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Ethical signposts for clinical geneticists in secondary variant and incidental finding disclosure discussions

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Abstract

While ethical and empirical interest in so-called secondary variants and incidental findings in clinical genetics contexts is growing, critical reflection on the ethical foundations of the various recommendations proposed is thus far largely lacking. We examine and critique the ethical justifications of the three most prominent disclosure positions: briefly, the clinical geneticist decides, a joint decision, and the patient decides. Subsequently, instead of immediately developing a new disclosure option, we explore relevant foundational ethical values and norms, drawing on the normative and empirical ethical literature. Four ethical signposts are thereby developed to help guide disclosure discussions. These are: respectful sharing of the clinician’s expertise; transparent communication; epistemic modesty; and respect for the embedded nature of the patient. We conclude by considering the most common current disclosure positions in the light of the four ethical signposts.

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Notes

  1. Note that we consistently use the term ‘genetic test’ (/’genetic testing’) throughout this paper, because of the focus on genetics contexts and geneticists. However, we are mainly referring to genomic tests, exomic tests, or tests that target a panel of genes. These tests utilise techniques such as array-comparative genomic hybridisation (array-CGH) and next generation sequencing (NGS). These techniques are increasingly being used in clinical contexts instead of older genetic techniques, and are more likely to generate SVs/IFs than previous techniques.

  2. For example, in 2013 the American College of Medical Genetics and Genomics (ACMG) published recommendations for the reporting of SVs/IFs in clinical exome and genome sequencing. The recommendations included a “minimum list” of secondary variants that laboratories should always seek and report to clinicians, whenever clinical sequencing is carried out. Secondary variants were admitted to the list if they were able to be confirmed by other diagnostic methods and were medically actionable based on current evidence and the clinical consensus of the authors of the recommendations. Such clinical consensus can be difficult to obtain, as evidenced by an article written by the same authors of the recommendations (cf. Green et al. 2012). Agreeing upon a list of secondary variants is thus still a work in progress.

  3. Taking the example of the list of secondary variants developed by the ACMG (endnote 2), their decisions were based on medical factors (verifiability and medical actionability of the variant), rooted in the ethical norm of the clinical duty to promote the wellbeing of patients.

  4. ‘Clinical utility’ can be defined as the likelihood that knowing the result will effect a positive change in clinical management, ending in net benefit for the patient (Cf. Sanderson et al. 2005).

  5. This is also true in research contexts (cf. Bredenoord et al. 2011a).

  6. ‘Actionability’ refers to whether knowing a result will lead to or enable some sort of action. For example, knowing that one harbours a mutation related to colon cancer is ‘actionable’ because there are certain preventive measures available such as increased screening; it is debatable whether knowing that one harbours a mutation related to Alzheimer’s disease is actionable, because there are no prevention or early treatment options available. ‘Clinical validity’ refers to the ability of the genetic result to predict that particular condition (Cf. Sanderson et al. 2005). Some results can be clinically valid without having clinical utility; other results might have neither clinical validity nor clinical utility, if the clinical consequences are unknown.

  7. For example, the oft-cited “binning method” for IFs developed by Berg et al. relies solely on clinically defined criteria (cf. Berg et al. 2011). A recent so-called ‘novel method’ for evaluating IFs for disclosure also bases itself heavily on clinically defined criteria, to the exclusion of other criteria (cf. Goddard et al. 2013). An alternative way of judging SVs/IFs would be to make room for other factors that might also be important for patients, such as the potential impact of the disease and the financial cost (cf. Bennette et al. 2013).

  8. We acknowledge that what follows is based on a relatively unsophisticated view of utilitarianism, emphasising utility and net benefit; this is all that is needed for the purposes of our argument. For a more detailed discussion (cf. e.g. Driver 2009).

  9. Cf. the results of two recent qualitative studies on the views of parents regarding the disclosure of SVs/IFs (Christenhusz et al. 2014 and Driessnack et al.). Many participants showed an openness to the ambiguities of life and a more integrated view of the potential impact of a given SV/IF than the concept of “net benefit” would seem to allow.

  10. For example, solidarity and relationality have entered the ethical debate on genetic and genomic issues in discussions on whether individuals might have a duty to share relevant, beneficial genetic results with their family members and partners.

  11. The “dynamic consent” model is one attempt to realise the process nature of consent practically (cf. Kaye et al. 2014). Dynamic consent utilises a personalised, digital communication interface between researchers and participants. The aim is participants who will be more engaged, informed and scientifically literate and thus able to tailor and manage their own consent and return of results (including SVs/IFs) preferences. Developed in biobanking contexts, it has application potential in other domains such as the clinic. It remains to be seen whether digital communication is a sufficient substitute for face-to-face contact especially in clinical contexts, or whether the two forms could be combined.

