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Table 2 gives a full and detailed account of issues identified. The full spectrum of ethical issues in genome-wide sequencing coding framework with example quotations

From: The full spectrum of ethical issues in pediatric genome-wide sequencing: a systematic qualitative review

THEME
CODE SUBCODE PUBLICATIONS EXAMPLE QUOTE
ISSUES RELATED TO WHEN TO USE GENOME-WIDE SEQUENCING
 Challenges in deciding who should be tested Risks of Direct-to-consumer Testing Bunnik, et al. 2013
Borry, et al. 2014
Howard, et al. 2015
Joseph, et al. 2016
Sabatello and Appelbaum 2016
Johnston, et al. 2018
Zacharias, et al. 2018
Benedetti and Marron 2021
Accordingly, the aim of DTC testing has shifted from the prediction of an individual’s genetic risk for a single disease to something like ‘getting to know as much as possible’ on the basis of a genome-wide scan. […] The standards of pre-test information provision and informed consent used in clinical genetics can hardly be met in a relatively under- regulated commercial context, in which professional knowledge, skills and values are often lacking. Lack of adequate information and informed consent may harm consumers both directly and indirectly: directly through the receipt of unwanted and potentially harmful information [e.g. knowing that one is at increased risk for an untreatable or unpreventable disease, such as Alzheimer’s disease], and indirectly through misunderstanding or misinterpretation, and associated personal, social and health risks. […] Informed consent is needed not only to help prevent the potential harms associated with personal genome testing, but also to help ensure that genetic testing is the result of an autonomous decision rather than the ‘inconsiderate’ acceptance of a commercial offer [38].
Risks of predictive testinggenerally ACMG 2013
Editorial 2013
Borry, et al. 2014
Knoppers, Avard, et al. 2014
Berg and Powell 2015
Botkin, et al. 2015
Char 2015(a)
Hens and Dierickx 2015
Levenson 2015
Sabatello and Appelbaum 2015
Bowdin et al. 2016
Hufnagel, et al. 2016
Sabatello and Appelbaum 2016
Johnson, et al. 2017
Casas 2018
Johnston, et al. 2018
Garrett, et al. 2019
Johnson, et al. 2019
Lantos 2019(a)
Szego, et al. 2019
Hay, et al. 2021
The family that has a baby’s genome sequenced just to see what might be found may spend years worrying about that cancer risk in their perfectly healthy child [39].
Risks of extending newborn screening with WGS/WES Goldenberg and Sharp 2012
Tarini and Goldenberg 2012
Bunnik, et al. 2013
Knoppers, Sénécal, et al. 2014
Landau, et al. 2014
Berg and Powell 2015
Botkin, et al. 2015
Howard, et al. 2015
Reinstein 2015
Botkin and Rothwell 2016
Joseph, et al. 2016
King and Smith 2016
Lantos 2016
Friedman, et al. 2017
Iskrov, et al. 2017
Seidel 2017
Yang, et al. 2017
Johnston, et al. 2018
Zacharias, et al. 2018
Boardman, et al. 2019
Genetti, et al. 2019
Rothwell and Botkin 2019
Chaudhari, et al. 2020
Downie, et al. 2020
Moultrie, et al. 2020
Wolf, et al. 2020
Cabello, et al. 2021
Levy 2021
Newson 2021
All of the ethical and public policy issues associated with current newborn screening practices apply to genome- wide sequencing as well, and many of these issues are exacerbated by the fact that genome-wide sequencing produces much more information about the individual than conventional testing does. For example, it is more difficult (or impossible) to justify mandatory screening, even if families have the ability to opt out, if many additional screening targets are added, especially if the benefits of screening for some of these additional targets are uncertain. At the very least, genomic newborn screening would require ensuring that parents have sufficient, clearly-understandable information available about the screening program and that the entire population has access to confirmatory diagnostic and treatment services, including genetic counselling. Maintaining effective governance and efficient administration of population-based genomic newborn screening programs would also be essential to avoid losing the high participation rates and widespread public support that these programs currently enjoy [40].
Challenge to deal with parental requests to test May 2013
Sabatello and Appelbaum 2016
1 author (TM) has seen the effect of pleas from parents for access to this new, and available, diagnostic technology. As we have discussed elsewhere, such pleas are often discounted in health care policy as emotion-based and therefore less worthy of recognition as legitimate motives to go forward with intervention (although often readily accepted as reasons to refrain). However, there are legitimate reasons to recognize the motivational force of emotions felt by parents when confronted by the uncertainties that accompany a confounding debilitating disease suffered by their children, and the cycle of testing and re-testing inflicted on the children for whom diagnosis, and therefore settled treatment approach, has eluded attending physicians [41].
