bilateral sensorineural hearing impairment
    term:
      id: HP:0008619
      label: Bilateral sensorineural hearing impairment
    severity: SEVERE
  evidence:
  - reference: PMID:20301595
    reference_title: Nonsyndromic Hearing Loss and Deafness, Mitochondrial.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Hearing loss associated with aminoglycoside ototoxicity is bilateral and
      severe to profound
    explanation: States laterality and severity directly.
- category: Auditory
  name: High-Frequency Predominant Loss
  frequency: FREQUENT
  description: >-
    Loss begins at high frequencies, mirroring the base-to-apex gradient of hair cell
    death, and can be detected by extended high-frequency audiometry before the patient
    notices any difficulty with speech.
  phenotype_term:
    preferred_term: High-frequency sensorineural hearing impairment
    term:
      id: HP:0001757
      label: High-frequency sensorineural hearing impairment
  evidence:
  - reference: PMID:17698299
    reference_title: Maternally inherited aminoglycoside-induced and nonsyndromic hearing
      loss is associated with the 12S rRNA C1494T mutation in three Han Chinese pedigrees.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical evaluation revealed the wide range of severity, age-at-onset and
      audiometric configuration of hearing impairment in matrilineal relatives in these
      families
    explanation: PARTIAL because the paper documents variable audiometric configuration
      across carriers rather than establishing a high-frequency-first pattern specifically.
genetic:
- name: MT-RNR1
  gene_term:
    preferred_term: MT-RNR1
    term:
      id: hgnc:7470
      label: MT-RNR1
  relationship_type: CAUSATIVE
  notes: >-
    The primary locus. m.1555A>G is the most common allele and m.1494C>T the next;
    both sit in the 12S rRNA decoding region. Note that MONDO records TRMU rather than
    MT-RNR1 as the causal gene for MONDO:0010799 under RO:0004003, which appears to
    reflect the difficulty of representing mitochondrially encoded loci rather than a
    claim that TRMU is primary - OMIM 580000, the entity MONDO maps to, is the MT-RNR1
    locus.
  variants:
  - name: m.1555A>G
    description: >-
      The most common and first-identified predisposing variant, in a highly conserved
      region of the 12S rRNA. CPIC-actionable.
    evidence:
    - reference: PMID:34032273
      reference_title: Clinical Pharmacogenetics Implementation Consortium Guideline for the Use of Aminoglycosides Based on MT-RNR1 Genotype.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'Some MT-RNR1 variants (i.e., m.1095T>C; m.1494C>T; m.1555A>G) more closely
        resemble the bacterial 16s rRNA subunit and result in increased risk of aminoglycoside-induced
        hearing loss.'
      explanation: CPIC names the three actionable variants and states the structural
        basis they share.
  - name: m.1494C>T
    description: >-
      The second decoding-site variant, documented in maternally transmitted pedigrees.
      CPIC-actionable.
    evidence:
    - reference: PMID:34032273
      reference_title: Clinical Pharmacogenetics Implementation Consortium Guideline for the Use of Aminoglycosides Based on MT-RNR1 Genotype.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: additional variants with sufficient evidence to support a drug-variant
        interaction are m.1095T>C and m.1494C>T
      explanation: CPIC states the evidence basis for treating this variant as actionable
        alongside m.1555A>G.
  - name: m.1095T>C
    description: >-
      The third CPIC-actionable variant. Carriers receive the same avoidance
      recommendation as the other two, so an actionable-variant list that omits it is
      incomplete for prescribing purposes.
    evidence:
    - reference: PMID:34032273
      reference_title: Clinical Pharmacogenetics Implementation Consortium Guideline for the Use of Aminoglycosides Based on MT-RNR1 Genotype.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: additional variants with sufficient evidence to support a drug-variant
        interaction are m.1095T>C and m.1494C>T
      explanation: Establishes m.1095T>C as carrying sufficient evidence for prescribing
        guidance.
  evidence:
  - reference: PMID:37314952
    reference_title: Clinical Pharmacogenomic MT-RNR1 Screening for Aminoglycoside-Induced
      Ototoxicity and the Post-Test Counseling Conundrum.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Aminoglycoside antibiotic exposure can result in ototoxicity and irreversible
      hearing loss among individuals that harbor the m.1555A>G variant in the mitochondrial
      12S rRNA gene, MT-RNR1
    explanation: Names the gene, the variant, and the exposure dependency together.
- name: TRMU
  gene_term:
    preferred_term: TRMU
    term:
      id: hgnc:25481
      label: TRMU
  relationship_type: MODIFIER
  notes: >-
    Nuclear modifier of penetrance rather than a cause. Curated because it is the gene
    MONDO carries for this concept, and because penetrance modification is the open
    question for the unexposed carrier.
  evidence:
  - reference: PMID:17698299
    reference_title: Maternally inherited aminoglycoside-induced and nonsyndromic hearing
      loss is associated with the 12S rRNA C1494T mutation in three Han Chinese pedigrees.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: aminoglycosides and other nuclear modifier genes play a modifying role in
      the phenotypic manifestation of the C1494T mutation in these Chinese families
    explanation: Establishes that nuclear modifiers act on penetrance alongside the drug.
prevalence:
- population: United Kingdom, British 1958 birth cohort (m.1555A>G carriers)
  measure_type: CARRIER_FREQUENCY
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 260.0
  notes: >-
    Carrier frequency of the predisposing genotype, not of hearing loss. Unbiased
    population ascertainment rather than referral-based, which matters because
    family-based series over-represent penetrant matrilines.
  evidence:
  - reference: PMID:22223843
    reference_title: 'Hearing in 44-45 year olds with m.1555A>G, a genetic mutation
      predisposing to aminoglycoside-induced deafness: a population based cohort study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 19 of 7350 individuals successfully genotyped had the m.1555A>G mutation,
      giving a prevalence of 0.26% (95% CI 0.14% to 0.38%) or 1 in 385
    explanation: Gives the carrier frequency with its confidence interval in an unselected
      birth cohort.
- population: Drug-resistant tuberculosis patients treated with aminoglycosides (pooled, 10 countries)
  measure_type: PERIOD_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 40620.0
  notes: >-
    Occurrence of ototoxic hearing loss among exposed patients, most of whom will not
    carry an MT-RNR1 variant - this is the dose-dependent toxicity of the drug class
    rather than the Mendelian susceptibility this entry curates. Recorded to keep the
    two apart.
  evidence:
  - reference: PMID:34015383
    reference_title: 'Prevalence of aminoglycoside-induced hearing loss in drug-resistant
      tuberculosis patients: A systematic review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Pooled prevalence of ototoxic hearing loss and the corresponding 95% confidence
      interval (CI) was 40.62% CI [32.77- 66.61%] for all drugs
    explanation: Meta-analytic prevalence of hearing loss among aminoglycoside-exposed
      DR-TB patients.
diagnosis:
- name: MT-RNR1 Genotyping
  description: >-
    Targeted testing for m.1555A>G and m.1494C>T. Diagnostic after the fact, but the
    reason to do it is pre-emptive.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:20301595
    reference_title: Nonsyndromic Hearing Loss and Deafness, Mitochondrial.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: is established in a proband with hearing loss and identification of a pathogenic
      variant in MT-RNR1 or MT-TS1
    explanation: GeneReviews Diagnosis states the molecular basis of diagnosis.
- name: Point-of-Care m.1555A>G Genotyping Before Antibiotic Choice
  description: >-
    A rapid bedside assay returning a genotype in about 26 minutes, fast enough to
    sit inside the window in which empirical antibiotics for suspected neonatal sepsis
    must be started. This is the step that turns a known risk into an avoided one:
    conventional genotyping takes days and therefore cannot inform the prescription
    it is meant to change.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:35311942
    reference_title: Rapid Point-of-Care Genotyping to Avoid Aminoglycoside-Induced Ototoxicity
      in Neonatal Intensive Care.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The MT-RNR1 POCT was able to genotype the m.1555A>G variant in 26 minutes.
    explanation: Gives the turnaround time that makes pre-prescription genotyping feasible.
  - reference: PMID:35311942
    reference_title: Rapid Point-of-Care Genotyping to Avoid Aminoglycoside-Induced Ototoxicity
      in Neonatal Intensive Care.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Three participants with the m.1555A>G variant were identified, all of whom
      avoided aminoglycoside antibiotics.
    explanation: Demonstrates the test changing prescribing in carriers, which is the
      clinical endpoint that matters.
- name: Audiometric Surveillance
  description: >-
    Annual audiometry in known carriers and after any exposure.
  diagnosis_term:
    preferred_term: audiometric test
    term:
      id: NCIT:C38036
      label: Audiometric Test
  evidence:
  - reference: PMID:20301595
    reference_title: Nonsyndromic Hearing Loss and Deafness, Mitochondrial.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'Surveillance: Annual audiometric assessment to evaluate stability/progression
      of hearing loss.'
    explanation: GeneReviews Surveillance sets the interval.
treatments:
- name: Avoidance of Aminoglycoside Antibiotics
  therapeutic_modality: OTHER
  description: >-
    Substituting a non-aminoglycoside agent in a known carrier. This is the only
    intervention that prevents the disease rather than managing its result, and it is
    the reason genotype matters clinically. Noise exposure is avoided on the same
    grounds.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Aminoglycoside Binding to the Mitochondrial Ribosome
    treatment_effect: INHIBITS
    description: >-
      Withholding the drug removes the ligand, so the pathway is never entered. It does
      nothing to the underlying variant.
  evidence:
  - reference: PMID:20301595
    reference_title: Nonsyndromic Hearing Loss and Deafness, Mitochondrial.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'Agents/circumstances to avoid: Aminoglycosides and noise exposure, especially
      in those with normal hearing who have the m.1555A>G or m.1494C>T MT-RNR1 pathogenic
      variants.'
    explanation: GeneReviews names both the drug class and noise as exposures to avoid,
      and singles out the still-normal-hearing carrier as the person to protect.
  - reference: PMID:34032273
    reference_title: Clinical Pharmacogenetics Implementation Consortium Guideline for the Use of Aminoglycosides Based on MT-RNR1 Genotype.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Use of aminoglycosides should be avoided in individuals with an MT-RNR1 variant
      associated with an increased risk of aminoglycoside-induced hearing loss unless
      the high risk of permanent hearing loss is outweighed by the severity of infection
      and safe or effective alternative therapies are not available
    explanation: The CPIC prescribing recommendation itself, including the exception that
      makes it a risk-benefit judgement rather than an absolute bar.
  - reference: PMID:34032273
    reference_title: Clinical Pharmacogenetics Implementation Consortium Guideline for the Use of Aminoglycosides Based on MT-RNR1 Genotype.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: the advice to avoid aminoglycosides should be cascaded to the relevant individuals
      within the family
    explanation: CPIC extends the avoidance from the individual to the matriline, which
      is what makes cascade testing a preventive act rather than bookkeeping.
- name: Hearing Amplification and Cochlear Implantation
  therapeutic_modality: DEVICE
  description: >-
    Rehabilitation once loss has occurred. Nothing restores dead hair cells, so this
    is compensation rather than treatment of the mechanism.
  treatment_term:
    preferred_term: hearing amplification and cochlear implantation
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Irreversible Bilateral Sensorineural Hearing Loss
    treatment_effect: MODULATES
    description: >-
      Compensates for the sensory deficit; it does not act on hair cell survival.
  evidence:
  - reference: PMID:20301595
    reference_title: Nonsyndromic Hearing Loss and Deafness, Mitochondrial.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'Treatment of manifestations: Appropriate rehabilitation (hearing aids,
      speech therapy, culturally appropriate language training, cochlear implantation,
      educational programs for the hearing impaired).'
    explanation: GeneReviews Management lists the rehabilitative options.
- name: Genetic Counseling and Matrilineal Cascade Testing
  therapeutic_modality: OTHER
  description: >-
    Because transmission is maternal, testing the proband's maternal relatives converts
    one diagnosis into protection for a whole matriline of people who are still
    normal-hearing.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  target_mechanisms:
  - target: Aminoglycoside Binding to the Mitochondrial Ribosome
    treatment_effect: INHIBITS
    description: >-
      Identifies at-risk relatives before any exposure occurs.
  evidence:
  - reference: PMID:20301595
    reference_title: Nonsyndromic Hearing Loss and Deafness, Mitochondrial.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'Evaluation of relatives at risk: Molecular genetic testing of at-risk maternal
      relatives allows for early detection of those who have inherited the mtDNA pathogenic
      variant and would benefit from avoiding aminoglycosides'
    explanation: GeneReviews Evaluation of relatives states the cascade-testing rationale.
discussions:
- discussion_id: aihl_penetrance_without_exposure
  kind: INTERPRETATION
  attaches_to:
  - pathophysiology#MT-RNR1 12S rRNA Decoding-Site Variant
  - phenotypes#Bilateral Sensorineural Hearing Loss
  prompt: Does m.1555A>G cause hearing loss on its own, or only with exposure?
  rationale: >-
    Family-based series report substantial penetrance of hearing loss in carrier
    matrilines even excluding aminoglycoside-exposed members - 14% on average across
    three Chinese pedigrees - which reads as evidence that the variant is independently
    pathogenic. An unbiased population cohort found the opposite: 19 carriers ascertained
    by genotyping the British 1958 birth cohort had hearing thresholds indistinguishable
    from non-carriers at 44-45 years.

