Genetic variation and testing

In the previous step, you learned about ototoxicity – inner ear damage which can be induced by aminoglycosides – and how some patients are genetically predisposed to aminoglycoside-induced hearing loss.

In rare cases, variation in the gene MT-RNR1, found in mitochondria, has been associated with increased rates of hearing loss following even just one single exposure to aminoglycosides. This variation is found in approximately 1 in 500 individuals, but does not guarantee development of hearing loss.

G variant. "MT-RNR1" is the gene symbol. "m." shows this gene is in the mitochondrial region of the genome. "1555" is the position on the gene. "A" is the reference nucleotide that is substituted out at this position. "G" is the substituted nucleotide.”>

Testing for variation focuses on a specific variation noted m.1555A>G and is referenced in a national 2021 MHRA alert, with evidence summarised in international guidelines by the Clinical Pharmacogenetics Implementation Consortium (CPIC).

Why is the gene implicated?

The MT-RNR1 gene codes for a 12s ribosomal RNA (rRNA) subunit, one of two subunits present in the mitochondrial ribosome. Ribosomes translate messenger RNA into polypeptide proteins.

Variation in the gene, including the variation m.1555A>G, appears to alter the 12s rRNA subunit to resemble a bacterial 16s rRNA subunit targeted by aminoglycosides; increasing the binding of aminoglycosides to the mitochondria and causing increased hearing loss from loss of mitochondria.

Evidence for the association of hearing loss in patients with variation in the MT-RNR1 gene is well summarised in guidelines produced by the CPIC and identifies patient case reports and population-based screening approaches, with screening programs mostly completed in neonatal intensive care units. In addition to m.1555A>G, two other variants in the MT-RNR1 gene are implicated: m.1494C>T and m.1095T>C.

The 2021 MHRA drug safety update highlighted the increased risk of aminoglycoside-associated ototoxicity in patients with mitochondrial mutations. Therefore, prior to starting recurrent or long-term treatment, it is important to identify whether or not a patient is at increased risk of ototoxicity. This can be achieved through genetic testing.

Genetic testing

There are several genetic testing approaches to identify variation in the MT-RNR1 gene, but all methods usually focus on identifying individual variants caused by a single change in a base pair within the patient’s DNA. These changes are called single nucleotide variants (SNV). As an example, for m.1555A>G, there is a single base change where adenine is replaced by guanine at the 1555th base pair on the mitochondrial DNA.

Testing may be conducted in a laboratory with scientific interpretation or completed using a near-patient point-of-care test, which provides a result based on the presence (or absence) of any SNVs that are targeted by that particular diagnostic test.

Laboratory testing is currently provided by the Genomic Medicine Service in England and is listed on the National Genomic Test Directory (denoted R65). Point-of-care testing, on the other hand, has no current commissioned routes, but devices are approved for use in the UK and are undergoing further assessment by NICE.

Further information

The genetic predisposition to aminoglycoside-induced hearing loss raises a number of issues relating to the use of genomic information in healthcare. The following resources may be useful to understand some of these issues:

• Meet the mitochondria
• SNVs
• Penetrance
• Prevalence

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