Deafness, aminoglycoside-induced

Summary

Deafness, aminoglycoside-induced (MONDO:0010799) is a disease with 4 cohort genes and 1 clinical trial. The dominant Reactome pathway is Mitochondrial translation termination (3 cohort genes).

At a glance

• Cohort genes: 4
• ClinVar variants: 98
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	deafness, aminoglycoside-induced
Mondo ID	MONDO:0010799
MeSH	C564013
OMIM	580000
Orphanet	168609
DOID	DOID:0111734
UMLS	C1838854
MedGen	374074
GARD	0018161
Is cancer (heuristic)	no

Also known as: aminoglycoside-induced hearing loss · deafness, aminoglycoside-induced · deafness, mitochondrial, modifier of, mitochondrial · deafness, streptomycin-induced · mitochondrial isolated neurosensory deafness with susceptibility to aminoglycoside exposure · mitochondrial isolated neurosensory hearing loss with susceptibility to aminoglycoside exposure · mitochondrial isolated sensorineural deafness with susceptibility to aminoglycoside exposure · mitochondrial isolated sensorineural hearing loss with susceptibility to aminoglycoside exposure · mitochondrial non-syndromic neurosensory deafness with susceptibility to aminoglycoside exposure · mitochondrial non-syndromic neurosensory hearing loss with susceptibility to aminoglycoside exposure · mitochondrial non-syndromic sensorineural deafness with susceptibility to aminoglycoside exposure · mitochondrial non-syndromic sensorineural hearing loss with susceptibility to aminoglycoside exposure · streptomycin ototoxicity

Data availability: 98 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › auditory system disorder › hearing disorder › hearing loss disorder › nonsyndromic genetic hearing loss › postlingual non-syndromic genetic hearing loss › deafness, aminoglycoside-induced

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

98 retrieved; paginated sample, class counts are floors:

51 likely pathogenic, 26 pathogenic/likely pathogenic, 5 uncertain significance, 4 pathogenic, 4 conflicting classifications of pathogenicity, 2 benign/likely benign, 2 likely benign, 1 pathogenic; drug response, 1 drug response, 1 likely pathogenic; drug response, 1 uncertain significance; drug response

ClinVar	Variant (HGVS)	Gene	Classification	Review
9628	NC_012920.1(MT-RNR1):m.1555A>G	MT-ND1	Pathogenic; drug response	reviewed by expert panel
9629	m.961delTinsC(2_7)	MT-RNR1	Pathogenic	no assertion criteria provided
1068790	NM_018006.5(TRMU):c.703C>T (p.Gln235Ter)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071658	NM_018006.5(TRMU):c.803del (p.Ala268fs)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076201	NM_018006.5(TRMU):c.880_898del (p.Arg294fs)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1291	NM_018006.5(TRMU):c.229T>C (p.Tyr77His)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1355265	NM_018006.5(TRMU):c.87C>G (p.Tyr29Ter)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1382748	NM_018006.5(TRMU):c.4C>T (p.Gln2Ter)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1395278	NM_018006.5(TRMU):c.428_459dup (p.Arg154fs)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1444343	NM_018006.5(TRMU):c.172_173dup (p.Arg59fs)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1979783	NM_018006.5(TRMU):c.1041_1044dup (p.Asp349fs)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2013097	NM_018006.5(TRMU):c.260_263del (p.Asn87fs)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2130554	NM_018006.5(TRMU):c.397del (p.Leu133fs)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215287	NM_018006.5(TRMU):c.718C>T (p.Arg240Ter)	TRMU	Pathogenic	criteria provided, multiple submitters, no conflicts
215292	NM_018006.5(TRMU):c.2T>G (p.Met1Arg)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2154507	NM_018006.5(TRMU):c.581dup (p.Leu195fs)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679271	NM_018006.5(TRMU):c.544C>T (p.Gln182Ter)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679273	NM_018006.5(TRMU):c.458del (p.Asn153fs)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679275	NM_018006.5(TRMU):c.706-2A>G	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2770287	NM_018006.5(TRMU):c.173dup (p.Tyr58Ter)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2852647	NM_018006.5(TRMU):c.692_705dup (p.Tyr236fs)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2867364	NM_018006.5(TRMU):c.234G>A (p.Trp78Ter)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30819	NM_018006.5(TRMU):c.835G>A (p.Val279Met)	TRMU	Pathogenic	criteria provided, multiple submitters, no conflicts
558684	NM_018006.5(TRMU):c.880del (p.Arg294fs)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
597202	NM_018006.5(TRMU):c.333dup (p.His112fs)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
631899	NM_018006.5(TRMU):c.96_97del (p.Phe35fs)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
856245	NM_018006.5(TRMU):c.117G>A (p.Trp39Ter)	TRMU	Pathogenic	criteria provided, multiple submitters, no conflicts
862828	NM_018006.5(TRMU):c.581del (p.Gly194fs)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
943468	NM_018006.5(TRMU):c.994C>T (p.Arg332Ter)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
970256	NM_018006.5(TRMU):c.824_825dup (p.Pro276fs)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 14 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRMU	Orphanet:217371	Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins
TRMU	Orphanet:254864	Mitochondrial myopathy with reversible cytochrome C oxidase deficiency
TRMU	Orphanet:90641	Rare mitochondrial non-syndromic sensorineural deafness
MT-CO1	Orphanet:104	Leber hereditary optic neuropathy
MT-CO1	Orphanet:254905	Isolated cytochrome C oxidase deficiency
MT-CO1	Orphanet:550	MELAS
MT-CO1	Orphanet:90641	Rare mitochondrial non-syndromic sensorineural deafness
MT-CO1	Orphanet:99845	Genetic recurrent myoglobinuria
MT-ND1	Orphanet:104	Leber hereditary optic neuropathy
MT-ND1	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND1	Orphanet:2609	Isolated complex I deficiency
MT-ND1	Orphanet:550	MELAS
MT-RNR1	Orphanet:551	MERRF
MT-RNR1	Orphanet:90641	Rare mitochondrial non-syndromic sensorineural deafness