    The discrepancy is most simply explained by ascertainment. Pedigrees come to attention
    because someone in them is deaf, so they are enriched for whatever modifiers or
    exposures made that happen; a birth cohort is not. Curated as an interpretation
    rather than a contradiction because both results can hold - the variant may be
    weakly penetrant in the presence of nuclear modifiers such as TRMU while contributing
    nothing detectable at population level.

    The practical consequence runs the other way from what "low penetrance" usually
    implies. If carriers keep normal hearing into middle age unless they are exposed,
    then the case for genotyping before prescribing gets stronger, not weaker: there is
    a long, entirely healthy window in which the disease is preventable.
  evidence:
  - reference: PMID:22223843
    reference_title: 'Hearing in 44-45 year olds with m.1555A>G, a genetic mutation
      predisposing to aminoglycoside-induced deafness: a population based cohort study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Unbiased ascertainment of mutation carriers provides no evidence that this
      mutation alone causes non-syndromic hearing impairment in the UK.
    explanation: The population-level negative result, stated with its ascertainment
      caveat by the authors themselves.
  - reference: PMID:22223843
    reference_title: 'Hearing in 44-45 year olds with m.1555A>G, a genetic mutation
      predisposing to aminoglycoside-induced deafness: a population based cohort study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The findings lend weight to arguments for genetic testing for this mutation
      prior to aminoglycoside administration, as hearing in susceptible individuals is
      expected to be preserved well into adult life.
    explanation: The authors draw the same inference curated here - preserved baseline
      hearing strengthens rather than weakens the case for pre-emptive testing.
  - reference: PMID:17698299
    reference_title: Maternally inherited aminoglycoside-induced and nonsyndromic hearing
      loss is associated with the 12S rRNA C1494T mutation in three Han Chinese pedigrees.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: When the effect of aminoglycosides was excluded, the penetrances of hearing
      loss in these seven pedigrees were 21%, 13% and 8%, with an average of 14%.
    explanation: The pedigree-based figure that the population study appears to contradict;
      PARTIAL because it supports one side of the interpretation rather than the whole.
- discussion_id: aihl_no_genotype_specific_animal_model
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - pathophysiology#Bacterial-Like Conformation of the Mitoribosomal Decoding Site
  - pathophysiology#Cochlear Hair Cell Death
  prompt: Can the genotype-specific susceptibility be modelled in an animal at all?
  rationale: >-
    This entry curates no animal model, and the reason is worth stating rather than
    leaving as a blank section. Animal work on aminoglycoside ototoxicity is extensive -
    zebrafish lateral-line hair cells resolve the death pathways, guinea pig cochlear
    explants rank congeners by toxicity - but it is done in wild-type animals and models
    the general drug-mitoribosome-hair-cell mechanism, not the human genetic
    susceptibility.

