Secondary findings from whole-exome/genome sequencing evaluating stakeholder perspectives. A review of the literature

Abstract

With the development of next generation sequencing, beyond identifying the cause of manifestations that justified prescription of the test, other information with potential interest for patients and their families, defined as secondary findings (SF), can be provided once patients have given informed consent, in particular when therapeutic and preventive options are available. The disclosure of such findings has caused much debate. The aim of this work was to summarize all opinion-based studies focusing on SF, so as to shed light on the concerns that this question generate. A review of the literature was performed, focusing on all PubMed articles reporting qualitative, quantitative or mixed studies that interviewed healthcare providers, participants, or society regarding this subject. The methodology was carefully analysed, in particular whether or not studies made the distinction between actionable and non-actionable SF, in a clinical or research context. From 2010 to 2016, 39 articles were compiled. A total of 14,868 people were interviewed (1259 participants, 6104 healthcare providers, 7505 representatives of society). When actionable and non-actionable SF were distinguished (20 articles), 92% of respondents were keen to have results regarding actionable SF (participants: 88%, healthcare providers: 86%, society: 97%), against 70% (participants: 83%, healthcare providers: 62%, society: 73%) for non-actionable SF. These percentages were slightly lower in the specific situation of children probands. For respondents, the notion of the «patient's choice» is crucial. For healthcare providers, the importance of defining policies for SF among diagnostic lab, learning societies and/or countries is outlined, in particular regarding the content and extension of the list of actionable genes to propose, the modalities of information, and the access to information about adult-onset diseases in minors. However, the existing literature should be taken with caution, since most articles lack a clear definition of SF and actionability, and referred to hypothetical scenarios with limited information to respondents. Studies conducted by multidisciplinary teams involving patients with access to results are sadly lacking, in particular in the medium term after the results have been given. Such studies would feed the debate and make it possible to measure the impact of such findings and their benefit-risk ratio.

Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes

“…It is thus expected, as observed here, that clinically significant variants with reduced penetrance and adult-onset conditions are detected with considerable frequency. While a majority of individuals are generally willing to receive identified actionable SF[24] and disclosure of positive results shows little to no adverse impact on participants and adds only modestly to near-term health-care costs (Hart MR 2019), the impact of reporting SF in IVF patients/gamete donors has not yet been sufficiently addressed. In 2014, a European Society of Human Reproduction and Embryology (ESHRE) task force[25] supported a broader view on preimplantation genetic testing for monogenic disease (PGT-M), including the health of third generations, which should be considered in light of recent developments in exome/genome sequencing-based PCS.…”

Parents’ motivations, concerns and understanding of genome sequencing: a qualitative interview study

“…The subject of secondary findings raises a number of ethical and clinical issues. Whilst studies have shown that most key stakeholders think that both actionable and nonactionable secondary findings should be returned [11,12], healthcare professionals have acknowledged the increase in workload of clinical scientists and clinicians in interpreting and returning such results [12]. Questions have also been raised about who should consent patients and deliver test results [13].…”

Criteria for reporting incidental findings in clinical exome sequencing – a focus group study on professional practices and perspectives in Belgian genetic centres

“…In that case, it is quintessential for every CMG to disclose its local policy. On the other hand, and in line with the non-standardised outcome of the interaction between the clinical significance of IFs and patient characteristics, a flexibility in guidelines’ application has been advocated so they can be accustomed to the particular context [44]. Together with the professional expertise in CMGs, this call for a personalised deliberation nuances the need for and effectiveness of a rigid “one model fits all” policy [23].…”