As the opportunities to undertake genomic sequencing in the clinical setting expand, physicians play an increasing role in the genetic testing process, both at the point of request and in receiving and communicating results. It is therefore paramount that doctors keep pace with all aspects of the genetic testing workflow, to provide high quality care. Here, Paul Newey considers the latest issues you can expect to encounter in the clinic.

Barely a week passes without a story hitting the headlines, heralding a major medical breakthrough only made feasible by the recent advances in DNA sequencing technology: ‘Shark DNA could help cure cancer’ ‘Skinny genes the secret to staying thin’ ‘Can your DNA tell you what to eat?’¹

Inevitably, such stories raise public expectations regarding the potential utility of genetic testing to improve health, and the impact on the public consciousness is borne out by an increasing demand for direct-to-consumer testing, offered by a growing number of commercial providers.

In the UK, successive governments have displayed similar enthusiasm for genetic testing, supporting major initiatives such as Genomics England’s 100,000 Genomes Project and, more recently, announcing an ambition to map 5 million genomes over the next 5 years.²

Although such large scale sequence projects can feel far removed from day-to-day medical practice, the indications and opportunities for genetic testing in the clinical setting continue to accelerate, such that all doctors require a working knowledge of the genetic testing process that is fit for purpose. This includes having the clinical acumen to select and utilise genetic tests appropriately, as well as the necessary tools to communicate results accurately and effectively to patients and their families.

Indeed, as genetic testing moves from dedicated clinical genetics services into mainstream medical clinics, physicians need to be aware of the many challenges associated with contemporary testing. Two such areas include ‘What constitutes informed consent?’ and ‘What should we do when we receive uncertain test results?’.

INFORMED CONSENT: IS GENETIC TESTING SPECIAL?

In the minds of both the medical profession and the general public, genomic data carry a special status. As a consequence, genetic testing has typically involved the provision of genetic counselling prior to seeking informed consent.

One reason for this ‘special’ status is the potential to ‘unlock’ information that has health implications for a wider circle of family members, for which the patient becomes gatekeeper. As a consequence, the genetic counselling and consent process has typically involved pre-emptive discussions on the implications of the test results, the willingness of the patient to share relevant genetic data with family members and, if appropriate, issues relating to the risks to existing and future offspring.

However, as the landscape of genetic testing changes, so do the considerations relevant to counselling and consent. For example, whilst traditional single gene tests for highly penetrant monogenic disorders have typically given binary results (i.e. positive or negative), the shift towards high-content testing (e.g. disease-targeted gene panels, whole genome sequencing (WGS)) raises many additional issues, not least a substantially increased likelihood of identifying uncertain test results (e.g. variants of uncertain significance, see below) or clinically relevant findings incidental to the indication for testing (i.e. ‘incidental findings’).

Indeed, the potential complexities of current high-content testing strategies ensure that it is not feasible to discuss all hypothetical outcomes of testing, although the possibility of ambiguous test results and/or IFs should be discussed, and specific consent sought to determine if ‘actionable’ IFs are to be disclosed.

Furthermore, high-content testing raises additional ethical considerations, including those relating to long term data storage, data sharing (whilst preserving patient privacy) and how to deal with newly available information that may impact upon earlier test results (e.g. variant re-classification, or emergence of new testing strategies).

It seems likely that, in the longer term, out of necessity, we will become more pragmatic about genetic data, and its ‘special’ status will diminish. In addition, the continued exponential rise in genetic testing ensures that existing models of care, based on one-to-one genetic counselling, are increasingly impractical.

Looking forward, it remains unclear how the consent process will evolve, although this is likely to be shaped by a combination of ethical concerns and practical considerations.

VARIANT INTERPRETATION: DEALING WITH UNCERTAINTY

The clinical utility of a given genetic test is dependent on the accuracy with which the result predicts a health outcome in the individual. For monogenic disorders this is dependent on several factors, including the disease penetrance (i.e. the likelihood that a mutation carrier will manifest disease), clinical expressivity (i.e. the range of phenotypes associated with the genetic abnormality) and, perhaps most importantly, the accuracy of variant interpretation. Unfortunately, many of our prior assumptions regarding these factors have turned out to be inaccurate. For example, both reporting and ascertainment biases have led often to estimates of disease penetrance being substantially overstated, whilst recent large scale sequencing projects have resulted in many previously reported pathogenic variants being reclassified as benign.^3,4

