Risk of ototoxicity

Pre-treatment screening for aminoglycosides is available to support recommendations in the MHRA drug safety update on the increased risk of deafness due to a mitochondrial genetic variant when patients are treated with aminoglycosides. This advice is also replicated in each of the relevant monographs in the British National Formulary (BNF).

The R65 Task and Finish Group have produced guidance to support implementation of the recommendations for genetic testing.

Genetic variation

Three variations in the gene are highlighted as being associated with an increased risk of ototoxicity, including when aminoglycoside serum levels are within the recommended ranges. These are denoted as m.1555A>G, m.1095T>C and m.1494C>T.

m.1555A>G

There is a single nucleotide substitution in the mitochondrial DNA at base pair 1555, with a change from adenine to guanine. This corresponds to a change in the MT-RNR1 gene.

m.1095T>C and m.1494C>T

Reflect the single nucleotide substitution in the mitochondrial DNA at base pair 1095 and 1494. These also correspond to a change in the MT-RNR1 gene.

Other genetic variants in the MT-RNR1 gene may be implicated in this genetic risk and identified as the evidence base grows.

R65 testing

Testing for this mitochondrial variation is available on the National Genomic Test Directory, if the eligibility criteria are met. The test is included in the rare and inherited disease directory and is denoted as R65.

Neonatal testing

Testing for the genetic variant m.1555A>G is available through point of care testing for neonates with sepsis. However, this is not currently commissioned nationally.

Further information is available in NICE’s early value assessment:
Genedrive MT-RNR1 ID Kit for detecting a genetic variant to guide antibiotic use and prevent hearing loss in babies.

Ototoxicity following exposure

Referring to audiology is recommended if you have a patient who has developed hearing loss following treatment with aminoglycosides. Genetic testing is available to confirm if aminoglycosides are likely to have contributed to the development of hearing loss.

Ordering genetic tests

To request testing for an eligible individual, requests must be sent to one of the seven commissioned NHS Genetic Laboratory Hubs (GLH), following regional protocols. The seven GLHs are:

• Central and South GLH
• East GLH
• North East GLH
• North Thames GLH
• North West GLH
• South East GLH
• South West GLH

Turnaround time

The standard turn around time of testing is six weeks.

Interpreting the test results

Interpretation of the genetic test is completed by the GLH. This will be reported in a standard format, stating whether a certain variation associated with a higher risk is present in the MT-RNR1 gene.

Counselling patients

When ordering testing for mitochondrial variation, patients should be counselled for the familial implications of testing.

Variants in mitochondrial DNA are inherited maternally and so any individuals carrying variation in the MT-RNR1 gene may have affected family members. If their relatives, such as mother or siblings also have a condition as per the eligibility criteria, they should also be informed so they can also access this test.

Discussions with clinical genetic services may be beneficial. Consent to discuss results with other family members is required, so consider asking the proband (affected individual) to involve family members.

Adding information to patient records

Consideration should be made to adding an entry against the patient’s electronic prescribing record if they are known to carry a mitochondrial variant associated with aminoglycoside-induced hearing loss.

Drug allergy section

Although not a true allergy, it may be helpful to add in information on the patient’s test and result in the drug allergy section of their record. This is so that the information can be transferred with the patient across care settings.

SNOMED Clinical Terms (CT)

For reporting in electronic records, the following SNOMED CT terms should be used. The reported SNOMED CT terms were updated in February 2025 to incorporate reporting of the affected gene rather than the originally coded single variant (m.1555A>G).

Reporting test results

Each SNOMED CT term has an identifier (SCTID) listed after the term. This is a unique integer identifier applied to each SNOMED CT component.

• At increased risk of aminoglycoside-induced hearing loss due to mitochondrially encoded 12S ribosomal ribonucleic acid genotype (finding) SCTID: 2365501000000102

• At normal risk of aminoglycoside-induced hearing loss based on mitochondrially encoded 12S ribosomal ribonucleic acid genotype (finding) SCTID: 365511000000100

Procedural code

• Mitochondrially encoded 12S ribosomal ribonucleic acid variant analysis (procedure)                                    SCTID: 2365491000000108

The gene symbol MT-RNR1 describes the mitochondrially encoded 12S ribosomal ribonucleic acid gene.

Implementation considerations

When implementing testing for a cohort of patients under a clinical specialty, the following considerations should be made to ensure a robust and equitable implementation, based on recommendations from the R65 Task and Finish Group.

Eligibility

It is important to ensure that patients planned to be tested are eligible and that whilst the patient’s prior aminoglycoside administration does not preclude testing, it may indicate an ability to tolerate aminoglycosides and absence of mitochondrial variation.

Capacity

Contact the local GLH to ensure testing capacity.

Using the results in practice

When using genetic information to influence prescription of a medicine, healthcare professionals should consider:

• the need for aminoglycoside treatment versus alternative options available
• other patient factors, such as renal function, age, weight, and so on

Prevalence of variation in the MT-RNR1 gene is rare, estimated at 1 in 500 patients in the UK. Penetrance (exhibiting signs or symptoms from variation in the gene) is still being established, and may be influenced by additional factors such as course-length of the aminoglycoside and high serum aminoglycoside levels.

Patient with a known variant

The National Genomics Education GeNotes page provides more information on next steps with a patient with a known variant and therefore at a higher risk of aminoglycoside-induced hearing loss:

Results: Patient with a known MT-RNR1 genotype requiring aminoglycoside antibiotics

Further information

More information is available at GeNotes: Genomic notes for clinicians.

The following recommended resources contain useful background information:

• National Institute of Mental Health (NIMH): What is Prevalence?
• GeNotes Core Concepts – Penetrance
• Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for the Use of Aminoglycosides Based on MT-RNR1 Genotype
• Rapid Point-of-Care Genotyping to Avoid Aminoglycoside-Induced Ototoxicity in Neonatal Intensive Care

The following resources are supported by individual genomic medicine service alliances:

• North Thames Genomics webinar on aminoglycosides pharmacogenetic testing and Best Practice Recommendations for MT-RNR1 testing
• Central and South Genomics article on genomic testing

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