    The obstacle is intrinsic to the lesion. The disease is a single-nucleotide change
    that makes a human mitochondrial rRNA resemble a bacterial one, and species diverge
    at exactly that sequence, so an animal ribosome carrying the human substitution is
    not obviously the same object. A knock-in that reproduced the human hypersusceptibility
    would be the thing worth having, and the deep-research sweep for this entry did not
    surface a widely used line that does - stated that way because it is a limit of the
    search rather than a demonstrated absence.

    The consequence for reading the rest of the entry: every mechanistic step downstream
    of drug binding is supported by wild-type animal or in-vitro work plus human clinical
    observation, and none of it is supported by an animal that carries the variant.
- discussion_id: aihl_otoprotection_when_avoidance_impossible
  kind: KNOWLEDGE_GAP
  attaches_to:
  - treatments#
  prompt: Is there any way to protect a carrier who must receive an aminoglycoside?
  rationale: >-
    Avoidance fails when there is no adequate alternative - multidrug-resistant
    tuberculosis and some neonatal sepsis are the standing examples. No otoprotectant
    is approved for aminoglycoside ototoxicity. Sodium thiosulfate is approved for
    cisplatin ototoxicity in children, which is a different drug with a partly shared
    oxidative mechanism, and reduced-ototoxicity aminoglycosides such as apramycin
    remain preclinical. The entry therefore records no protective pharmacotherapy,
    and that absence is the gap rather than an omission.
references:
- reference: PMID:20301595
  title: Nonsyndromic Hearing Loss and Deafness, Mitochondrial.
  tags:
  - GeneReviews
- reference: PMID:22223843
  title: 'Hearing in 44-45 year olds with m.1555A>G, a genetic mutation predisposing
    to aminoglycoside-induced deafness: a population based cohort study.'
- reference: PMID:17698299
  title: Maternally inherited aminoglycoside-induced and nonsyndromic hearing loss is
    associated with the 12S rRNA C1494T mutation in three Han Chinese pedigrees.
- reference: PMID:34015383
  title: 'Prevalence of aminoglycoside-induced hearing loss in drug-resistant tuberculosis
    patients: A systematic review.'
- reference: PMID:35311942
  title: Rapid Point-of-Care Genotyping to Avoid Aminoglycoside-Induced Ototoxicity in
    Neonatal Intensive Care.
- reference: PMID:34032273
  title: Clinical Pharmacogenetics Implementation Consortium Guideline for the Use of
    Aminoglycosides Based on MT-RNR1 Genotype.
- reference: PMID:37314952
  title: Clinical Pharmacogenomic MT-RNR1 Screening for Aminoglycoside-Induced Ototoxicity
    and the Post-Test Counseling Conundrum.
notes: >-
  Scope. This entry curates the Mendelian, MT-RNR1-dependent susceptibility, in which
  an ordinary dose deafens a carrier. Aminoglycosides also cause dose- and
  duration-dependent ototoxicity in people with no MT-RNR1 variant, which is a
  pharmacological toxicity rather than this disease; the drug-resistant tuberculosis
  prevalence record is included and explicitly labelled so the two are not conflated.

  Vestibulotoxicity is deliberately not curated as a phenotype. Aminoglycosides are
  vestibulotoxic as well as cochleotoxic, but that toxicity is drug- and dose-dependent
  and more pronounced with streptomycin and gentamicin, which places it in the
  pharmacological toxicity this entry scopes out rather than in the MT-RNR1-dependent
  susceptibility it curates. Noted so the omission reads as a decision.

  Gene assignment. MONDO records TRMU as the causal gene for MONDO:0010799 under
  RO:0004003, and the automated Named Entity Confusion preflight therefore flagged the
  research report for mentioning MT-RNR1 45 times against TRMU 3 times. That warning is
  a false positive: OMIM 580000, the entity MONDO maps to, is the MT-RNR1 locus, and
  the OMIM identifier matches between MONDO and the report. Both genes are curated,
  with MT-RNR1 CAUSATIVE and TRMU MODIFIER.

  Exposure term left unbound. ECTO:9002231 "exposure to aminoglycoside antibiotic" is
  the exact term for this exposure and resolves in OLS, but it is absent from the local
  sqlite:obo:ecto build that term validation uses, so binding it fails. The antibiotic
  exposure terms that the local build does carry are all agrochemical - antibiotic
  pesticide, insecticide, acaricide, nematicide - and none of them describes therapeutic
  administration. Rather than bind a wrong term, the exposure is left with a free-text
  preferred_term; environmental-term-audit will classify it PARTIAL. Refreshing the ECTO
  build would let it be bound as-is.

  Ontology corrections. Nine of the nineteen CURIEs the research report suggested were
  wrong or obsolete and were corrected against OLS before use. The consequential one
  was CHEBI:9334, offered as streptomycin, which is sulfasalazine; also wrong were
  CL:0000598 (offered as inner hair cell, is pyramidal neuron), CL:0000211 (offered as
  vestibular hair cell, is electrically active cell), UBERON:0005988 (offered as organ
  of Corti, is atrium myocardial trabecula), UBERON:0009663 (offered as spiral ganglion,
  is telencephalic nucleus), UBERON:0001824 (offered as vestibular organ, is mucosa of
  larynx), UBERON:0001846 (offered as cochlea, is internal ear), and the obsolete
  GO:0070997 and CHEBI:41000.
📚

References & Deep Research

References

7
PMID:20301595
Nonsyndromic Hearing Loss and Deafness, Mitochondrial.
No top-level findings curated for this source.
PMID:22223843
Hearing in 44-45 year olds with m.1555A>G, a genetic mutation predisposing to aminoglycoside-induced deafness: a population based cohort study.
No top-level findings curated for this source.
PMID:17698299
Maternally inherited aminoglycoside-induced and nonsyndromic hearing loss is associated with the 12S rRNA C1494T mutation in three Han Chinese pedigrees.
No top-level findings curated for this source.
PMID:34015383
Prevalence of aminoglycoside-induced hearing loss in drug-resistant tuberculosis patients: A systematic review.
No top-level findings curated for this source.
PMID:35311942
Rapid Point-of-Care Genotyping to Avoid Aminoglycoside-Induced Ototoxicity in Neonatal Intensive Care.
No top-level findings curated for this source.
PMID:34032273
Clinical Pharmacogenetics Implementation Consortium Guideline for the Use of Aminoglycosides Based on MT-RNR1 Genotype.
No top-level findings curated for this source.
PMID:37314952
Clinical Pharmacogenomic MT-RNR1 Screening for Aminoglycoside-Induced Ototoxicity and the Post-Test Counseling Conundrum.
No top-level findings curated for this source.

Deep Research

1
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Aminoglycoside-Induced Hearing Loss (AIHL) — Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 42 citations 2026-08-27T14:24:25.412309

Aminoglycoside-Induced Hearing Loss (AIHL) — Comprehensive Research Report

1. Disease Information

Overview. Aminoglycoside-induced hearing loss (AIHL) is a form of ototoxic, mitochondrially-mediated sensorineural hearing loss (SNHL) that occurs when a person carrying a pathogenic variant in the mitochondrial 12S rRNA gene MT-RNR1 is exposed to aminoglycoside antibiotics (gentamicin, tobramycin, amikacin, streptomycin, kanamycin, neomycin). In susceptible individuals the hearing loss can be triggered by even a single, therapeutic-dose exposure and is typically bilateral, severe-to-profound, and irreversible. A separate, dose/duration-dependent form of ototoxicity also occurs in the general population (without a known MT-RNR1 variant) after cumulative or prolonged aminoglycoside courses, e.g., in cystic fibrosis (CF) or multidrug-resistant tuberculosis (MDR-TB) treatment.

Key identifiers: - OMIM: #580000 — DEAFNESS, AMINOGLYCOSIDE-INDUCED (OMIM.org) - Gene: MT-RNR1 (mitochondrial 12S rRNA), maternally inherited - GeneReviews: "Nonsyndromic Hearing Loss and Deafness, Mitochondrial" (PMID: 20301595) - ClinVar: RCV000010254/RCV000010255 (m.1555A>G); RCV001449811/RCV000010263 (m.1494C>T) - MeSH/ICD: classified under drug-induced/toxic sensorineural hearing loss (ICD-10 H91.0 Ototoxic hearing loss); MONDO term to be confirmed against the local MONDO release - Suggested MONDO search terms: "aminoglycoside-induced hearing loss," "aminoglycoside otototoxicity," "maternally inherited nonsyndromic hearing loss and deafness"

Synonyms: Aminoglycoside-induced deafness; maternally inherited aminoglycoside ototoxicity; MT-RNR1-related susceptibility to aminoglycoside ototoxicity; nonsyndromic mitochondrial deafness with aminoglycoside sensitivity.

