As alluded to above, the increasing use of high-throughput technologies and approaches in genomics, both in the research and clinical contexts, has increased stakeholders’ focus on the topic of unsolicited findings. Unsolicited findings have also been referred to as incidental findings, unsolicited variants, unanticipated results, secondary variants, unexpected or off-target results, unsought results, or unrelated findings [19], as well as non-incidental secondary findings, serendipitous, or iatrogenic findings [20]. The exact meaning of each term as well as their merits has, to some extent, been debated and could, arguably, be even further discussed [19, 21, 22]. However, for the purpose of this chapter, we will use the term unsolicited finding to mean a result found during research or clinical testing that is beyond the aims of the study or the original reason to conduct clinical testing.

Although unsolicited findings are not specific to genomics, the phenomenon is viewed as needing particular attention given the fact that we can now generate unprecedentedly large quantities of sequencing data in a very short time and therefore have access to a lot of information, whether or not it is related to the initial question posed [23]. Many authors have discussed whether or how unsolicited results should be returned to patients in the clinic [24] or to research participants in a research study [25]. Although there remains a lot of discussion regarding details, there appears to be a consensus taking shape: should a clinician or researcher discover a medically actionable variant with established health impact, this information should be returned to patients/participants [26, 27]. For example, the European Society of Human Genetics recommends “If the detection of an unsolicited genetic variant is indicative of serious health problems (either in the person tested or his or her close relatives) that allow for treatment or prevention, in principle, a health-care professional should report such genetic variants” [18]. This being said, the details regarding which variants have utility or impact and the criteria needed to make these decisions are still being debated [23].

Closely related to this topic is the notion of the “duty to hunt” for genomic variants that may have a health impact for patients; that is to say, when performing WES/WGS, do physicians and/or researchers have a duty to actively search the sequence data for variants known to have a health impact but that are not necessarily related to the indication for performing the sequencing in the first place? Although some authors have referred to the findings obtained through this “hunt” as incidental findings [20], others have commented that such intentional “hunting” or searching could not be described as “incidental,” at least not in the “usual sense of the term” and have described the phenomenon as “opportunistic screening” [28, 29]. The discussion regarding the return of results, including the duty to hunt, differs somewhat depending on the context, clinical, or research [30]; herein, we focus on the issue of the duty to hunt in the clinical context.

Perhaps, the most well-known stance supporting a duty to hunt in the clinical context comes from the American College of Medical Genetics and Genomics (ACMG) which, in the first half of 2013, published recommendations supporting “that laboratories performing clinical sequencing seek and report mutations of the specified classes or types in the genes listed here. This evaluation and reporting should be performed for all clinical germline (constitutional) exome and genome sequencing, including the “normal” of tumor-normal subtractive analyses in all subjects, irrespective of age but excluding fetal samples” [20]. The ACMG provided a list of 56 genes associated with 24 inherited conditions that should be screened whenever a patient (of any age) is offered sequencing. The list was developed based on what the ACMG called a “consensus-driven assessment of clinical validity and utility” and focuses on conditions with relatively high penetrance and for which an intervention may be possible. Importantly, the list does not include conditions that are already part of newborn screening. The initial recommendations proposed that patients could not refuse the testing of these 56 genes without also forfeiting the access to WES/WGS. However, in the face of criticisms concerning the lack of support for patient autonomy, shared decision-making, and for patients’ right “not to know” [28, 31, 32], the ACMG changed their stance on this point the following year [33]. The rationale for opportunistic screening is based mainly on the medical benefit for patients and their families, where the identification of a genetic risk could allow for the early adoption of prevention or treatment measures. Furthermore, it is based on the fiduciary duty of clinicians and laboratory personnel to prevent harm. It should be noted, however, that these recommendations are not meant for sequencing done in the context of preconception, prenatal, or newborn sequencing, nor do they apply to the sequencing of healthy children and adults [20].

A number of concerns have been raised in reaction to these recommendations, including a lack of evidence for establishing the list of genes and the lack of information about frequencies of variants in healthy or not-at-risk populations [28]. Such a lack of information could subsequently lead to erroneous classifications of variants as pathogenic, which could cause needless anxiety and cause patients to seek inappropriate and costly follow-up medical procedures [34]. The fact that important stakeholders, such as members of the public and primary care physicians, were absent from the discussion [32] has also been mentioned as a weakness. Of major concern is also the potentially extremely high costs in terms of time, resources, effort, and money to conduct such screening [32]. Furthermore, there has been criticism regarding the screening of children in this context, especially for adult-onset disorders (see below).