  12. Principlism has received so much critique over the years that this hardly needs repeating here.

  13. Moreover, autonomous choice can only be expressed fully in a society in which the consequences of that choice are possible. For example, there is something lacking in the autonomous choice to be tested for the BRCA1 mutation associated with an increased risk of breast and ovarian cancer, if the recommended prevention strategies of increased screening and a prophylactic mastectomy are unavailable in one’s country. It must be acknowledged that the present article has been written from a Western perspective, in which the medical actionability of at least some SVs/IFs is a ready possibility.

  14. For example, the question of whether it is just to devote public resources to the increased follow-up costs of genetic tests conducted on individuals.

  15. A typical pleiotropic association is the ApoE gene; mutations in this gene are associated with increased risk of cardiac disease and Alzheimer’s disease.

  16. A form of non-coercive paternalism that involves presenting a range of options in such a way that people are more likely to choose what will most enhance their welfare. A similar, earlier concept is ‘informative paternalism’ (cf. Nikku 1997).

  17. Clinical validity and clinical utility have been defined above (endnotes 4 and 6). ‘Analytic validity,’ as defined by Sanderson et al., refers to how accurately and reliably a given genetic test identifies a certain genotype. Analytic validity is measured in a laboratory, not in a clinical setting.

  18. There are arguments in favour of limiting the number of SVs/IFs as far as possible before conducting a genomic test; e.g. Christenhusz et al. 2012. Unrestricted choice before the test is carried out can be overwhelming (cf. Bredenoord et al. 2011b; Bowdin et al. 2014). Also, information-overload through disclosing too many results runs the risk of drowning out the seriousness of the truly important findings (cf. Christensen and Green 2013).

  19. E.g. heart disease might be nothing big for one person and the end of the world for someone else. One person may explicitly desire to know an SV/IF indicating Alzheimer’s disease because their mother had it, while their sibling may explicitly not want to know because of the same experience. The ‘phenotype-meaning gap’ is analogous to the established ‘genotype-phenotype gap,’ the phenomenon that the same genetic profile can sometimes be expressed in a variety of ways, thus limiting the predictive power of genetic information.

  20. Epistemology refers to the study of knowledge. With the term “epistemic modesty” we mean to refer to a conscious acknowledgement of the limitations of knowledge and thus the limitations of what can be communicated about SVs/IFs.

  21. At this time, this clinical benefit is especially evident in their use in gene identification for unresolved genetic disorders in individuals with developmental disabilities or congenital anomalies.

  22. Although the primary finding may not always be ‘found’; i.e., some conditions may remain undiagnosed genetically.

  23. E.g. childhood, early adulthood, early career and/or family life, middle age, retirement.

  24. For example, when disclosing an SV/IF predicting Huntington’s disease in a patient who is just about to start a family, it would be appropriate to also discuss their options regarding having children. If the patient already had adult children, it would be appropriate to also discuss how they might disclose this information to their children. The varying impact of SVs/IFs at different points in the life cycle has been raised as an issue in empirical research; e.g. Christenhusz 2014.

  25. Very few genetic conditions will develop with 100 % certainty. Huntington’s disease is one of the rare examples, but even then there is the uncertainty of when it will manifest.

  26. As evidenced for example by two studies involving Dutch general practitioners, gynaecologists, paediatricians, and medical students (cf. Baars et al. 2005a, b).

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Acknowledgments

K. Devriendt and H. Van Esch are senior clinical investigators of the FWO-Vlaanderen and of the “Interuniversity Attraction Poles” programme of the Belgian federal scientific policy office, Project P7/43 “BeMGI.”

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Centre for Biomedical Ethics and Law, KU Leuven, Kapucijnenvoer 35, 3000, Leuven, Belgium

    Gabrielle M. Christenhusz & Kris Dierickx

  2. Centre for Human Genetics, KU Leuven, Leuven, Belgium

    Koenraad Devriendt & Hilde Van Esch

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  1. Gabrielle M. Christenhusz
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Correspondence to Gabrielle M. Christenhusz.

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Christenhusz, G.M., Devriendt, K., Van Esch, H. et al. Ethical signposts for clinical geneticists in secondary variant and incidental finding disclosure discussions. Med Health Care and Philos 18, 361–370 (2015). https://doi.org/10.1007/s11019-014-9611-8

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