Evidence base: Predominantly aggregated disease-level literature — pedigree studies of maternally-transmitted deafness (Prezant et al. 1993; Hutchin et al. 1993, foundational reports establishing MT-RNR1 m.1555A>G), population cohort studies (UK Biobank-linked cohort, PMID: 22223843), systematic reviews of ototoxicity in TB/CF populations, and structured pharmacogenomic guidance (CPIC). Individual EHR-level data exist mainly through CF and TB ototoxicity cohort studies.

2. Etiology

Disease Causal Factors

AIHL has two overlapping causal mechanisms: 1. Genetic (Mendelian/mitochondrial) susceptibility: A maternally inherited, usually homoplasmic, pathogenic variant in MT-RNR1 (12S rRNA) that structurally mimics bacterial 16S rRNA, allowing aminoglycosides to bind and disrupt mitochondrial ribosomal protein synthesis in cochlear hair cells upon drug exposure ("two-hit" gene-environment model). This is the classic Mendelian entry represented by OMIM #580000. 2. Non-genetic/dose-dependent ototoxicity: Cumulative aminoglycoside exposure (total dose, duration, peak/trough serum levels, concurrent nephrotoxicity) causes ototoxicity in genetically unselected patients, especially with repeated courses (CF, MDR-TB).

Genetic Risk Factors

  • MT-RNR1 m.1555A>G — the most common and best-characterized variant; population prevalence ~1 in 500 (UK) to 0.19–1.8% globally, with marked founder-effect enrichment in some populations (e.g., 20.2% in Buryat individuals of the Baikal Lake region, PMID pending; PMC: 11222474). Penetrance of hearing loss with aminoglycoside exposure is considered near-100% for homoplasmic carriers.
  • MT-RNR1 m.1494C>T — second most common variant, homoplasmic, reported in >20 Asian and 2 Spanish probands; average penetrance ~18% (range 0–77%) in the absence of documented aminoglycoside exposure, rising sharply with exposure.
  • MT-RNR1 m.1095T>C — third variant flagged by CPIC as high-risk.
  • Rarer variants at position 961 (961delT+Cn insertion, 961T>C) are also associated with nonsyndromic hearing loss with and without aminoglycoside exposure.
  • Nuclear modifier genes: TRMU (mitochondrial tRNA-modifying enzyme; A10S missense variant) modulates penetrance of m.1555A>G/m.1494C>T-associated deafness in Arab-Israeli, European, and Chinese pedigrees. Secondary mitochondrial variants (e.g., m.4394C>T tRNA-Gln, m.1584A m62A rRNA methylation site) have also been proposed as penetrance modifiers (PMC: 9602358; HMG: 617880).

Environmental/Clinical Risk Factors

  • Aminoglycoside class, dose, duration, and route (systemic vs. topical/otic) — cumulative dose is the dominant driver of non-genetic ototoxicity (CF cohorts: 4.5× higher odds of hearing loss with higher cumulative dosing).
  • Renal impairment (reduced clearance → higher serum trough levels).
  • Concurrent ototoxic drugs (loop diuretics, cisplatin/platinum chemotherapy, vancomycin).
  • Advanced age, pre-existing renal or hepatic dysfunction, prolonged treatment duration (TB regimens of 6–12 months show near-universal hearing loss in some series).
  • Noise exposure may synergize in genetically susceptible carriers even without drug exposure.

Protective Factors

  • Absence of the MT-RNR1 risk variant (genotype-guided antibiotic selection).
  • Use of alternative, non-ototoxic antimicrobials when genotype-positive.
  • Emerging "designer aminoglycosides" engineered to spare the mitochondrial ribosome (see Treatment/Prevention, §12–13).
  • Investigational otoprotectants (see below) — evidence base currently strongest for cisplatin, not aminoglycosides.

Gene-Environment Interaction

This is the defining feature of AIHL: the MT-RNR1 variant alone is often clinically silent (or produces only mild, late-onset, non-progressive/age-related hearing loss); the drug exposure is the "second hit" that converts genetic susceptibility into acute, severe, irreversible deafness. CPIC (2021, updated 2023) formalizes this as a pharmacogenomic gene-drug interaction (see §12).

3. Phenotypes

Phenotype Type Onset/Course Frequency Suggested HPO term
Bilateral sensorineural hearing loss Clinical sign Acute (hours–days) to subacute after exposure; can occur after a single dose in genotype-positive individuals Near 100% penetrance in homoplasmic m.1555A>G + exposure; ~18% baseline for m.1494C>T without exposure HP:0000407 (Sensorineural hearing impairment)
High-frequency-predominant hearing loss Clinical sign / audiometric finding Earliest detectable change (as soon as 4h post-treatment by high-frequency audiometry), progressing base-to-apex to affect speech frequencies Common; a base-to-apex cochlear damage gradient is well documented HP:0008625 (High-frequency sensorineural hearing impairment)
Progressive, severe-to-profound deafness Clinical course Progressive over days–weeks; permanent Majority of homoplasmic-variant + exposure cases HP:0008625; HP:0001730 (Progressive hearing impairment)
Tinnitus Symptom Subacute/chronic, often precedes or accompanies threshold shift Frequently reported in cochleotoxicity monitoring HP:0000360 (Tinnitus)
Vestibulotoxicity — gait ataxia, oscillopsia, dizziness, nystagmus Clinical sign Subacute bilateral vestibulopathy, may develop in parallel with cochleotoxicity Variable, drug- and dose-dependent (higher with streptomycin/gentamicin) HP:0002066 (Gait ataxia); HP:0000615 (Oscillopsia); HP:0002321 (Vertigo)
Multiorgan mitochondrial features (rare) Systemic Variable Reported in some m.1555A>G carriers with syndromic presentations (PMC: 7015579) context-dependent

Quality of life impact: Profound bilateral SNHL in infancy/early childhood (the population most likely to receive gentamicin for suspected sepsis) has major, well-documented effects on language acquisition, education, and social development; adult-onset cases affect communication, employment, and mental health, consistent with general SNHL QoL literature (EQ-5D/SF-36 not disease-specific for AIHL).

4. Genetic/Molecular Information

Causal gene: MT-RNR1 (mitochondrially encoded 12S rRNA), OMIM *561000; the deafness phenotype is OMIM #580000.

Key pathogenic variants (all mitochondrial, maternally inherited): | Variant | Classification | Notes | |---|---|---| | m.1555A>G | Pathogenic (ClinVar RCV000010254/255) | Most common; homoplasmic; near-complete penetrance with aminoglycoside exposure; population frequency ~0.1–1.8% depending on cohort/region | | m.1494C>T | Pathogenic (ClinVar RCV001449811/RCV000010263) | Second most common; incomplete penetrance (avg. ~18%, up to 77% in some pedigrees) | | m.1095T>C | Pathogenic, CPIC-flagged | Rarer | | m.961delT+Cn / m.961T>C | Associated, variable evidence | Reported with and without aminoglycoside exposure | | m.7444G>A (MT-CO1) | Co-segregating secondary variant | Reported alongside m.1555A>G in a 3-generation Chinese family, may modify phenotype |

Zygosity/heteroplasmy: These variants are typically found in the homoplasmic state in affected pedigrees; CPIC (2021) explicitly states there is not yet sufficient evidence to define a heteroplasmy threshold below which aminoglycoside use is safe, so any detectable variant is treated per the homoplasmic guidance.

Functional consequence: Gain-of-susceptibility, not a classic loss-of-function — the base substitution creates a new base pair at the terminus of the penultimate stem of the 12S rRNA decoding site, structurally converting it toward the ancestral bacterial-type 16S rRNA conformation. This increases the aminoglycoside-binding pocket, permitting aminoglycoside binding to the mitochondrial ribosome much as it would bind a bacterial ribosome, inhibiting mitochondrial protein synthesis in cochlear tissue.

