Criteria for reporting incidental findings in clinical whole exome sequencing : professional practice and perspective in Belgian genetic centres

Background: Incidental findings (IFs) are highly discussed as potential consequences of whole exome sequencing in a clinical context (clinical WES) and international recommendations on the guiding criteria for reporting, largely vary. Even though the American College of Medical Genetics and Genomics advises to additionally analyse a panel of 59 highly-penetrant and medically actionable genes in every case of clinical WES, this opportunistic screening has been criticized for holding additional health risks, overwhelming patients with (ambivalent) information and stimulating a trend of medicalization. Therefore, various professional boards advocate to minimize the possibility of IFs by targeted panel testing and by a strictly necessary and proportional application of WES. Patient opt-out possibilities are another contested topic regarding IFs, and values of professional duty and patient autonomy are variably used to support divergent policy recommendations. The guidelines’ diversity permits a non-standardized practice, which might result in highly variable care between and within countries. Our study aimed to determine the actual implementation of international guidelines regarding IFs and their impact on national procedures. Methods: To realize an insight in a national practice and implementation of guidelines, a qualitative study has been undertaken with a focus group discussion in each of the eight Belgian Centres for Medical Genetics (CMG). Data were analysed thematically, resulting in six main themes, including one regarding the criteria for reporting IFs in a context of clinical WES in adults. Results: Despite the limited experience with IFs in clinical WES, professionals discerned two groups of criteria for reporting: first, characteristics of the IF (clinical significance and actionability) and, second, patient-related factors (personal characteristics and the preference to know). First, CMGs refer to similar characteristics of the IF, being clinical significance and actionability, but these characteristics’ definitions occurred to be challenging, which results in a diversity among CMGs concerning specific requirements for reporting. The sometimes unclear relevance of a VUS (variant of uncertain significance), the dynamic nature of variant classifications and discussions on the clinical relevance of a carrier status might complicate an IF’s pathogenic classification. Actionability, as a second important and generally approved condition for reporting an IF, was depicted as difficult to define and delineate. Moreover, not reporting non-actionable but severe IFs can be a burdensome decision for professionals. Second, an IF’s characteristics interact with a patient’s personal characteristics, such as her reproductive plans, family history of illness or primary condition (for which the test is initiated). The result of this interaction is not standardized, and therefore, the decision on reporting frequently requires a professional and multidisciplinary deliberation. Furthermore, opt-out possibilities regarding IFs strongly diverge between Belgian CMGs, ranging from no opt-out opportunity for actionable IFs to an absolute opt-out possibility. Remarkably, several CMGs considered exceptions on or even a re-evaluation of their current practice to be possible. Conclusion: The challenging interpretation of criteria results in a varied perspective on the reporting of IFs within Belgian CMGs, which echoes the international variation in recommendations. Moreover, the interaction between criteria hinders the uniformity of general guidelines and results in a casuistic and contextualized practice. Therefore, (inter)national guidelines on the reporting of IFs can only be effective when they are, on the one hand, sufficiently detailed and fine-grained regarding the definitions of used criteria, and, on the other hand, flexible enough to fit the particularity of every patient’s situation