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

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.

A prospective study of the clinical utility of prenatal chromosomal microarray analysis in fetuses with ultrasound abnormalities and an exploration of a framework for reporting unclassified variants and risk factors.

PURPOSE: To evaluate the clinical utility of chromosomal microarrays for prenatal diagnosis by a prospective study of fetuses with abnormalities detected on ultrasound. METHODS: Patients referred for prenatal diagnosis due to ultrasound anomalies underwent analysis by array comparative genomic hybridization as the first-tier diagnostic test. RESULTS: A total of 383 prenatal samples underwent analysis by array comparative genomic hybridization. Array analysis revealed causal imbalances in a total of 9.6% of patients (n = 37). Submicroscopic copy-number variations were detected in 2.6% of patients (n = 10/37), and arrays added valuable information over conventional karyotyping in 3.9% of patients (n = 15/37). We highlight a novel advantage of arrays; a 500-kb paternal insertional translocation is the likely driver of a de novo unbalanced translocation, thus improving recurrence risk calculation in this family. Variants of uncertain significance were revealed in 1.6% of patients (n = 6/383). CONCLUSION: We demonstrate the added value of chromosomal microarrays for prenatal diagnosis in the presence of ultrasound anomalies. We advocate reporting back only copy-number variations with known pathogenic significance. Although this approach might be considered opposite to the ideal of full reproductive autonomy of the parents, we argue why providing all information to parents may result in a false sense of autonomy.

Focus group discussions on secondary variants and next-generation sequencing technologies.

The clinical application of new genetic technologies will be and already is of great benefit to children with unexplained developmental disabilities or congenital anomalies. In most cases, it will be their parents who, together with medical professionals, make decisions about what should be disclosed and how the information will be used. We conducted eight exploratory focus group discussions with stakeholders to provide a broad sketch of concerns and ideas around the communication of results from next-generation sequencing technologies involving children. Stakeholders included those with (grand-) children of various ages and those without children; those involved professionally with genetics and those who were not; and a range of ages. Participants were asked to focus on which secondary variants they would and would not want disclosed about their (hypothetical) children or themselves. While the literature often concentrates on the medical and scientific characteristics of secondary variants, focus group participants were also interested in factors involving the parent-child relationship and the broader context. This resulted in more flexibility surrounding the types of secondary variants disclosed to parents than much of the literature currently supports. In addition, participants would on occasion use the same factors to argue opposing positions. The "Family Illness Paradigms model" can help explain this seeming contradiction. This model emphasises the importance of how the family reacts to personal and family experiences of disease and loss, more than the fact of having these experiences.

Towards a European consensus for reporting incidental findings during clinical NGS testing.

In 2013, the American College of Medical Genetics (ACMG) examined the issue of incidental findings in whole exome and whole genome sequencing, and introduced recommendations to search for, evaluate and report medically actionable variants in a set of 56 genes. At a debate held during the 2014 European Society for Human Genetics Conference (ESHG) in Milan, Italy, the first author of that paper presented this view in a debate session that did not end with a conclusive vote from the mainly European audience for or against reporting back actionable incidental findings. In this meeting report, we elaborate on the discussions held during a special meeting hosted at the ESHG in 2013 from posing the question 'How to reach a (European) consensus on reporting incidental findings and unclassified variants in diagnostic next generation sequencing'. We ask whether an European consensus exists on the reporting of incidental findings in genome diagnostics, and present a series of key issues that require discussion at both a national and European level in order to develop recommendations for handling incidental findings and unclassified variants in line with the legal and cultural particularities of individual European member states.

To tell or not to tell? A systematic review of ethical reflections on incidental findings arising in genetics contexts.

Any test that produces visual images or digital or genetic sequences will tend to produce incidental findings because more will be visible than what was originally sought. We conducted a systematic review of the ethical reasons presented in the literature for and against the disclosure of incidental findings arising in clinical and research genetics contexts. A search of electronic databases resulted in 13 articles included for systematic review. Articles presented reasons for and against disclosure, and reasons for proceeding with caution when making decisions about disclosure. One major recommendation of the reviewed articles is in favor of qualified disclosure: incidental findings with confirmed clinical utility where there is the possibility of treatment or prevention should be disclosed, with exceptions. A second type of recommendation is that disclosure should proceed with caution, especially in the context of new genetic technologies and genetic testing involving minors. It is also recommended that the number of possible incidental findings be limited even before genetic testing is carried out. Such a policy, which we advocate, would show preference for non-disclosure.

Disclosing incidental findings in genetics contexts: a review of the empirical ethical research.

The disclosure of incidental findings, also called unsolicited findings, unexpected results, and secondary variants, is increasingly recognised as an issue in clinical and research genetics contexts. The rise of next generation sequencing methods has only intensified the issue, increasing the likelihood of incidental findings appearing. This review focuses on empirical research on the ethical issues involved. Electronic databases were searched for articles covering quantitative and qualitative research on the ethical issues involved in the disclosure of incidental findings in clinical and research genetics contexts. 16 articles were ultimately accepted for review. Data was extracted and synthesised on the factors that should be taken into account during the decision-making process surrounding the disclosure of an incidental finding in a genetics context. These factors include the possibility of disclosure, various practical and technical factors, and various ethical factors. We suggest the development of a decision-making tree, involving an exploration of the practical and ethical concerns raised by the studies. This is in our view the best way of handling the wide variety of both possible incidental findings and parties interested in the disclosure of incidental findings.

Secondary variants--in defense of a more fitting term in the incidental findings debate.

New genetic technologies are capable of returning far more information than the single answer to the single question posed when conducting a given genetic test. Genetics contexts consequently stand on the brink of an explosion of what have traditionally been called 'incidental findings'. However, the continued use of this term is controversial. Various replacements for 'incidental findings' have been attempted, but none with widespread success. Agreement on terminology and definitions is vital so that the legal and ethical debate around incidental findings can proceed. We highlight the difficulties raised by the various terms currently used as alternatives, and end by defending our choice for the term 'secondary variants'.

Invasive hyphal growth: an F-actin depleted zone is associated with invasive hyphae of the oomycetes Achlya bisexualis and Phytophthora cinnamomi.

We have compared F-actin patterns in invasive and non-invasive oomycete hyphae. In Achlya bisexualis an F-actin depleted zone is present in 70% of invasive but only 9% of non-invasive hyphae. In Phytophthora cinnamomi these figures are 74 and 20%, respectively. Thus, the F-actin depleted zone appears to be associated with invasive growth. TEM images indicate that it is unlikely to represent areas of vesicle accumulation. Measurements of turgor indicate no significant increase under invasive conditions (0.65 MPa (invasive) and 0.63 MPa (non-invasive)). Similarly we found no difference in burst pressures (1.04 MPa (invasive) and 1.06 MPa (non-invasive)), although surrounding agarose may lead to overestimates of invasive tip strength. An F-actin depleted zone has the potential, along with wall softening, to increase protrusive force in the absence of turgor increases. Staining of F-actin in hyphae under hyperosmotic conditions suggests that decreases in F-actin at growing tips may also enable non-invasive growth at very low turgor.