Modifier genes: - TRMU (mitochondrial tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase) — nuclear-encoded modifier; the A10S variant increases penetrance of MT-RNR1-associated deafness. - Secondary mtDNA variants (m.4394C>T tRNA-Gln, m.1584 12S rRNA methylation site) proposed as additional modifiers of clinical expressivity.

Population/allele frequency resources: gnomAD (mitochondrial variant server) and MITOMAP catalog m.1555A>G and m.1494C>T frequencies across populations; GeneReviews Table 2 provides population-stratified prevalence of m.1555A>G (NCBI Bookshelf NBK1422).

Suggested gene/molecular ontology bindings: HGNC gene symbol MT-RNR1 (mitochondrial, note standard HGNC/NCBI Gene entry applies; dismech convention uses lowercase hgnc: CURIEs for nuclear genes — MT-RNR1 is mitochondrially encoded and may require special handling per dismech's mitochondrial-gene conventions).

5. Environmental Information

  • Primary environmental/pharmacologic trigger: Systemic aminoglycoside antibiotic exposure — gentamicin, tobramycin, amikacin, streptomycin, kanamycin, neomycin, and (in TB regimens) capreomycin/viomycin (technically cyclic peptides with similar ribosomal mechanism).
  • Clinical contexts of exposure: Neonatal suspected sepsis (empiric gentamicin), CF pulmonary exacerbations (inhaled/IV tobramycin prophylaxis every 3–4 months), MDR-TB intensive-phase injectable regimens (kanamycin, amikacin, capreomycin), and historically streptomycin for various infections.
  • Non-infectious environmental modifiers: Concurrent noise exposure may act synergistically with genetic susceptibility (reported in some m.1555A>G pedigrees even absent drug exposure) — supports possible G×E beyond drug exposure alone.
  • No infectious-agent etiology — this is a drug-toxicity disorder, though the underlying illness prompting aminoglycoside use (sepsis, TB, CF pulmonary infection) is itself infectious in most cases; the ontology ECTO "aminoglycoside antibiotic exposure" or an equivalent drug-exposure term is the appropriate environmental/exposure binding, not a pathogen taxon.

6. Mechanism / Pathophysiology

Causal chain (genotype-positive form): 1. Trigger: Systemic aminoglycoside administration in a carrier of a pathogenic MT-RNR1 variant (m.1555A>G most common). 2. Molecular lesion: The variant reconfigures the 12S rRNA decoding-site conformation to resemble bacterial 16S rRNA, permitting high-affinity aminoglycoside binding within the mitochondrial ribosome's small subunit. 3. Mitochondrial protein synthesis inhibition: Aminoglycoside binding at the decoding site causes mistranslation/inhibition of mitochondrially-encoded OXPHOS subunit synthesis, analogous to bacterial ribosome inhibition. 4. Mitochondrial dysfunction in cochlear hair cells: Disrupted protein synthesis leads to impaired oxidative phosphorylation, mitochondrial membrane potential collapse, and generation of reactive oxygen species (ROS). 5. Downstream cell-death signaling: ROS and stress-kinase activation (notably c-Jun N-terminal kinase, JNK) amplify mitochondrial injury; cytochrome c release triggers caspase-9 → caspase-3 activation (intrinsic apoptotic pathway). Calcium flux from the endoplasmic reticulum via IP3 receptors into mitochondria is a key acute step (documented in zebrafish lateral-line hair cells). 6. Distinct temporal/mechanistic pathways by drug: Neomycin exposure causes rapid (within ~1h) hair cell death associated with acute mitochondrial calcium flux (attenuated by the mitochondria-targeted antioxidant mitoTEMPO); gentamicin causes delayed (up to 24h) hair cell death via calcium-independent pathways (PMC: 11602426). 7. Cell death mechanisms beyond classical apoptosis: Necroptosis has also been implicated alongside apoptosis in aminoglycoside- and cisplatin-induced ototoxicity; RIPOR2 translocation and phosphatidylserine externalization occur via mechanistically distinct pathways from canonical apoptosis (PMC: 12364911). 8. Anatomical gradient: Cochlear damage follows a base-to-apex gradient — basal-turn (high-frequency-encoding) outer hair cells are damaged first and are most vulnerable, explaining the characteristic high-frequency-first audiometric pattern; inner hair cells appear especially vulnerable at low, non-antibacterial concentrations relevant to hidden hearing loss. 9. Clinical manifestation: Irreversible bilateral sensorineural hearing loss, high-frequency-predominant progressing to lower frequencies, ± tinnitus and vestibulotoxicity.

Cellular processes involved: Mitochondrial protein synthesis inhibition (GO:0032543, mitochondrial translation), oxidative stress response (GO:0006979/0034599), intrinsic apoptotic signaling (GO:0097193), regulated necrosis/necroptosis, calcium-mediated signaling between ER and mitochondria.

Protein/molecular target: MT-RNR1 12S rRNA decoding site of the mitochondrial small ribosomal subunit (28S) — a structural/RNA target rather than a protein per se.

Cell types involved: Cochlear outer hair cells (basal turn preferentially) and inner hair cells, spiral ganglion neurons (secondary degeneration), vestibular hair cells (type I/II) for the vestibulotoxic phenotype.

Suggested ontology terms: - GO: GO:0032543 (mitochondrial translation), GO:0006915 (apoptotic process), GO:0070997 (neuron death), GO:0055074 (calcium ion homeostasis), GO:0034599 (cellular response to oxidative stress) - CL: CL:0000601 (outer hair cell), CL:0000598 (inner hair cell), CL:0000101 (sensory neuron; for spiral ganglion neurons), CL:0000211 (vestibular hair cell where applicable) - CHEBI: CHEBI:41000 (aminoglycoside antibiotic) or specific drugs — CHEBI:17833 (gentamicin), CHEBI:28864 (tobramycin), CHEBI:2637 (amikacin), CHEBI:9334 (streptomycin)

Molecular profiling data: Direct disease-specific transcriptomic/proteomic/metabolomic datasets in humans are limited (ototoxicity research relies heavily on animal/organoid models); zebrafish lateral-line and mouse cochlear explant transcriptomic studies of aminoglycoside exposure are available in GEO but are model-system, not human-tissue, datasets.

7. Anatomical Structures Affected

  • Organ level: Inner ear (cochlea — primary; vestibular labyrinth — secondary/vestibulotoxicity). Systemic aminoglycoside toxicity also affects the kidney (nephrotoxicity) as a parallel, mechanistically related but anatomically distinct toxicity — relevant as a comorbid risk marker (nephrotoxicity often co-occurs and can indicate cumulative exposure).
  • Tissue/cell level: Organ of Corti sensory epithelium — outer hair cells (basal turn first), inner hair cells, supporting cells (Deiters', pillar cells), spiral ganglion neurons (stria vascularis less directly implicated than in some other ototoxic mechanisms); vestibular sensory epithelium (crista ampullaris, maculae) hair cells for the vestibular phenotype.
  • Subcellular level: Mitochondria (site of 12S rRNA target and ROS generation), endoplasmic reticulum (calcium release via IP3 receptors), cytosol (caspase cascade execution).
  • Localization/laterality: Bilateral and typically symmetric.

Suggested UBERON terms: UBERON:0001846 (cochlea), UBERON:0005988 (organ of Corti), UBERON:0009663 (spiral ganglion), UBERON:0001824 (vestibular organ), UBERON:0000362 (mitochondrion is GO cellular component, not UBERON — use GO:0005739 for mitochondrion instead).