Challenge to deal with minor’s request to test without parental permission Clayton 2015
Sabatello and Appelbaum 2016
The simple answer is that unemancipated minors have virtually no legal rights to obtain genetic or genomic testing without parental permission [42].
Challenge to decide whether and under which conditions children should participate in genomic research Wilfond and Diekema 2012
Knoppers, Avard, et al. 2014
Rahimzadeh 2017
Sundby, et al. 2018
Research with children, and indeed with situationally vulnerable groups generally, therefore raise an ethical tension. Children warrant special ethical protections as a result of their situational vulnerability. They should not, however, be categorically excluded from research that anticipates the contribution of new knowledge that could improve their health and well-being. Although this tension is not new, the types of risks genomic data sharing poses to children and the approaches research ethics review committees employ to minimize them are unique [43].
Challenge to decide who should get priority Gyngell, et al. 2019 In the absence of sufficient capacity to offer RGT for all infants in the NICU who may potentially benefit, there will be a need to prioritize. It is likely that in the early phase at least, RGT will be restricted to those infants with clinical features that are highly suggestive of an underlying genetic condition. […] An alternative approach would be to prioritize infants where the result of RGT is expected to be of high clinical utility, for example where a diagnosis would potentially help parents considering treatment limitation decisions, an expensive intervention such as transplantation, or in cases where parents are considering adoption. These are the ‘weightiest’ choices parents can make, and they should have access to useful information to help inform those decisions [44].
Challenge to decide whether to use as first tier test or after more limited genetic testing Botkin, et al. 2015
Levenson 2015
Newson and Schonstein 2016
Rogers and Zhang 2016
Bertier, et al. 2017
Szego, et al. 2019
ASHG recommends that, in the context of diagnostic testing for a child with a most likely genetic disorder, genome-scale sequencing is appropriate when prior, more limited genetic testing failed to identify a causative mutation. Depending on the clinical presentation and on the quality and availability of appropriate targeted testing, comprehensive testing such as genome-scale sequencing might also be indicated in certain circumstances, even in the absence of prior, more limited genetic testing [45].
Challenge to decide whether to do only child or trio testing Char 2015(b)
Bertier, et al. 2017
Casas 2018
Eno, et al. 2018
Vears, et a. 2018
Cornelis and Wouters 2019
There also was debate as to whether just the proband, or the affected child and both parents (trio analysis), should be sequenced. Although the production of sequencing data for trios is three times as expensive, it allows rapid identification of de novo mutations in the proband. Therefore, this approach may be particularly valuable in cases where there is a strong suspicion that the causal mutation appeared de novo in the affected child, or that it has a recessive mode of inheritance [28].
 Challenges for decision-making Risk of lack of experts Beale, et al. 2015
Johnston, et al. 2018
Graf, et al. 2019
Szego, et al. 2019
The main resource-related issues pertaining to service provision are the need for additional computing capacity, more bioinformaticians, more genetic counsellors and also genetics-related training for the public and a wide range of staff. It is also considered that, as the number of children undergoing genetic testing increases, there will be an increase in demand for information and support for families [46].
Challenges of cross-disciplinary collaboration ACMG 2013
Burke 2015
Burke and Clarke 2016
Johnson, et al. 2017
Diamonstein 2019
Gyngell, et al. 2019
Szego, et al. 2019
Chaudhari, et al. 2020
Deuitch, et al. 2020
Caring for children and families who have genetic differences requires a partnership between the primary care pediatrician and the appropriate specialists. Undertaking WES/WGS testing also requires a partnership between pediatricians and genetic specialists until the nuances of genomic testing become better understood by the majority of pediatricians [47].
Risk of lacking expertise, training and time ACMG 2013
Knoppers, Sénécal, et al. 2014
Beale, et al. 2015
Botkin, et al. 2015
Burke 2015
Howard, et al. 2015
Bowdin, et al. 2016
Burke and Clarke 2016
Green, et al. 2016
Lantos 2016
Bertier, et al. 2017
Iskrov, et al. 2017
Graf, et al. 2019
Szego, et al. 2019
Byrjalsen, et al. 2020
Deuitch, et al. 2020
Odgis, et al. 2021
In addition to understanding the ethical framework for the disclosure of genomic testing results, pediatricians must have sufficient knowledge of the testing procedures themselves. In the midst of the ethical decisions that must be made in terms of genome sequencing in children is the question regarding the comfort level of the pediatricians in discussing complex genetic test results and testing procedures [47].
