By Helena Carley, Kate Sahan, Helen Hanson, Katie Snape, Sarah Westbury, Michael J Parker, & Anneke M Lucassen

Current popular discourse surrounding genomics is frequently one of ‘clarity’ and ‘transformation’, concepts projected by the NHS 10 year plan and echoed in the media. Technological advances in genomics over recent years have been impressive: whole genome sequencing (WGS) is now routinely offered in the UK for the investigation of rare disease and can be used in acute settings to inform clinical decision-making. Whilst we share the optimism and hope surrounding genomic medicine, genomic practice on the frontline continues to generate new, complex ethical questions about how to act on genomic findings, how we should counsel patients and relatives, and how specialisms should work together when findings are uncertain but action must be taken quickly.

In this paper we show, through a clinical case example of a variant of uncertain significance identified in the context of stem cell donation for leukaemia, how uncertainty can influence clinical decision-making, impact upon interprofessional working and affect the care of patients and their families. We highlight this as one of a number of examples of uncertainty within genomic medicine, arising at various points in the patient pathway:

• During variant interpretation: different laboratories may disagree about a variant’s role in disease aetiology which can lead to patients with the same variant receiving different care. As we note in the paper, accumulating evidence can mean that the interpretation of variants change over time impacting on clinical recommendations.
• During clinical assessment: population studies show that the likelihood of a given genomic variant exerting an effect is dependent upon the context in which it is detected. Variants once thought to be strongly linked to a particular disease – because they were found in a disease population – often predict that disease much more weakly in a general population setting. Now that genomic testing is routinely much broader than the genes linked to a particular disease, it is less clear how such ‘incidental’ or ‘off-target’ genomic variants should be managed.
• During clinical discussions : even in seemingly straightforward monogenic disorders (where a pathogenic variant might be identified in the context of a consistent clinical history), elements of uncertainty often remain – for example, the way in which a disease will affect an individual and their relatives, and at what age.
• During familial discussions: given scientific and clinical uncertainty, individuals, relatives and practitioners are faced with tough decisions, particularly in our case where the risks of donor derived disease makes a related donor’s cells potentially risky, but even so the donor might feel a familial duty to ‘do something’ for the patient.

In our experience, managing such uncertainty is complex, especially for patients, the general public and health professionals less familiar with genomic medicine. As genomics expands into the prediction of future disease (highlighted through large scale research studies currently investigating WGS in newborn babies to screen for serious treatable early-onset genetic disorders and the use of polygenic risk scores to predict common adult-onset disease), we need to consider how we can make space to discuss these uncertainties in practice. We think this requires wider discussion than health professional circles, so that patients and the public are included and the promise of genomics and its real life limitations are made clear and expectations become more realistic. To this end, cultivating an ethically prepared workforce plus sustained public engagement is crucial to make sense of, and harness maximum value from, advances in genomic science and medicine.

• 1 South East Thames Regional Genetics Service, Guy’s Hospital, London, UK.
• 2 University of Oxford Nuffield Department of Medicine, Oxford, UK.
• 3 The Ethox Centre, Nuffield Department of Population Health, University of Oxford, Oxford, UK 
• 4 Peninsula Regional Genetics Service, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.
• 5 Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK.
• 6 South West Thames Centre for Genomics, St George’s University Hospitals NHS Foundation Trust, London, UK.
• 7 City St George’s, University of London, London, UK.
• 8 Translational Health Sciences, Bristol Medical School, Bristol, UK.
• 9 Department of Haematology, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK.
• 10 The Ethox Centre, Nuffield Department of Population Health, University of Oxford, Oxford, UK
• 11 Oxford Clinical Genetics service, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

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Conflicts of Interest: None to declare