The majority of molecular genetic laboratories now adopt the American College of Medical Genetics and Genomics (ACMG) guidelines for variant interpretation, which consider multiple variant- and gene-specific features, to categorise variants into one of five groups (‘pathogenic’, ‘likely pathogenic’, ‘variant of uncertain significance’ (VUS), ‘likely benign’, and ‘benign’).⁵ However, variant interpretation remains imprecise and these groups are not absolute. The VUS designation occurs when there is insufficient evidence to support a more definitive interpretation (either benign or pathogenic), often arising when relevant information is either absent, incomplete or conflicting. With high-content tests, this situation arises frequently, reflected by the observation that ~40% of all variants in the ClinVar database have a VUS designation.⁶

Unfortunately, the ‘uncertainty’ of a VUS result can spread to the clinician’s decision-making. Whilst, by definition, the VUS category is not sufficient to make a molecular diagnosis, it is important to consider the result in the overall clinical context of the patient. For example, how does the result ‘fit’ with the clinical phenotype and family history? This may help to establish if further clinical follow up or investigation is warranted. In addition, acknowledging that the VUS category covers a range of probabilities, maintaining good lines of communication with the clinical and molecular genetics team may allow a more refined estimate of disease risk. When a VUS is identified, cascade testing of asymptomatic family members is not usually appropriate, although the testing of affected members may increase (or refute) support for pathogenicity.

Finally, it is important to highlight that variant interpretation should not be considered as a static one-off event, but rather as a dynamic process that may change as new information comes to light. As such, establishing procedures that allow periodic re-evaluation of variants is likely to be of benefit.

STEAMING FORWARD OR ‘ICEBERG AHEAD’?

The recent rapid progress in DNA sequencing technology has far outpaced our ability to accurately interpret the huge wealth of data generated. However, as the costs of high-content genetic tests plummet to those of other routinely used diagnostic tools (e.g. cross-sectional imaging), it seems unlikely that, as a profession, we will be able to resist the temptation to deploy testing on a population scale.

For example, many already advocate population-level primary screening for the first wave of hereditary cancer predisposition genes (e.g. BRCA1, BRCA2, MLH1, MSH2),⁷ whilst arguments extending such testing to additional genes, including those associated with monogenic endocrine tumour disorders (i.e. SDHB, SDHD, MEN1, VHL, RET) are not likely to be far behind.

However, several studies have reported an unexpectedly high frequency of apparent mutation carriers in the background population, indicating that the implementation of such population-level testing would probably result in a huge demand for downstream tumour surveillance programmes.³ Therefore, until we have more robust methods for variant interpretation and establishing accurate estimates of disease penetrance, such population-level approaches are likely to prove problematic.

Outside the confines of the medical clinic, the recent US Food and Drug Administration (FDA) approval of the first direct-to-consumer genetic testing for a limited number of BRCA1/BRCA2 mutations suggests a public appetite for primary prevention genetic testing,⁸ and, increasingly, patients are likely to attend medical clinics with the results of genetics tests from private providers. Doctors will need the skills to understand these test results and to determine appropriate courses of action.

Finally, despite the enormous apparent progress, it remains unclear to what extent the genetic testing revolution will deliver truly transformative health benefits. As we approach the 20-year anniversary of the completion of the first draft of the Human Genome Project, it is worth reflecting how far (or not) we have come. Announcing this event in June 2000, US President Bill Clinton stated: ‘Genome science will have a real impact on all our lives – and even more, on the lives of our children. It will revolutionise the diagnosis, prevention and treatment of most, if not all, human diseases.’⁹ Nearly two decades later, we remain a long way from such aspirations and, until our understanding of the complexity of genetic information and its relevance to health improves, the utility of genetic testing on a global level may be modest. In reality, the field of clinical genetic testing remains at the start of its journey. As a profession, we probably have no choice but to climb on board, albeit ensuring we have a life jacket packed.

Paul J Newey, Senior Lecturer and Honorary Consultant in Endocrinology, Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee

REFERENCES

1. BBC News 2019 www.bbc.co.uk/news/topics/c40rjmqdw54t/genetics.
2. Genomics England 2018 www.genomicsengland.co.uk/matt-hancock-announces-5-million-genomes-within-five-years.
3. Newey PJ et al. 2017 Journal of the Endocrine Society 1 1507–1526.
4. Lek M et al. 2016 Nature 536 285–291.
5. Richards S et al. 2015 Genetics in Medicine 17 405–424.
6. Manolio TA et al. 2017 Cell 169 6-12.
7. Turnbull C et al. 2018 Nature Genetics 50 1212–1218.
8. Gill J et al. 2018 JAMA 319 2377–2378.
9. CNN 2000 transcripts.cnn.com/TRANSCRIPTS/0006/26/bn.01.html