Challenge of high responsibility for clinicians/researchers May, et al. 2013
Knoppers, Sénécal, et al. 2014
Burke 2015
Friedman, et al. 2019
Gyngell, et al. 2019
Ross and Clayton 2019
Byrjalsen, et al. 2020
There is emerging evidence that healthcare providers who must make high-stakes irrevocable treatment decisions involving genomic results are already experiencing moral distress. There is therefore a need to articulate practical procedures, underpinned by consistent normative principles and values, to help clinicians decide […] [44].
Challenge to assess clinical value and personal utility of genome-wide sequencing Beale, et al. 2015
Howard, et al. 2015
Botkin 2016
Bowdin, et al. 2016
Bertier, et al. 2017
Friedman, et al. 2017
Chassagne, et al. 2019
Friedman, et al. 2019
Lantos 2019(a)
Malek, et al. 2019
It has been argued that the clinical utility of a genetic test should also include consideration of ethical, legal, and social issues related to the diagnosis, prevention, or treatment of the disease that is being tested. Even this broad definition of clinical utility may not be fully inclusive of the overall costs and benefits of genetic testing: elements of “personal utility” may also need to be considered. As a practical matter, however, personal utility and social consequences are difficult to measure and have contributed little to the funding decisions healthcare systems and insurers have made regarding genetic testing to date [48].
Difficulty to determine best interests principle Bush 2014
Holm 2014
Zawati, et al. 2014
Anderson, et al. 2015
Kesserwan, et al. 2016
Newson and Schonstein 2016
Sabatello and Appelbaum 2016
Johnson, et al. 2017
Newson 2017
Friedman, et al. 2019
The central ethical tenet of clinical pediatrics is that the best interests of the child are paramount, but determining the best interests of a severely ill infant may be challenging. For example, some of the benefits attributed to diagnostic GWS result from avoidance of high-intensity treatment and risky medical or surgical interventions in favor of palliative “comfort care” for infants who have uncontrollable suffering or whose prognosis is dismal. Is it in a baby’s best interests for his parents to find out that he has an untreatable genetic condition that has been fatal within the first few months of life in all previously reported cases? [48]
Risk of rising physical burdens due to increased testing Tarini and Goldenberg 2012
Bunnik, et al. 2013
Howard, et al. 2015
Lantos 2016
Wouters, et al. 2017
Horton and Lucassen 2019
Lantos 2019(a)
Lantos 2019(b)
Sachdev, et al. 2021
Ackerman et al.‍ reported a case in which the possibility of inappropriate treatment is illustrated. Doctors tested a first-degree relative of a patient who died of sudden cardiac death. The relative had a genetic finding that was interpreted as likely pathogenic for long QT syndrome (LQTS). The man had no signs or symptoms of LQTS at the time of the molecular diagnosis. Nevertheless, on the basis of that genomic result, the doctor recommended, and the patient received, an implantable defibrillator. The authors criticized the decision and warned that, “The mere presence of a rare variant in a bona fide LQTS- susceptibility gene should not compel a pathogenic, probably deleterious variant rendering.” We do not know how common such situations are, but we do know that interpretations of the likelihood that a particular variant will be classified as pathogenic are constantly changing.‍ Such findings will always create uncertainty among both doctors and patients [49].
Risk of rising psychological burdens due to increased testing Goldenberg and Sharp 2012
Tarini and Goldenberg 2012
Abdul-Karim, et al. 2013
Bunnik, et al. 2013
Editorial 2013
Dimmock and Bick, 2014
Knoppers, Avard, et al. 2014
Knoppers, Sénécal, et al. 2014
Allain 2015
Clayton 2015
Hens and Dierickx 2015
Howard, et al. 2015
Reinstein 2015
Bowdin, et al. 2016
Lantos 2016
Newson 2017
Wouters, et al. 2017
Johnston, et al. 2018
Friedman, et al. 2019
Lantos 2019(a)
Lantos 2019(b)
Robinson, et al. 2019Szego, et al. 2019
Savatt, et al. 2020
There are also potential psychological harms such as alteration of self-image, distortion of parental perception of the child, increased anxiety and guilt, familial stress related to the identification of other at-risk family members, difficulty obtaining life and/or disability insurance, and the detection of non-paternity [50].