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TRMU	HGNC:25481	ENSG00000100416	O75648	Mitochondrial tRNA-specific 2-thiouridylase 1	clinvar
MT-CO1	HGNC:7419	ENSG00000198804	P00395	Cytochrome c oxidase subunit 1	clinvar
MT-ND1	HGNC:7455	ENSG00000198888	P03886	NADH-ubiquinone oxidoreductase chain 1	clinvar
MT-RNR1	HGNC:7470	ENSG00000211459	A0A0C5B5G6	Mitochondrial-derived peptide MOTS-c	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRMU	Mitochondrial tRNA-specific 2-thiouridylase 1	Catalyzes the 2-thiolation of uridine at the wobble position (U34) of mitochondrial tRNA(Lys), tRNA(Glu) and tRNA(Gln).
MT-CO1	Cytochrome c oxidase subunit 1	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.
MT-ND1	NADH-ubiquinone oxidoreductase chain 1	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.
MT-RNR1	Mitochondrial-derived peptide MOTS-c	Regulates insulin sensitivity and metabolic homeostasis.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	2	6.0×	0.074
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TRMU	Enzyme (other)	yes	2.1.1.61	MnmA-like, Rossmann-like_a/b/a_fold, MnmA-like_central_sf
MT-CO1	Enzyme (other)	yes	7.1.1.9	Cyt_C_Oxase_1, Cyt_c_Oxase_su1_BS, Cyt_c_oxase-like_su1_dom
MT-ND1	Other/Unknown	no		NADH_UbQ_OxRdtase_su1/FPO, NADH_UbQ_OxRdtase_su1_CS
MT-RNR1	Other/Unknown	no		MT-RNR1

Expression context

Cohort genes with no expression data: 0.

4 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	2
apex of heart	1
metanephros cortex	1
right hemisphere of cerebellum	1
rectum	1
stromal cell of endometrium	1
adipose tissue	1
frontal cortex	1
gastrocnemius	1
monocyte	1
prefrontal cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRMU	259	ubiquitous	marker	apex of heart, right hemisphere of cerebellum, metanephros cortex
MT-CO1	134	ubiquitous	marker	granulocyte, stromal cell of endometrium, rectum
MT-ND1	134	ubiquitous	marker	adipose tissue, gastrocnemius, frontal cortex
MT-RNR1	134	ubiquitous	marker	granulocyte, monocyte, prefrontal cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MT-CO1	3,547
MT-ND1	3,537
TRMU	1,739
MT-RNR1	4

Intra-cohort edges

A	B	Sources
MT-CO1	MT-ND1	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MT-ND1	P03886	5
MT-CO1	P00395	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TRMU	O75648	89.60
MT-RNR1	A0A0C5B5G6	72.00