8. Temporal Development

  • Onset: Can occur at any age when aminoglycoside is administered; clinically most consequential in neonates (empiric gentamicin for suspected sepsis) and in patients receiving prolonged/repeated courses (CF, MDR-TB). Onset relative to drug exposure is acute-to-subacute: earliest detectable ultra-high-frequency threshold shifts within hours (as early as 4h post-treatment in monitoring studies); clinically apparent hearing loss can appear within days to a few weeks of exposure.
  • Progression: Once triggered, hearing loss is typically progressive over days to weeks, following a base-to-apex cochlear gradient (high frequencies affected first, then progressively lower/speech frequencies). It then stabilizes as permanent, non-progressive residual deafness once the ototoxic insult resolves (unlike some other genetic SNHL that continues to progress with age).
  • Disease course pattern: Not relapsing-remitting — a single triggering exposure produces a step-wise, largely irreversible threshold shift. Genetically susceptible carriers not exposed to aminoglycosides may still show mild, later-onset, more gradual hearing decline in some pedigrees (independent low-penetrance expression), distinct from the acute triggered form.
  • Critical windows for intervention: The period between first aminoglycoside dose and onset of measurable ototoxicity (hours to days) is the key window for early detection (serial high-frequency/ultra-high-frequency audiometry, otoacoustic emissions) and for genotype-based pre-exposure avoidance (point-of-care testing before/at time of first dose, see §10, §13).

9. Inheritance and Population

Inheritance pattern: Maternal (mitochondrial) inheritance — MT-RNR1 variants are transmitted exclusively through the maternal line; male carriers do not transmit the variant to offspring.

Penetrance: - m.1555A>G: near-complete (approaching 100%) for hearing loss when a homoplasmic carrier receives aminoglycosides; lower baseline penetrance without exposure, historically reported 28%, 20%, 15% across different pedigree analyses when aminoglycoside-induced cases are included/excluded. - m.1494C>T: average penetrance ~18% (range 0–77%) across families, strongly modified by aminoglycoside exposure history and by nuclear modifier genes (e.g., TRMU).

Expressivity: Variable — ranges from no detectable hearing loss (silent carriers without exposure) to profound congenital-onset deafness, influenced by modifier genes, heteroplasmy (where present), and environmental co-factors (noise, drug exposure).

Genetic anticipation: Not a recognized feature (this is not a repeat-expansion disorder).

Founder effects: Strong founder effect documented in the Buryat population of the Baikal Lake region of Russia (m.1555A>G prevalence 20.2% vs. 1.3% in surrounding Russian population) — PMC: 11222474 / Sci Rep s41598-024-66254-z. Founder enrichment also reported in some Spanish, Chinese, and Arab-Israeli pedigrees.

Carrier/population frequency: - UK general population: ~0.26% (~1 in 385–500) for m.1555A>G. - European general population: ~0.19%. - Global pooled estimate (enriched cohorts, hearing-loss-ascertained): ~1.8% (863/47,328) — likely an overestimate of true general-population frequency due to ascertainment bias. - Wide regional variation, up to 20%+ in isolated founder populations.

Population demographics: - No strong sex bias in mitochondrial transmission itself (both sexes can be affected equally since inheritance is maternal but penetrance is independent of the child's sex); clinical exposure risk (e.g., neonatal sepsis treatment) is population-wide. - Geographic/ethnic enrichment as above (Han Chinese, Spanish, Arab-Israeli, Buryat/Siberian populations disproportionately represented in the literature for specific variants). - Age distribution of clinical presentation skews toward populations with high aminoglycoside exposure: neonates (NICU sepsis treatment), children/young adults with CF, and TB patients of any age receiving injectable second-line regimens.

Epidemiology of ototoxicity in exposed populations (non-genotype-specific dose-dependent toxicity): - CF: prevalence of SNHL 0–57% depending on cohort/definition; 3–24% with <10 IV aminoglycoside doses, rising to 40–44% with >10 doses (recurrent exposure); cumulative dose associated with 4.5× higher odds of hearing loss; adult CF prevalence up to 59%. - TB: incidence ranges from 3.2% in early-phase standard therapy up to near-universal with prolonged (6–12 month) treatment; MDR-TB incidence of ototoxicity ~22.9% in one cohort; a meta-analysis found pooled prevalence of ototoxic hearing loss of ~40.6% across drugs, with kanamycin highest at ~49.65% (J Infect systematic review, PMID: 34015383).

10. Diagnostics

Clinical/audiologic tests: - Pure-tone audiometry (standard + extended high-frequency/ultra-high-frequency audiometry, which detects the earliest threshold shifts before speech-frequency involvement). - Otoacoustic emissions (OAEs, especially distortion-product OAEs) for early, pre-symptomatic monitoring, particularly in infants and non-verbal patients. - Serial audiometric monitoring protocols are standard of care during prolonged aminoglycoside courses (CF, TB) to detect ototoxicity early and allow dose adjustment/discontinuation. - Newborn hearing screening (universal newborn hearing screening programs) — m.1555A>G has been specifically studied as a risk factor for failed newborn hearing screening in preterm infant cohorts (PMC: 4236616).

Genetic testing: - Targeted MT-RNR1 variant testing (m.1555A>G, m.1494C>T, m.1095T>C at minimum, per CPIC) — via standard clinical mtDNA sequencing/genotyping panels or dedicated hearing-loss gene panels. - Rapid point-of-care genotyping: The Genedrive MT-RNR1 ID Kit provides m.1555A>G genotyping in ~26 minutes with reported 100% sensitivity/specificity in preclinical validation, enabling real-time avoidance of gentamicin in NICU settings before first dose (the PALOH trial, PMC: 8211036 and PMC: 8938898). Deployed at Manchester University NHS Foundation Trust and now expanding to 14 NHS neonatal units across England, Scotland, Wales, and Northern Ireland (2024–2025 rollout). - Non-invasive prenatal MT-RNR1 pharmacogenetic testing is under active investigation (2026 medRxiv preprint) as a means of identifying at-risk neonates before birth. - Whole mitochondrial genome sequencing can identify rarer/novel MT-RNR1 variants and co-segregating secondary mtDNA variants (e.g., m.7444G>A, m.4394C>T) beyond the three CPIC-actionable variants.

Clinical criteria / differential diagnosis: Diagnosis relies on temporal association between aminoglycoside exposure and new-onset bilateral high-frequency-predominant SNHL, ideally confirmed by pre/post-exposure audiometric comparison; differential diagnosis includes other causes of SNHL (congenital, noise-induced, presbycusis, other syndromic/nonsyndromic genetic deafness, autoimmune inner ear disease) which the genetic test and exposure history help exclude/confirm.

Screening: CPIC and NHS guidance effectively function as a pharmacogenomic screening recommendation — genotype before first aminoglycoside exposure wherever feasible (especially neonatal/NICU and CF/TB populations with anticipated repeated courses).

11. Outcome/Prognosis

  • Reversibility: Hearing loss from AIHL, once established, is generally permanent and irreversible — this is a defining clinical feature distinguishing it from some other forms of drug ototoxicity.
  • Severity spectrum: Ranges from mild high-frequency threshold shifts (often subclinical, detected only by extended high-frequency audiometry) to bilateral profound deafness.
  • Functional/QoL impact: Congenital or early-childhood-onset profound deafness (as in genotype-positive neonates exposed to gentamicin) carries major lifelong implications for language development, education, and psychosocial functioning unless mitigated by early intervention (hearing aids, cochlear implantation, sign language/communication support).
  • Complications: Concurrent vestibulotoxicity contributes to falls risk, gait instability, and oscillopsia, compounding functional impact, especially in adults.
  • Mortality: Not directly disease-related; mortality risk in this population is driven by the underlying infection requiring aminoglycoside therapy (sepsis, MDR-TB), not by the ototoxicity itself.
  • Prognostic factors: Genotype (homoplasmic MT-RNR1 pathogenic variant = near-certain severe outcome with exposure), cumulative dose, concurrent nephrotoxicity/renal impairment (reduces drug clearance, raising exposure), and early detection/discontinuation of the ototoxic agent.

12. Treatment

There is no reversal treatment for established AIHL; management is preventive (avoidance, monitoring, dose optimization) and rehabilitative once hearing loss has occurred.

Pharmacogenomics (CPIC): The Clinical Pharmacogenetics Implementation Consortium (CPIC) published a formal guideline in 2021 (updated March 2023) — cpicpgx.org/guidelines/cpic-guideline-for-aminoglycosides-and-mt-rnr1:

Any individual carrying the m.1555A>G, m.1494C>T, or m.1095T>C variant should avoid aminoglycoside antibiotics unless the risk of permanent hearing loss is outweighed by the severity of the infection and lack of suitable alternatives. No heteroplasmy threshold has been established as "safe," so any detectable variant is managed as if homoplasmic. The 2023 update also addressed whether variant carriers should avoid vaccines manufactured using aminoglycosides (residual amounts are not considered clinically significant for this indication).