 Risks of injustice Challenge of fair distribution of resources in healthcare system Goldenberg and Sharp 2012
Editorial 2013
Dimmock and Bick, 2014
Howard, et al. 2015
Bowdin, et al. 2016
Lantos 2016
Rogers and Zhang 2016
Wouters, et al. 2017
Johnston, et al. 2018
Chassagne, et al. 2019
Gyngell, et al. 2019
Hart, et al. 2019
Lantos 2019(a)
Szego, et al. 2019Cabello, et al. 2021
Newson 2021
Although genetic services and screening programmes aim to improve the health of the population, there is growing concern that the increasing number of genetic tests becoming available at lower costs could compromise the viability of the healthcare system. Even though the tests themselves may be inexpensive and suitable for large-scale use, the infrastructure and human resources needed to provide appropriate education, counseling, interventions and follow-up are likely to be far more costly. When it comes to the allocation of scarce resources, economic considerations must be considered alongside ‘notions of justice, equity, personal freedom, political feasibility, and the constraints of current law [51].
Risk of unequal access to genome-wide sequencing May, et al. 2013
Green, et al. 2016
Casas 2018
Grebe, et al. 2020
Cabello, et al. 2021
Odgis, et al. 2021
Chief among these are moral concerns about justice, disparities in access to both testing and intervention, and the differing risks and benefits that may result given different socioeconomic status or racial background. Indeed, the report accompanying the joint AAP/ACMG Policy Statement suggests less actual harm from testing than anticipated but also notes that the little evidence assembled dispropotionately reflects white individuals of higher socioeconomic status. This itself is likely a reflection of disparities in access to new health care technologies. Far more effort is needed, then, to ensure that the significant potential benefits of WGS are fairly distributed and that risks are assessed through consideration of disparate circumstances and resources [52].
Lack of formal health technology assessments comparing the cost-effectiveness to alternative approaches Beale, et al. 2015
Bowdin, et al. 2016
Gyngell, et al. 2019
However, despite calls for research focusing on the comparative downstream costs and clinical practice implications of WES/WGS, empiric research is limited. We currently lack formal health technology assessments comparing the cost-effectiveness of WGS to alternative approaches, a major evidence gap that is only just beginning to be rectified. Due to the continual decline in the laboratory costs of sequencing we are approaching the fabled ‘US$1000 genome’. However these are only the incremental laboratory costs for a high-throughput sequencing facility, they do not include capital infrastructure costs, the costs of clinical interpretation, or the health services associated with test ordering and/or follow-up care [53].
Risk of unequal access to reimbursement by insurances Bertier, et al. 2017
Johnson, et al. 2017
Casas 2018
Johnston, et al. 2018
Grebe, et al. 2020
Variations in insurance coverage, parental socioeconomic status, and geographic location are three factors that may limit access to germline genomic sequencing. The cost of testing and subsequent cancer screening may be overly burdensome for those with limited economic resources and poor insurance coverage. Efforts to integrate NGS into clinical practice should include advocacy for equitable access to genetic counseling, tumor, and germline sequencing and clinical follow-up as indicated based upon test results [54].
Risk of biased treatment due to WGS result Char 2015(a)
Deem 2016
Bell, 2018
Graf, et al. 2019
Gyngell, et al. 2019
PGS- revealed findings may have unanticipated or unintended consequences for the individual patient, particularly the acutely ill patient: the potential to be used as justification to withhold certain therapeutic options; to decide the futility of others; to withdraw care; and, to ration scarce resources, such as organ transplantation, to one patient over another [55].
Risk of reinforcing negative social attitudes towards disability Deem 2016
Bell, 2018
However, several disability rights advocates have expressed concern that clinical use of genetic technologies may reinforce and perpetuate stigmatization of and discrimination against disabled persons in medical and social contexts. There is growing need, then, for clinicians and bioethicists to consider how the clinical use of WGS in the newborn period might exacerbate such harms to persons with disabilities [56].
Risk of clinicians and bioethicists focus on common set of ethical issues (neglect other important ethical issues) Deem 2016
Cabello, et al. 2021
Newson 2021
With respect to addressing specific ethical challenges that incidental findings pose to acquiring informed consent from patients or their families, the focus of clinicians and bioethicists tends to converge on a common set of issues. These include the patient’s or family’s preferences about which results will be returned, their understanding of the risks posed by routine data sharing and storage to their confidentiality and privacy, and their attitudes toward future use of genomic data and recontacting [56].