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 4 evidence-associated genes (4 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mitochondrial translation termination	3	82.4×	5e-05	MT-CO1, MT-ND1, MT-RNR1
Mitochondrial protein degradation	2	57.1×	0.004	MT-CO1, MT-ND1
Respiratory electron transport	2	47.6×	0.004	MT-CO1, MT-ND1
FASTK family proteins regulate processing and stability of mitochondrial RNAs	1	713.8×	0.006	MT-RNR1
tRNA processing in the mitochondrion	1	571.0×	0.006	MT-RNR1
Mitochondrial RNA degradation	1	407.9×	0.007	MT-RNR1
rRNA processing in the mitochondrion	1	317.2×	0.008	MT-RNR1
tRNA modification in the mitochondrion	1	259.6×	0.009	TRMU
rRNA modification in the mitochondrion	1	219.6×	0.009	MT-RNR1
tRNA processing	1	89.2×	0.020	TRMU
Complex IV assembly	1	57.1×	0.028	MT-CO1
Cytoprotection by HMOX1	1	46.0×	0.032	MT-CO1
Complex I biogenesis	1	41.4×	0.033	MT-ND1
TP53 Regulates Metabolic Genes	1	32.4×	0.034	MT-CO1
Mitochondrial translation initiation	1	31.7×	0.034	MT-RNR1
Mitochondrial translation elongation	1	31.7×	0.034	MT-RNR1
Mitochondrial ribosome-associated quality control	1	30.7×	0.034	MT-RNR1
Metabolism of RNA	1	10.4×	0.093	TRMU

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
aerobic respiration	2	123.9×	0.002	MT-CO1, MT-ND1
tRNA wobble position uridine thiolation	1	1053.2×	0.007	TRMU
response to hypoxia	2	47.9×	0.007	MT-CO1, MT-ND1
skeletal muscle tissue growth	1	702.2×	0.007	MT-RNR1
response to hydroperoxide	1	421.3×	0.007	MT-ND1
activation of protein kinase activity	1	383.0×	0.007	MT-RNR1
response to copper ion	1	383.0×	0.007	MT-CO1
osteoblast proliferation	1	351.1×	0.007	MT-RNR1
positive regulation of protein serine/threonine kinase activity	1	324.1×	0.007	MT-RNR1
respiratory electron transport chain	1	210.7×	0.010	MT-CO1
mitochondrial electron transport, cytochrome c to oxygen	1	191.5×	0.010	MT-CO1
response to electrical stimulus	1	162.0×	0.011	MT-CO1
cellular respiration	1	108.0×	0.015	MT-CO1
mitochondrial respiratory chain complex I assembly	1	102.8×	0.015	MT-ND1
mitochondrial electron transport, NADH to ubiquinone	1	89.6×	0.015	MT-ND1
cerebellum development	1	89.6×	0.015	MT-CO1
proton motive force-driven mitochondrial ATP synthesis	1	65.8×	0.019	MT-ND1
response to oxidative stress	1	32.7×	0.035	MT-CO1
osteoblast differentiation	1	30.3×	0.036	MT-RNR1
response to xenobiotic stimulus	1	17.3×	0.060	MT-ND1
regulation of transcription by RNA polymerase II	1	2.9×	0.302	MT-RNR1
regulation of carbohydrate utilization	1	—	—	MT-RNR1
purine-containing compound biosynthetic process	1	—	—	MT-RNR1
negative regulation of phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity	1	—	—	MT-RNR1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 4

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TRMU	0	0
MT-CO1	0	0
MT-ND1	0	0
MT-RNR1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MT-CO1	19	Binding:12, Functional:4, ADMET:2, Toxicity:1
MT-ND1	5	Binding:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TRMU	2.1.1.61	tRNA 5-(aminomethyl)-2-thiouridylate-methyltransferase
MT-CO1	7.1.1.9	cytochrome-c oxidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
MT-RNR1	1

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	MT-CO1
D	Druggable family + AlphaFold only, no drug	1	TRMU
E	Difficult family or no structure, no drug	2	MT-ND1, MT-RNR1

Undrugged target profiles

4 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TRMU	0	—
MT-CO1	19	—
MT-ND1	5	—
MT-RNR1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05847556	Not specified	UNKNOWN	Video Game Hearing Tests for Remote Monitoring of Ototoxicity