Although other professional associations’ and policy groups’ guidelines have mentioned opportunistic screening, they have not outright recommended it [29, 35]. Moreover, the European Society of Human Genetics’ guidelines on the use of WGS in health care advise that approaches such as targeting and filtering be used employed to reduce the chances of even encountering unsolicited findings: “When in the clinical setting either targeted sequencing or analysis of genome data is possible, it is preferable to use a targeted approach first in order to avoid unsolicited findings or findings that cannot be interpreted. Filtering should limit the analysis to specific (sets of) genes. Known genetic variants with limited or no clinical utility should be filtered out (if possible neither analyzed nor reported)” [18]. Although only indirectly addressed within the context of the management of incidental findings in the clinical context, the Presidential Commission for the Study of Bioethical Issues recommends that “Medical educators, both in the classroom and clinic, should continue to cultivate ‘diagnostic elegance’ and ‘therapeutic parsimony’ amongst practitioners—ordering and conducting only tests and interventions necessary for addressing health concerns related to their patient” [36].

In conclusion, currently, there is no general agreement regarding whether clinicians who use WGS or WES for diagnostic purposes also have a duty to hunt for other variants with health impacts. There is, however, a large consensus that much more evidence is needed [20, 28, 34] regarding opportunistic screening and its potential impact on the healthcare system and on patients. Even the ACMG recognizes that “there are insufficient data on penetrance and clinical utility to fully support these recommendations, and we encourage the creation of an ongoing process for updating these recommendations at least annually as further data are collected” [20].

As previously mentioned, the introduction of WES/WGS in the clinic may revolutionize the potential for finding the (molecular) diagnosis of genetic conditions, including movement disorders. Although this may confer benefits in terms of reducing the diagnostic odyssey, and/or improving patient management [7] as well as revealing potential risks for relatives, it also raises ethical issues in relation to genetic testing in children.

As described in the previous section, the use of WES/WGS raises the question as to whether laboratories should limit their reporting of results only to the findings that are relevant to the clinical question at stake or to “hunt” for other variants known to have a health impact. The previously mentioned ACMG guidelines, which recommend the active search of a selected group of genes, including those for conditions with adult onset, have led to a heated debate regarding whether these recommendations should also apply to children. The ACMG states that “masking or tailoring the reporting of such information according to the age of the patient could place an unrealistic burden upon laboratories facing increasing volumes of clinical sequencing. The Working Group also felt that the ethical concerns about providing children with genetic risk information about adult-onset diseases were outweighed by the potential benefit to the future health of the child and the child’s parent of discovering an incidental finding where intervention might be possible. Therefore, the Working Group recommended that recommendations for seeking and reporting incidental findings not be limited by the age of the person being sequenced” [20].

These recommendations appear to be in stark contrast to previous recommendations for predictive testing in children as well as to a set of guidelines which were jointly released by the American Academy of Pediatrics (AAP) and the ACMG in 2013 [37, 38]. The AAP/ACMG guidelines recommend that children should generally not receive genetic testing for adult-onset disorders, particularly where no treatment is available [37, 38]. It should be noted, however, that the contextual background of testing differs somewhat for each set of guidelines. The AAP/ACMG guidelines are generally situated in a clinical setting where parents may request predictive testing for their child for an adult-onset condition that is already known in the family [37, 38]; no particular strategy or tool for testing is mentioned nor do they mention a situation of opportunistic screening. The ACMG guidelines, on the other hand, relate specifically to a situation such as Jack’s, described above, where WES/WGS is used as a diagnostic approach [20].

This contextual difference translates to two important distinctions between the WES/WGS diagnostic approach from the standard predictive testing context [39]. First, the nature of the tools or approach used for diagnostic purposes in Jack’s case means that the sequence data is already available for the “hunt” rather than a specific test being performed only for the reason of testing an adult-onset condition. Second, the genetic predisposition Jack carries for BRCA1 may not have been identified previously in the family, and reporting of the variant could, therefore, potentially lead to early detection of risk and implementation of screening for both Jack in the future and also for relatives. These are the primary drivers of the ACMG’s recommendations for reporting these variants [20].

Although the reporting of results from opportunistic screening might result in health benefits for the children or their family, we must also consider the potential (harmful) impact when one of these variants is identified in a child and disclosed to the family. Standard genetic guidelines for predictive testing in children often indicate that when there is no medical benefit from performing predictive testing, then it is in the child’s best interests to postpone testing until the child is able to make an autonomous decision [37, 38, 40–42]. That being said, the AAP/ACMG guidelines also leave some room for alternate routes when they state that “…after careful genetic counseling, it may be ethically acceptable to proceed with predictive genetic testing to resolve disabling parental anxiety or to support life-planning decisions that parents sincerely believe to be in the child’s best interest” [38]. One of the challenges in the context of genetic testing is that there are many different views regarding exactly what constitutes as being in the child’s best interests [43].