Risk of researchers separating ethics from what they deem as purely scientific or technological actions Abdul-Karim, et al. 2013
Thornock 2016
Researchers might be tempted to separate ethics from what they deem as purely scientific or technological actions. For instance, in WGS research, it may be tempting to see ethics as an integral component at the bookends of a study, at the beginning when obtaining consent or at the end when returning results, but see other steps (sequencing, analyzing, verification, storage) as wholly technological or scientific endeavors separate from ethics. However, these actions are not devoid of ethics because they are directly related to how researchers provide value to their stakeholders. Researchers should not assume that the storage of sequences is merely a technological or pragmatic necessity devoid of ethical obligations [57].
Challenge to publish guidelines for standardized testing Zawati, et al. 2014
Beale, et al. 2015
Bertier, et al. 2017
Rahimzadeh 2017
According to various authors, in order for WES to be offered in a standardized manner, formal guidelines, including strict quality control measurements, must be published. While some have called for this regulation to be provided by the Food and Drug Administration (in the USA), this may be challenging for regulators given the amount of data to be analyzed from a whole exome (about 30 million base pairs, or 1% of a whole genome) [28].
Risk of outdated distinction between research and clinical care Lunshof 2012
Botkin, et al. 2015
Newson and Schonstein 2016
Wouters, et al. 2017
Rotz and Kodish 2018
Byrjalsen, et al. 2020
Clinical application of research-stage procedures can save lives, as the exemplary case of the 15-month-old boy shows. In this case, the institutional review board-approved the use of nonvalidated experimental methods precisely because the primary purpose was to obtain a diagnosis for a patient; had the aim been gaining generalizable knowledge this would have turned it formally into research. This reasoning, however, is based on a questionable and probably outdated distinction between research and clinical care that takes systematic recording of outcomes as the decisive criterion for research. Moreover, can there be any instance of a diagnostic or therapeutic procedure – experimental or routine – that does not record results or yield generalizable knowledge? Also, clinical care and n = 1 studies are essentially connected. One could say that in ‘personalized’ medicine – and good medicine is always personalized – every medical intervention in an individual is a type of n = 1 study [58].
ISSUES RELATED TO PRETEST COUNSELLING
 Risk of unequal access to high-quality counselling   Sabatello and Appelbaum 2016
Bertier, et al. 2017
Rotz and Kodish 2018
Smith, et al. 2019
Szego, et al. 2019
For example, genomic counseling services may be more available in urban medical centers than in the rural setting. Genomic testing without genetic counseling is associated with a lack of informed decision making, misinterpretation of results and inappropriate clinical management, potential breaches of ethical standards, and adverse psychosocial outcomes [59].
 Challenges for the informed consent process Challenge of creating appropriate consent forms Burke and Clarke 2016
Eno, et al. 2018
Hitchcock, et al. 2020
The challenges in creating appropriate consent forms are notable; there is a delicate balance in keeping the readability manageable while acknowledging a number of potential complications that may arise [20].
Risk of traditional concept of informed consent no longer being feasible Wilfond and Diekema 2012
Bunnik, et al. 2013
Bowdin, et al. 2016
Burke and Clarke 2016
Li, et al. 2016
Iskrov, et al. 2017
Newson 2017
Wouters, et al. 2017
Diamonstein 2019
Gore, et al. 2019
Gyngell, et al. 2019
Yu, et al. 2019
Byrjalsen, et al. 2020
Hitchcock, et al. 2020
Wolf, et al. 2020
Lynch, et al. 2021
Vears, et al. 2021
How can a valid, adequately informed consent be ensured given the volume and complexity of data generated, particularly with regard to incidental findings and variants of unknown significance? It may even be doubted that ‘informed consent’, as traditionally defined, is attainable in everyday practice [60].
Different forms of required consent and amount of information depending on individual need Burke and Clarke 2016
Li, et al. 2016
Diamonstein 2019
Informational requirements are complex and highly situated in terms of time, place and the individual situation in question. The informational needs of a family whose young child is undergoing investigation for severe impairment, as in case 1, who potentially will not attain medical decision-making autonomy, might differ from those such as the parents in case 2, particularly with regard to the management of incidental or uncertain information [60].