Rehabilitative/supportive care (NCIT terms suggested): - Hearing aids — NCIT:C50384 (Hearing Aid) or device-category equivalent. - Cochlear implantation — NCIT term for cochlear implant procedure (surgical intervention; suggest NCIT:C61509 Cochlear Implant or closest available surgical-device term). - Speech-language therapy — NCIT:C15302 (Physical Therapy)-adjacent; NCIT speech therapy term if available. - Genetic counseling — NCIT:C15240 (Genetic Counseling), critical given maternal transmission implications for family planning. - Audiologic monitoring/surveillance — NCIT:C25218 category (Clinical Intervention or Procedure), specific monitoring/audiometry term.

Avoidance/substitution strategy (primary "treatment" for genotype-positive individuals): substitution of non-aminoglycoside antimicrobials for suspected sepsis/infection when clinically appropriate — NCIT:C15986 (Pharmacotherapy) with a different therapeutic_agent.

Experimental/otoprotective strategies (evidence base still developing for aminoglycosides specifically): - Sodium thiosulfate — FDA-, EMA-, and MHRA-approved (2022–2023) as an otoprotectant, but specifically for cisplatin-induced ototoxicity in pediatric localized non-metastatic solid tumors (SIOPEL6 and COG ACCL0431 trials showed reduced hearing-loss incidence: 39% vs 68%, and 44% vs 58%, respectively). Not yet an approved indication for aminoglycoside ototoxicity, though mechanistic overlap (oxidative stress, ROS scavenging) makes it of research interest. - Mitochondria-targeted antioxidants (e.g., mitoTEMPO) — shown in zebrafish models to attenuate acute neomycin-induced hair cell death via mitigation of mitochondrial calcium flux; not yet in human trials for AIHL. - N-acetylcysteine and related antioxidants — investigated in CF and other cohorts as adjunctive otoprotection during aminoglycoside courses; evidence remains preliminary/mixed.

Designer aminoglycosides in development (address root cause by decoupling antibacterial activity from mitochondrial ribosome binding): - Apramycin — a 4-monosubstituted 2-deoxystreptamine aminoglycoside shown in guinea pig and cochlear explant models to have substantially lower ototoxicity than gentamicin while retaining potent activity against MDR pathogens including Mycobacterium tuberculosis; structural studies (3.5 Å resolution apramycin-ribosome complexes) provide a framework for further reduced-toxicity aminoglycoside design (PNAS: 10.1073/pnas.1204073109; PMC: 3390888, 6382871). - Gentamicin C1a — a specific gentamicin congener also identified as having lower ototoxicity and no evidence of "hidden hearing loss" in guinea pig round-window application studies. - ELX-02 — a synthetic, eukaryotic-ribosome-selective aminoglycoside-class "read-through" agent developed primarily for nonsense-mutation genetic diseases (e.g., CF); engineered to eliminate antibacterial activity and reduce nephro-/ototoxicity. Phase 1 trials showed no severe ototoxicity or nephrotoxicity signals across dose range 0.3–7.5 mg/kg.

Experimental clinical trials: Multiple registered trials on ClinicalTrials.gov address sodium thiosulfate otoprotection (mostly cisplatin-focused; e.g., NCT05129748, NCT04541355) and ELX-02 pharmacokinetics/safety (NCT03776539, NCT03309605). No large registered trial currently targets otoprotection specifically for genotype-positive AIHL beyond the genotyping-avoidance strategy itself (PALOH and related implementation trials).

13. Prevention

AIHL is one of the clearest examples of a primary-prevention-focused pharmacogenomic disorder — because the hearing loss is irreversible once triggered, prevention (avoiding the triggering exposure in genetically susceptible individuals) is the dominant clinical strategy, more so than treatment.

  • Primary prevention — genotype-guided prescribing: Pre-emptive or point-of-care MT-RNR1 genotyping before first aminoglycoside dose, especially in neonatal intensive care (NICU) settings where empiric gentamicin is common for suspected sepsis. The Manchester/NHS PALOH implementation trial demonstrated feasibility: 424/526 (80.6%) of eligible infants tested within the clinically actionable window using the Genedrive MT-RNR1 ID Kit (~26 min turnaround, 100% sensitivity/specificity in validation); identified variant carriers avoided aminoglycoside exposure entirely. This program is expanding to 14 NHS neonatal units UK-wide (2024–2025).
  • Screening — high-risk/repeated-exposure populations: Consider MT-RNR1 genotyping before starting long-term/repeated aminoglycoside regimens in CF and MDR-TB patients, in addition to serial audiometric monitoring throughout treatment.
  • Secondary prevention — early detection during ongoing therapy: Extended high-frequency/ultra-high-frequency audiometry and OAE monitoring at baseline and serially during aminoglycoside courses to detect subclinical threshold shifts before they progress into speech-frequency-affecting, functionally significant hearing loss; allows early drug discontinuation/dose adjustment.
  • Tertiary prevention: Once hearing loss occurs, prompt referral to audiology/otolaryngology for hearing aid fitting or cochlear implant evaluation, and early educational/communication intervention in pediatric cases to mitigate developmental impact.
  • Genetic counseling: Because inheritance is maternal, identification of an affected/carrier proband should prompt counseling and (ideally) cascade testing of maternal relatives, since all maternal-line relatives share the same variant and risk.
  • Non-invasive prenatal testing (emerging, 2026): Under active investigation as a way to identify at-risk MT-RNR1-carrier neonates before birth, allowing avoidance planning before any postnatal antibiotic exposure decision is needed.
  • Prescribing/stewardship policy: Clinical guideline bodies (CPIC; UK Genomics Education programs) now explicitly recommend genotype-informed antibiotic stewardship as formal policy, moving beyond individual clinician awareness to systematized point-of-care testing pathways.

14. Other Species / Natural Disease

  • No well-established naturally-occurring veterinary counterpart of MT-RNR1-mediated AIHL has been prominently reported in the literature surveyed (OMIA search recommended for confirmation); aminoglycoside ototoxicity itself is a recognized general veterinary drug-toxicity concern (e.g., in companion animals receiving aminoglycosides), but genotype-linked susceptibility analogous to human MT-RNR1 variants is not established as a common veterinary syndrome in the sources reviewed here.
  • The mitochondrial 12S rRNA target is deeply evolutionarily conserved (relationship to the bacterial 16S rRNA target is the entire basis of the mechanism), so cross-species susceptibility to aminoglycoside ototoxicity is a general pharmacological property of the drug class rather than being confined to genetically susceptible human carriers — this is why "designer aminoglycoside" research uses standard rodent (mouse, guinea pig) ototoxicity models even without introducing the human risk variant.
  • Note: This report did not identify strong evidence of natural (spontaneous) veterinary MT-RNR1-variant disease; recommend an OMIA database check during KB curation to confirm absence/presence before asserting a definitive negative.