One way of determining what is in the child’s best interests might be to assess the harms of reporting and not reporting the results from opportunistic screening (or unsolicited findings). Some authors have proposed that the harms of reporting such results in children are limited to the imposition of undesired genetic information on the child and their family [44]. They argue that this is outweighed by the potential harm of removing family members’ opportunities to avoid illness through screening [44]. Although genetic guidelines generally recommend against providing predictive testing in young children, few studies have investigated the psychological impact of testing [40–42, 45]. There is, therefore, little in the way of evidence to suggest that identification of an unsolicited finding (or results from opportunistic screening) predisposing a child to a genetic condition would cause psychological harm. However, lack of evidence does not equate to evidence of a lack of harm, and therefore, additional empirical studies to investigate this are required.

The ACMG has taken a more family-based approach to what is in the child’s best interests. They argue that identification of these pathogenic variants in children benefits the child, first by providing them with important information about their future health risks and, second, through the potential health benefits to their parents should they be detected prior to displaying symptoms of the genetic condition for which a mutation was detected. Therefore, the ACMG believes that the ethical concerns are outweighed by the “potential benefit to the future health of the child and the child’s parents” [20]. For this reason, their follow-up recommendations indicated that it could be viewed as unethical if laboratories do not report these unsolicited findings, because they are failing to allow parents to act in their child’s best interests and avoid preventable harm [44, 46]. This is in line with literature acknowledging that parents are best placed to consider all the factors that impact on their family and should therefore be allowed to make decisions in a way that takes the family’s best interests into account [47]. This being said, whether parents will be sufficiently informed regarding the unsolicited information they might receive in order to make decisions on behalf of their children and their broader family is unclear.

One should consider what else is at stake for the child if we report the results of opportunistic screening (or unsolicited results). A commonly stated argument against predictive testing in children is that, as well as removing their right to privacy (regarding their genetic result), it impinges on their future autonomy, specifically the child’s ability to make his/her own decisions about whether they want to know their genetic status when they are older [42]. This concept has been referred to as “the child’s right to an open future” and rests on the notion that genetic testing would narrow the child’s future options [48, 49]. Likewise, when the results of opportunistic screening are reported to the clinician and subsequently to Jack’s parents and Jack, we are removing the child’s right not to know whether he has a BRCA1 mutation. From this perspective, preservation of the child’s future autonomy would involve either not conducting the screening at all for adult-onset disorders or, in the case of a truly “stumbled upon” incidental finding, to not report it to the clinician. Alternatively, the result could be reported to the clinician and held in trust until the child is able to make an autonomous decision. However, one might also view that by disclosing the results of opportunistic screening to the family, we are in fact broadening the options available to Jack and his family by providing them with opportunities for further screening and preventative care.

Debate continues as to whether laboratories should “hunt for” and report back results for a preset list of genes when WES/WGS is conducted in the clinical setting in children or whether reporting should be restricted to findings relevant to the quest for a diagnosis. Ultimately, it depends on the importance one places on the preservation of the child’s right not to know information about their genetic risks compared to the potential health benefits for the family. Given that once information is known, it cannot be “unknown,” perhaps the initial premise should be to remain cautious until more evidence is amassed regarding the impact of returning results to children for adult-onset disorders and limit reporting to the original clinical question and, in doing so, promote the child’s future autonomy.

Informed consent in clinical practice functions as a permission given for the performance of a medical procedure by a capacitated patient to whom the information about the procedure has been given, who understands it fully, and voluntarily consents to it. Informed consent has been integrated in most jurisdictions as a legal requirement and supported ethically as ultimate respect for the autonomy of individuals and their right to self-determination [17]. It has been argued that in order to obtain genuine informed consent, the information about the procedure (or in this context the genetic test) presented to a patient should be accurate, relevant, and understandable, and the patient should have the opportunity to freely withdraw consent [17, 50]. Yet, obtaining valid and adequate informed consent for some medical procedures poses challenges such as those related to proper communication of the information and its comprehension, which is particularly relevant for informed consent for genetic testing. The fact that clinical genetic testing is usually offered with both pre- and post-test genetic counseling is an indication of how important and potentially complex communication can be in this context. Herein, we offer a list of issues that should be considered when planning for the informed consent procedure for WES/WGS.