Degree of directiveness (depending on clinical situation/urgency or personal need) Botkin, et al. 2015
McCullough, et al. 2015
Wouters, et al. 2017
Diamonstein 2019
Gyngell, et al. 2019
Jamal, et al. 2020
Vears, et al. 2021
The nascent use of genomic testing in healthy individuals has also led some to argue that directive genetic counseling – where a professional takes a more active role in providing advice, guidance or recommendations – can be condoned. We suggest that directive genetic counseling may also be appropriate for at least some RGT in the NICU. While parents need to be able to both understand the possible outcomes of the test and should have the chance to reflect critically on their decision to have RGT, the known clinical utility of these tests means that the test can frequently have direct implications for subsequent treatment. This could be said to make RGT more like the kinds of medical tests that are routinely performed in NICU without explicit parental consent. However, given the possible implications for other family members, potential for future discrimination, combined with often uncertain direct benefit, gaining explicit consent to RGT remains prudent. Further, any directive counseling should not amount to coercion [44].
Risk of undue influence regarding consent in research Wilfond and Diekema 2012
Byrjalsen, et al. 2020
Finally, how should voluntariness and undue influence be understood in the context of assent? (e.g., does it matter if the research team offers the child $20 or if the parents offer to take the child for pizza if she agrees?) [61]
Challenge of emotionally charged situation with high psychosocial needs Oberg, et al. 2015
Li, et al. 2016
Rosell, et al. 2016
Clowes Candadai, et al. 2019
Diamonstein 2019
Gyngell, et al. 2019
Hill, et al. 2020
Lynch, et al. 2021
Participants described factors that contributed to their psychosocial needs, such as having a good HCP–parent relationship and HCPs’ consideration of parents’ well-being. […] Aspects such as trust and the provision of emotional support have been found to lead to more positive working relationships and less decisional conflict. Thus, it is important for HCPs to be mindful of the aspects of the relationship that have the potential to impact parents’ psychosocial needs and their decision making. Participants’ psychosocial needs may be as important as their informational need [62].
Challenge for parents to really overlook decisions in advance Abdul-Karim, et al. 2013
Burke and Clarke 2016
Wouters, et al. 2017
Vears, et al. 2020
To assert the ‘right not to know’ may be incoherent when it is not yet known that there is anything to (not) know, presenting a challenge to how advance instructions and preferences can be meaningfully established and respected [60].
Risk that hope for cure makes parents consent to everything Oberg, et al. 2015
Diamonstein 2019
Gore, et al. 2019
Gyngell, et al. 2019
With hopes for a cure, parental motivation to participate in WGS research may be high without fully understanding the range of results that may be returned, including variants of unknown significance and secondary findings [63].
Risk of inflicted ought Newson 2017
Malek, et al. 2019
The parents did not, however, hold a uniformly positive view of the choice to receive adult-onset SVs. Despite this, they felt a moral obligation to learn about SVs; that they would be ‘remiss … to not know what is knowable’. […] Anderson et al. reframe this as ‘inflicted ought’—some parents were given insight into genomic knowledge that they did not necessarily want to know, but felt they should nonetheless come to learn. […] It is also worth noting that the mere offer of a test may not be neutral. If a particular suite of information is being offered, that offer may be interpreted as implicit encouragement to accept it. This too could contribute to inflicted ought [26].
Risk of too narrow understanding of autonomy Newson 2017
Wouters, et al. 2017
Jamal, et al. 2020
There is a tendency in some bioethics discourse to construe autonomy superficially, such as presenting it as a property of decisions and inextricably tying it to informed consent. If a decision is supported by information and is made voluntarily with appropriate understanding, then it is said to be autonomous. However, this places too much emphasis on information [and its transfer] at the expense of the process of the decision and the psychological properties of the person involved [26].
Challenge to determine how much choice parents should be given regarding which findings they can receive Lunshof 2012
ACMG 2013
Bunnik, et al. 2013
May, et al. 2013
Bush 2014
Holm 2014
Holm, et al. 2014
Knoppers, Avard et al. 2014
Zawati, et al. 2014
Anderson, et al. 2015
Ayuso, et al. 2015
Beale, et al. 2015
Berg and Powell 2015
Botkin, et al. 2015
Clayton 2015
Hens and Dierickx 2015
Levenson 2015
McCullough, et al. 2015
Sénécal, et al. 2015
Botkin 2016
Bowdin, et al. 2016
Burke and Clarke 2016
Hufnagel, et al. 2016
Joseph, et al. 2016
Krabbenborg, et al. 2016
Kesserwan, et al. 2016
Newson and Schonstein 2016
Sabatello and Appelbaum 2016
Bertier, et al. 2017
Friedman, et al. 2017
Johnson, et al. 2017
Wouters, et al. 2017
Bell 2018
McGowan, et al. 2018
Vears, et al. 2018
Chassagne, et al. 2019
Cornelis and Wouters 2019
Hart, et al. 2019
Holm, et al. 2019
Ormond, et al. 2019
Ross and Clayton 2019
Wong, et al. 2019
Downie, et al. 2020
Hoell, et al. 2020
Savatt, et al. 2020
Sofer 2020
Vears 2021
The mainstream consensus of the bioethics community appears to be that adult-onset disorders with no effective prevention or treatment should be off-limits to parents and are most appropriate for informed decision-making by the individual when he or she becomes an adult. That being said, some argue that even these disorders fall within a parent’s responsibility to raise their child to the best of their ability and prepare them for any eventuality, that the theoretical harms are less significant than initially supposed and that parents are in the best position to make decisions relative to their child’s best interests [64].