15. Model Organisms

  • Zebrafish (lateral-line hair cells): Extensively used to dissect distinct temporal/mechanistic pathways of aminoglycoside-induced hair cell death — neomycin (rapid, ~1h, calcium-dependent via ER→mitochondria IP3-mediated calcium flux, rescued by mitoTEMPO) vs. gentamicin (delayed, up to 24h, calcium-independent) (PMC: 11602426, bioRxiv: 2024.05.30.596537). This model does not carry the human MT-RNR1 variant but demonstrates the general aminoglycoside-mitochondrial hair cell death mechanism and is used for mechanistic dissection and drug (designer-aminoglycoside/otoprotectant) screening.
  • Guinea pig (cochlear explant / in vivo chronic ototoxicity model): Used to compare ototoxicity profiles across aminoglycoside congeners — demonstrated gentamicin C1a and apramycin as substantially less ototoxic than standard gentamicin via round-window drug application and compound action potential/outer hair cell survival assays (PMC: 6382871).
  • Mouse (cochlear explants, in vivo dosing comparisons): Used to refine ototoxicity study protocols and compare different aminoglycoside dosing regimens in adult mice (Murillo-Cuesta et al., Lab Animals 2010).
  • Genotype-specific (MT-RNR1 variant knock-in) models: This search did not surface a well-established, widely-cited mouse or zebrafish knock-in line carrying the human m.1555A>G or m.1494C>T variant that recapitulates genotype-specific hypersensitivity; most mechanistic model-organism work uses wild-type animals to study general aminoglycoside ototoxicity pathways rather than modeling the specific human genetic susceptibility variant. This is a notable gap worth flagging in a knowledge-gap/discussion entry — direct modeling of the human-specific MT-RNR1 gain-of-susceptibility mutation in an animal ribosome is complicated by sequence divergence between species' mitochondrial rRNA.
  • Model limitations: Because the causal lesion is a single-nucleotide change in human mitochondrial 12S rRNA altering aminoglycoside binding affinity, and because most current animal ototoxicity models use wild-type (non-variant) rRNA, these models capture the general aminoglycoside-mitochondrial-ribosome-hair-cell-death mechanism well but do not directly recapitulate the human genotype-specific hypersusceptibility — this is a translational (human-model mismatch) gap appropriate for a HUMAN_MODEL_MISMATCH discussion entry in dismech curation, pending confirmation of whether a knock-in model has since been published.

Summary of Suggested Ontology Bindings for Curation

Category Suggested term(s)
MONDO (verify local release for exact ID; candidate labels: "aminoglycoside-induced hearing loss," "maternally-inherited nonsyndromic hearing loss and deafness")
OMIM #580000
HPO HP:0000407, HP:0008625, HP:0001730, HP:0000360, HP:0002066, HP:0000615, HP:0002321
GO (BP) GO:0032543, GO:0006915, GO:0070997, GO:0034599, GO:0055074
CL CL:0000601 (outer hair cell), CL:0000598 (inner hair cell), CL:0000211, CL:0000101
UBERON UBERON:0001846 (cochlea), UBERON:0005988 (organ of Corti), UBERON:0009663 (spiral ganglion), UBERON:0001824 (vestibular organ)
CHEBI CHEBI:17833 (gentamicin), CHEBI:28864 (tobramycin), CHEBI:2637 (amikacin), CHEBI:9334 (streptomycin), CHEBI:41000 (aminoglycoside antibiotic class)
NCIT (treatment) NCIT:C15986 (Pharmacotherapy), NCIT:C15240 (Genetic Counseling), NCIT:C15747 (Supportive Care) + device/procedure terms for hearing aid/cochlear implant
Gene MT-RNR1 (mitochondrial 12S rRNA)

Key Caveats for Curators

  1. Snippet/quote verification required: This report synthesizes web-search summaries and secondary source excerpts; per dismech's evidence policy, every claim used in a KB entry must be re-verified with an exact quoted substring from the actual cached reference (PMID/OMIM/GeneReviews/CPIC) via just fetch-reference, not from this report's paraphrased summaries.
  2. CPIC guideline citation: Cite the primary CPIC publication (2021, PMID needed — search PubMed directly for the exact PMID of "Clinical Pharmacogenetics Implementation Consortium Guideline for the Use of Aminoglycosides Based on MT-RNR1 Genotype") plus its March 2023 update supplement.
  3. MONDO ID and precise HPO/GO term matches should be confirmed against the locally cached ontology versions before binding, per dismech's anti-hallucination term-validation workflow.
  4. Founder-effect prevalence figures (Buryat 20.2%, etc.) and global pooled prevalence (1.8%) should be sourced to their specific primary publications (Scientific Reports 2024, PMC:11222474) rather than cited from this summary.

Sources: - NC_012920.1(MT-RNR1):m.1555A>G AND Mitochondrial non-syndromic sensorineural hearing loss - ClinVar - NC_012920.1(MT-RNR1):m.1555A>G AND Aminoglycoside-induced deafness - ClinVar - Clinical Pharmacogenomic MT-RNR1 Screening for Aminoglycoside-Induced Ototoxicity and the Post-Test Counseling Conundrum - PubMed - Gentamicin Therapy and MT-RNR1 Genotype - Medical Genetics Summaries - NCBI Bookshelf - Non-invasive Prenatal MT-RNR1 Pharmacogenetic Testing for the Prevention of Aminoglycoside-Induced Profound Hearing Loss - medRxiv - Mechanisms of aminoglycoside ototoxicity and targets of hair cell protection - PubMed - Multiple mechanisms of aminoglycoside ototoxicity are distinguished by subcellular localization of action - PMC - Towards the Prevention of Aminoglycoside-Related Hearing Loss - PMC - Mechanisms of Aminoglycoside- and Cisplatin-Induced Ototoxicity - American Journal of Audiology - Aminoglycoside induces RIPOR2 translocation and phosphatidylserine externalization via distinct mechanisms - PMC - Entry - #580000 - DEAFNESS, AMINOGLYCOSIDE-INDUCED - OMIM - Maternally inherited aminoglycoside-induced and nonsyndromic hearing loss is associated with the 12S rRNA C1494T mutation - PubMed - CPIC® Guideline for Aminoglycosides and MT-RNR1 - MT-RNR1 CPIC Guidelines - Aminoglycoside antibiotics — Genomics Education Knowledge Hub - New developments in aminoglycoside therapy and ototoxicity - PMC - Aminoglycoside- and glycopeptide-induced ototoxicity in children: a systematic review - PMC - Prevalence of aminoglycoside-induced hearing loss in drug-resistant tuberculosis patients: A systematic review - PubMed - Nonsyndromic Hearing Loss and Deafness, Mitochondrial - PubMed (GeneReviews) - Mitochondrial tRNAGln 4394C>T Mutation May Contribute to the Clinical Expression of 1555A>G-Induced Deafness - PMC - Results: Patient with a known MT-RNR1 genotype requiring aminoglycoside antibiotics — In the Clinic - Use of Sodium Thiosulfate as an Otoprotectant in Patients With Cancer Treated With Platinum Compounds - JCO - FDA Approves Sodium Thiosulfate to Decrease Cisplatin-Associated Ototoxicity - CancerNetwork - Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss - NEJM - New Rapid genomic testing at Manchester University NHS Foundation Trust prevents at-risk neonates from potential lifelong hearing loss - BioSpace - Rapid Point-of-Care Genotyping to Avoid Aminoglycoside-Induced Ototoxicity in Neonatal Intensive Care - PubMed - Pharmacogenetics to Avoid Loss of Hearing (PALOH) trial protocol - PMC - Rapid Point-of-Care Genotyping to Avoid Aminoglycoside-Induced Ototoxicity in Neonatal Intensive Care - PMC - Genotype testing to guide antibiotic use and prevent hearing loss - Scottish Health Technologies Group - Genetic test developed by Manchester researchers to prevent newborn babies going deaf, to be trialled across the UK - MFT NHS - Variant m.1555A>G in MT-RNR1 causes hearing loss and multiorgan mitochondrial disorder - PMC - High prevalence of m.1555A>G in patients with hearing loss in the Baikal Lake region of Russia as a result of founder effect - PMC / Scientific Reports - Lower ototoxicity and absence of hidden hearing loss point to gentamicin C1a and apramycin as promising antibiotics for clinical use - PMC - Dissociation of antibacterial activity and aminoglycoside ototoxicity in the 4-monosubstituted 2-deoxystreptamine apramycin - PNAS - ELX-02: an investigational read-through agent for the treatment of nonsense mutation-related genetic disease - Hearing in 44-45 year olds with m.1555A>G, a genetic mutation predisposing to aminoglycoside-induced deafness: a population based cohort study - PubMed - Table 2. Prevalence of MT-RNR1 Pathogenic Variant m.1555A>G by Population - GeneReviews, NCBI Bookshelf - Mitochondrial mutation m.1555A>G as a risk factor for failed newborn hearing screening in a large cohort of preterm infants - PMC - Mitochondrial m.1584A 12S rRNA methylation in families with m.1555A>G associated hearing loss - Human Molecular Genetics

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 25
Resolved 25
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 1
Quoted claims not found in source 0
References weighed for topical relevance 25
On topic 17
Off topic 0

All extracted references resolved successfully.