Finding the broken helix: The mainstreaming of genomic medicine into clinical biochemistry

‘It was a frightening and confusing year’, says sixteen-year-old Michelle, whose mother had recently been diagnosed with breast cancer. Earlier in the same year, her grandmother had succumbed to the same illness. ‘My sister and I had heard that there were tests available to screen for cancer but there was confusion about what the results meant and whether it was better to know the results’, she said. Her sister Lucy was more stoical. ‘It is better to know if you are at risk or affected so that you can prepare yourself’. Unlike her sister, Lucy believed to be forewarned was to be better prepared. ‘When I decided to have the test done I wasn’t going to coerce my sister into having it too’, she said, ‘but I was frightened with the prospect of having to spend the rest of my life, if found to be positive, with the anxiety of impending doom’

This is one typical scenario when it comes to screening for all kinds of diseases. When is it ethical to have such tests? Does a young person have a right to such tests? Many misunderstandings abound about the validity and veracity of tests offered by commercial organisations looking to make a ‘fast buck’ at the expense of the ‘worried well’. The renowned Hollywood actor Angelina Jolie sums it up well when she says, ‘Once I knew that this was my reality, I decided to be proactive and to minimise the risks as much as I could’. ¹ It is well known that Angelina had a preventative double mastectomy.

The rise of screening tests: Is it justifiable?

Screening for diseases, genetic or otherwise, may be defined as the process of identifying the presence of disease before it manifests itself. ² Although the central tenet is a laudable one, there are some limitations with screening when it comes to genetics as will be discussed below. With advances in genomic technology, it is now possible to determine rapidly and at reduced cost the sequence of the whole genome or the exome, which is the portion of the genome known to encode proteins. ³ However, determining whether any given variant is disease-associated remains a major challenge especially for rare diseases where a variant might be unique for a single individual. ⁴ Thanks to the ‘Angelina Jolie effect’ ⁵ the breast cancer genes (BRCA) have captured the public’s imagination in recent times, offering both an opportunity and a challenge.

Genetic testing in the United Kingdom National Health Service: Who gets tested?

In the UK, genetic testing is available through a network of laboratory ‘hubs’ under the aegis of NHS Genomic Medicine Service ⁶ that specialise in offering testing for a number of heritable conditions. They have an ambitious aim of sequencing 500,000 whole genomes by 2023/24. There is a National Genomic Test Directory available, setting out the minimum criteria for testing variants together with other useful information. ⁶ These criteria are by no means infallible and have likely been drawn up to balance sensitivity against specificity; clinical effectiveness against financial viability.

Commercial genetic testing: Direct-to-consumer or direct-to-confusion?

As the NHS criteria pose some limitations to availability, commercial organisations offering direct-to-consumer (DTC) genetic tests have grown in number recently. They offer genetic information regarding family trees, ancestry, multi-factorial conditions, likelihood of inherited diseases and phenotypic traits like eye colour. ⁷ However, these companies have come under increasing criticism lately because they do not provide a comprehensive genetic risk assessment as they do not include all the genes associated with a given condition. ³ Ironically, the reports issued bear disclaimers that the results may not be accurate and are not for clinical purposes, which calls into question their clinical utility. In addition, the nomenclature they use is not consistent with the internationally recognised guidelines which can mislead both patients and clinicians. ⁷ Whether DTC testing is a positive step in the right direction or is generating additional confusion remains to be established but it appears they are destined to stay.

Genetic testing: Promises and pitfalls

Much has been said about the promises of the ‘clinical genomics revolution’ but caution is necessary. ⁸ It is known that as a result of changes to DNA other than sequence alterations also known as ‘epigenetics’, which is induced by environmental or other factors, a gene sequence may not always be reflective of a phenotype. ⁷ Thus, there is potential for confusion if there is no expert counselling available. As most of the DTC companies do not yet provide full comprehensive testing of all potential disease-associated variants, there is potential for giving a false sense of security to an individual if they harbour a specific disease-associated variant that has not been tested (false negative result), for example, there are numerous variants associated with the BRCA genes, ⁹ yet one DTC company only tests for three variants. ⁵ In addition, it has been reported that DTC tests can result in misclassified variants, for example, calling a variant ‘of unknown significance’ when in fact it is disease-associated. ¹⁰ Also, an incidental finding not related to the initial request for a genetic test may result in additional anxiety for both the individuals and their families. As there is rarely any pre-test or post-test counselling provided by the DTC companies, an incidental finding especially if not treatable raises an interesting ethical dilemma. One of the principles of a screening test is that the condition should be treatable otherwise it serves no useful purpose. An important criticism levelled against DTC companies is the lack of quality assurance schemes to guarantee the veracity of the results they provide. ¹¹ Perhaps regulation may be necessary to enforce this. Although there has been progress in the ‘bioinformatics’ processing of sequence data in terms of identifying whether a variant is associated with a disease, this still remains a challenge as evidenced by the number of genetic reports issued with ‘variants of unknown significance’. Continued developments in computer technology including artificial intelligence could help manage this better. Storage of genetic information also needs to be taken into consideration and carries both logistical and ethical implications. For insurance coverage, a positive diagnostic genetic test for any condition is part of an individual’s medical history and can adversely affect the outcome of a policy.

Yet another role for the clinical biochemist

In recent years, clinical biochemists have seen a rise in the number of genetic tests being requested. We all welcome scientific developments, but this needs to be coupled with appropriate training and resourcing. Hospitals with biochemical genetics, new-born screening or paediatric clinical biochemistry laboratories may have expertise in handling these requests; however, genetic testing may be necessary in many day-to-day biochemistry scenarios:

• Puzzling thyroid function tests that may point to thyroid hormone resistance syndromes (RTH) or familial dysalbuminaemic hyperthyroxinaemia (FDH). ¹²

• Calcium-related disorders caused by variants in the calcium-sensing receptor. ¹³

• Variants that cause hypophosphataemia that mostly go undiagnosed in many individuals. ¹⁴

• Endocrine-related conditions such as MODY, MEN and phaeochromocytoma. ¹⁵

• Bone-related disorders such as hypophosphatasia, a condition that presents with low alkaline phosphatase (ALP) and is known to be a commonly missed diagnosis. ¹⁶

This list is by no means exhaustive. As more variants of clinical significance are linked to various common disorders, requests for testing are likely to increase in the very near future. Already access to some therapy is predicated based on results from genetic testing. Most biochemistry departments would have seen an upsurge in requests for dihydropyrimidine dehydrogenase (DPD) genotyping before chemotherapy with fluoropyrimidines, which is the most commonly used cytostatic drug in the systemic treatment of cancer prescribed. ¹⁷ The key question is whether the profession has fully come to grips with the fact that genomic medicine has surreptitiously been ‘mainstreamed’ into clinical biochemistry.

Are we prepared for the next revolution in clinical biochemistry?

For the NHS, the shortage of skilled genetic counsellors poses a huge barrier to engaging with patients effectively. There is evidence that patients are presenting to their primary care physicians with genetic reports demanding access to all sorts of treatments. In many cases, physicians may not be familiar with the report format, the terminology used nor have recourse to further guidance. We need to start preparing to embrace this new opportunity because the breakthroughs are unravelling at a fast pace. Genomics holds great promise for revolutionising healthcare both from a patient’s and clinician’s perspective. As clinical biochemists, we play a pivotal role in understanding the science, liaising with the clinicians and vetting requests appropriately. Until then, the quest for finding the broken helix continues.