Challenge of parental decision making on behalf of child Lunshof 2012
Wilfond and Diekema 2012
Abdul-Karim, et al. 2013
Holm 2014
Holm, et al. 2014
Knoppers, Avard, et al. 2014
Zawati, et al. 2014
Berg and Powell 2015
Botkin, et al. 2015
Clayton 2015
Hens and Dierickx 2015
Bowdin, et al. 2016
Newson and Schonstein 2016
Sabatello and Appelbaum 2016
Bertier, et al. 2017
Johnson, et al. 2017
Newson 2017
McGowan, et al. 2018
Rotz and Kodish 2018
Vears, et al. 2018
Cornelis and Wouters 2019
Gore, et al. 2019
Gyngell, et al. 2019
Chaudhari, et al. 2020
Hoell, et al. 2020
Dondorp, et al. 2021
Tibben, et al. 2021
Vears 2021
Indeed, application of principles regarding adult whole genome screening does not entail just implementing proxy consent and laying the burden of decision making with the caregivers. Children have special status in medical care: They are vulnerable in that they are dependent on others for their own health care. Respect for children as they are also includes respect for the fact that they will eventually grow up to be autonomous adults. Hence, choices made for them should in principle not rule out the possibility that they can make different choices in the future [65].
Challenge to giving appropriate role to adolescents (capable of assent) Wilfond and Diekema 2012
Abdul-Karim, et al. 2013
Holm, et al. 2014
Knoppers, Avard, et al. 2014
Zawati, et al. 2014
Ayuso, et al. 2015
Botkin, et al. 2015
Clayton 2015
Hens and Dierickx 2015
McCullough, et al. 2015
Sabatello and Appelbaum 2015
Bowdin, et al. 2016
Newson and Schonstein 2016
Sabatello and Appelbaum 2016
Johnson, et al. 2017
McGowan, et al. 2018
Cornelis and Wouters 2019
Gore, et al. 2019
Pervola, et al. 2019
Wong, et al. 2019
Hoell, et al. 2020
Lewis, et al. 2020
Dondorp, et al. 2021
Tibben, et al. 2021
Vears 2021
The common practice is for parents to determine what is in their children’s best interests, with adolescents at most asked to acquiesce. Even if we assume that most parents strive to make decisions that promote their children’s best interests, the lack of adolescents’ involvement raises the risk that parents’ views and anxieties—rather than those of the adolescent—will dominate the decision. Further complicating the situation is that as minors mature, they may hold values and preferences different from their parents’. How to balance parental authority against adolescents’ growing autonomy is not always clear [66].
Risk of conflict of interests for parents Berg and Powell 2015
Clayton 2015
Sabatello and Appelbaum 2015
Bowdin, et al. 2016
Sabatello and Appelbaum 2016
Bertier, et al. 2017
Holm, et al. 2019
Gyngell, et al. 2019
Tibben, et al. 2021
Finally, lack of adolescents’ involvement raises the risk that parents will conflate their interests and their adolescent’s interests, leading to SF-related decisions that reflect parents’ preferences (and anxieties) rather than those of the adolescent. […] Opinions are split, however, about returning SFs for carrier status with reproductive implications (e.g., carrier state for cystic fibrosis), disorders for which interventions will be deferred to adulthood (e.g., BRCA1/2), and adult-onset conditions without treatments that offer clear clinical benefit (e.g., Alzheimer disease). Whereas expert panels and professional guidelines generally suggest that these be deferred until adolescents reach maturity and can decide for themselves, studies indicate that many parents desire to learn all about their children’s genetic makeup. Although parents believe that it is their right and duty to access and manage their children’s genomic data, professionals often view themselves as the guardians of adolescents’ genomic-related rights in decisions that are intrinsically family-oriented. And whereas professionals call for distinctions based on medical utility and scientific validity, studies indicate that parents’ rationales may include not only personal and familial medical interests but also mere curiosity. Even if we assume that most parents (and professionals) strive to make decisions that promote children’s best interests, there is a risk that adolescents’ right (not) to know will not only be in conflict with familial interests, but also subjugated to parents’ (or others’) rights, interests and whims [41].
