Pharmacogenomics: Commissioned tests
Only a few pharmacogenomic tests are currently commissioned by the NHS. However as more genomic information becomes available, personalised medicine becomes more embedded in healthcare and more drugs requiring genomic testing are licensed this is likely to change.In England, information on what tests are commissioned can be found in the National Genomic Test Directory (NGTD). There is no directory specifically for pharmacogenomic tests: you will need to check either the directory for rare and inherited diseases, or the one for cancer. Currently the NGTD includes the following;
Some patients carry specific variants in the DPYD gene which can result in deficiency of dihydropyrimidine dehydrogenase (DPD), which is an enzyme responsible for metabolising systemic fluoropyrimidine cancer chemotherapy (e.g. capecitabine, 5-fluorouracil). Use of these drugs in these patients could result in severe or life-threatening adverse effects (e.g. stomatitis, diarrhoea, mucosal inflammation, neutropenia and neurotoxicity). Therefore patients who require systemic fluoropyrimidines must undergo pharmacogenomic testing before starting treatment. If they are found to have a variant that results in reduced activity of the enzyme, then patients may be offered alternative therapy or a lower dose of the drug.
6-mercaptopurine is prescribed for patients with acute lymphoblastic leukaemia (ALL). It is extensively metabolised by the enzymes TPMT and NUDT15. Variants in the TPMT and/or NUDT15 genes can result in reduced enzyme activity and increased risk of toxicity (e.g. bone marrow suppression). Therefore genetic testing for TPMT and NUDT15 is commissioned for patients with ALL who require treatment with 6-mercaptopurine. Note that genetic testing is not commissioned for other indications requiring 6-mercaptopurine or azathioprine (e.g. autoimmune disorders) which rely on biochemical testing of the activity of the enzymes.
3. Aminoglycoside exposure posing a risk to hearing (R65)
If an individual with a variant of the MT-RNR1 gene has previously received aminoglycosides and not developed hearing loss, this does not exclude them from developing it with subsequent doses. A normal test result does not eliminate the risk of aminoglycoside-induced hearing loss as there are other mechanisms that can cause this.
As described on the previous page, systemic aminoglycoside use (e.g. gentamicin, amikacin and streptomycin) can result in rare cases of ototoxicity and there is some evidence to suggest an association with specific mitochondrial mutations. Currently the commissioned test looks specifically for the presence of the MT-RNR1 m.1555A>G variant (estimated prevalence 1 in 500). Further variants are being added to the NGTD in April 2024.
Tests in the NGTD have a clinical indication identifier code: this test is R65 and you may hear or see it referred to in this way. Patients who have this variant have an increased risk of hearing loss. The test has a 4-6 week turnaround time and so is not suitable for use in acute situations and treatment should not be delayed.
If an individual with a variant of the MT-RNR1 gene has previously received aminoglycosides and not developed hearing loss, this does not exclude them from developing it with subsequent doses. A normal test result does not eliminate the risk of aminoglycoside-induced hearing loss as there are other mechanisms that can cause this.
It may be considered for patients with a predisposition to gram negative infections, for example, due to known respiratory disease (e.g. cystic fibrosis, bronchiectasis) or due to structural or voiding genitourinary disorders. It may also be relevant for patients with hearing loss who have been exposed to aminoglycosides.
Testing for the human leukocyte antigen variant HLA-B*57:01 in patients needing abacavir predated the creation of the NGTD. However it routinely happens in the NHS and is usually available through tissue typing laboratories. Other HLA testing (e.g. for allopurinol, carbamazepine/oxcarbazepine) may be available locally if required.
Some medicines such as siponimod for multiple sclerosis, and mavacamten for symptomatic obstructive hypertrophic cardiomyopathy require genetic testing to guide dosage for their use, but testing is currently provided by the drug manufacturer and is not commissioned by the NHS.
For the devolved nations the All Wales Medical Genomics Service offers tests listed in the NGTD. The Scottish Strategic Network for Genomic Medicine Laboratory offers genomic tests in accordance with Scottish Genomic Test Directory for Cancer and the Scottish Genomic Test Directory for Rare and Inherited Disease. More information for Northern Ireland Regional Genetics Laboratories – Molecular Genetics can be found on their website.
Direct-to-consumer (DTC) testing
DTC tests can be arranged by patients themselves via non-NHS routes without going through a clinician, usually through a private company, and are becoming more widely available. While many tests are concerned with ancestry or heritage, companies may also offer testing for genetic predisposition to certain diseases, carrier testing for inherited conditions (e.g. cystic fibrosis) or for variants within known disease-causing genes.
DTC tests can be arranged by patients themselves via non-NHS routes without going through a clinician, usually through a private company, and are becoming more widely available. While many tests are concerned with ancestry or heritage, companies may also offer testing for genetic predisposition to certain diseases, carrier testing for inherited conditions (e.g. cystic fibrosis) or for variants within known disease-causing genes.
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DTC pharmacogenomic tests relating to variants that might affect drug metabolism are also becoming more commonly available. These may offer a breakdown of a patient's metaboliser status for various CYP enzymes and other enzymes involved in drug metabolism. However the validity, sensitivity, and utility of private DTC tests, including pharmacogenomic tests, are not subject to the same regulation or standards as NHS laboratories so may significantly vary, resulting in risks of false positive or false negative results. It is also unlikely that any counselling or interpretation for the results will be offered.
The Royal College of General Practitioners (RCGP) and the British Society for Genetic Medicine (BSGM) have produced a genomic position statement about DTC genomic or genetic testing.