Presentation: Patient requiring aminoglycoside antibiotics

A four-year-old boy with recurrent chest infections has been newly diagnosed with cystic fibrosis. You recognise that he will likely require broad-spectrum antibiotics during his disease course, so you decide to undertake pharmacogenomic testing for variants in the MT-RNR1 gene in advance of possible aminoglycoside antibiotic exposure.

• Genomic testing should be considered whenever there is the potential for significant exposure to aminoglycosides that would pose a risk of ototoxicity (the development of hearing and/or balance problems). This includes:
  • individuals with a predisposition to gram-negative infections due to a known respiratory disease (such as bronchiectasis or cystic fibrosis) or structural or voiding genitourinary tract disorders; and
  • individuals with hearing loss who have been exposed to aminoglycosides in the past.
• In some scenarios, such as in the treatment of neonatal sepsis, testing for MT-RNR1 variants is not possible using standard genomic testing approaches because antibiotics should be administered as soon as possible after recognition of sepsis. There are ongoing efforts to utilise rapid point-of-care testing strategies to overcome this implementation barrier, but they are not yet used in routine clinical practice.

• Consult the National Genomic Test Directory. From here, you can access the rare and inherited disease eligibility criteria document, which provides information about individual tests and their associated eligibility criteria. You can also access a spreadsheet that contains details of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• For this indication, the appropriate panel to choose is:
  • R65 Aminoglycoside exposure posing risk to hearing. This is a targeted test for MT-RNR1 1555A>G, the most common clinically relevant MT-RNR1 genetic variant, with a population prevalence of around 1 in 500 in the UK. It also tests for the less common MT-RNR1 m.1095T>C and m.1494C>T variants. (Always check the latest test directory to ensure the test code is correct.)
• For DNA-based tests, an EDTA sample is required.
• To find out the procedure for completing test order forms and obtaining patient consent for testing, contact your local Genomic Laboratory Hub.
• MT-RNR1 variants are subject to mitochondrial inheritance, so families should be counselled that any positive genomic testing result would be relevant to relatives along the maternal lineage. If you need further information or advice on this matter, contact the genomic counselling team within your regional clinical genetics service.
• Information about patient eligibility and test indications were correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• Medicines and Healthcare products Regulatory Agency: Drug safety update: Aminoglycosides (gentamicin, amikacin, tobramycin and neomycin): Increased risk of deafness in patients with mitochondrial mutations
• National Library of Medicine: Gentamicin therapy and MT-RNR1 genotype
• NHS England: National Genomic Test Directory

References:

• McDermott JH, Mahaveer A, James RA and others. ‘Rapid point-of-care genotyping to avoid aminoglycoside-induced ototoxicity in neonatal intensive care‘. Journal of the American Medical Association Pediatrics 2022: volume 176, issue 5, pages 486–492. DOI: 10.1001/jamapediatrics.2022.0187
• McDermott JH, Wolf J, Hoshitsuki K and others. ‘Clinical Pharmacogenetics Implementation Consortium guideline for the use of aminoglycosides based on MT-RNR1 genotype‘. Clinical Pharmacology & Therapeutics 2022: volume 111, issue 2, pages 366–373. DOI: 10.1002/cpt.2309