Risk of conflict between parents May, et al. 2013
Holm, et al. 2014
Berg and Powell 2015
Chassagne, et al. 2019
Holm, et al. 2019
In addition, even the decision making process could lead to strife between parents if they are unable to agree about whether or not to learn such information [64].
Risk of conflict between HPCs/researchers and parents McCullough, et al. 2015
Sabatello and Appelbaum 2016
Friedman, et al. 2019
Parents may have reasonable views about the implications of the best interests standard in its psychosocial dimensions for their child’s clinical care and well-being that differ from those of the child’s pediatrician for non–life-threatening conditions. In such cases, parents may appeal to values and beliefs that are not exclusively health-related when they more broadly conceptualize their child’s best interests. As a consequence, parents may reach an informed and considered judgment about the benefits and risks of receiving or not receiving results of genomic sequencing about non–life- threatening conditions that differ from the prima facie ethical obligations of pediatricians, as described above. Given the uncertainty of long-term psychological and social outcomes of genomic sequencing, parental judgments about psychosocial benefits and harms of such sequencing results typically will have as much authority as those of the pediatrician [67].
Challenge due to complexity of issues Wilfond and Diekema 2012
Bunnik, et al. 2013
Beale, et al. 2015
Berg and Powell 2015
Oberg, et al. 2015
Bowdin, et al. 2016
Burke and Clarke 2016
Deem 2016
Green, et al. 2016
Krabbenborg, et al. 2016
Lantos 2016
Li, et al. 2016
Bertier, et al. 2017
Werner-Lin, et al. 2018
Chassagne, et al. 2019
Clowes Candadai, et al. 2019
Cornelis and Wouters 2019
Diamonstein 2019
Gore, et al. 2019
Johnson, et al. 2019
Smith, et al. 2019
Yu, et al. 2019
Byrjalsen, et al. 2020
Hill, et al. 2020
Vears, et al. 2021
Genetic counselors (GCs) have expressed challenges with the length, complexity, and content of the GWS consent process. Specifically, GCs had difficulty ensuring their patients accurately understood the benefits, limitations, potential results, and implications of GWS for themselves and their family members […] Most participants thought that large volumes of information given at one time can result in “information overload” [62].
Challenges due to time pressure/ time restraints Bowdin, et al. 2016
Li, et al. 2016
Bertier, et al. 2017
Clowes Candadai, et al. 2019
Gyngell, et al. 2019
Sanderson, et al. 2019
Smith, et al. 2019
Hill, et al. 2020
Lynch, et al. 2021
Vears, et al. 2021
Initial reports described the informed consent process for pediatric WES as requiring 3–6 h. Recently, it has been suggested that the WES consent process could be shortened to 30–60 min depending on the type and timing of secondary analysis performed. In contrast, we find that the process of obtaining informed consent for WGS testing of children is complex and requires multiple encounters with genetics professionals, in part due to the predictive component of the test and the number of individuals potentially affected by test results [53].
Challenge of expertise and training for effective communication McCullough, et al. 2015
Burke and Clarke 2016
Li, et al. 2016
Sabatello and Appelbaum 2016
Bertier, et al. 2017
McGowan, et al. 2018
Clowes Candadai, et al. 2019
Diamonstein 2019
Gore, et al. 2019
Johnson, et al. 2019
Sanderson, et al. 2019
Smith, et al. 2019
Yu, et al. 2019
To ensure quality clinical practice, the ASHG recommends that HCPs involved with pediatric genetic testing need to have appropriate training. With the expected growth of genomic testing, there may be inadequate trained medical geneticists and counselors to support patients and families [62].
 Challenges for what should be discussed/ Content Explain to parents and families the potential for all the types of findings ACMG 2013
Ayuso, et al. 2015
Blackburn, et al. 2015
Botkin, et al. 2015
Levenson 2015
McCullough, et al. 2015
Bowdin, et al. 2016
Burke and Clarke 2016
Li, et al. 2016
Rosell, et al. 2016
Bertier, et al. 2017
Johnson, et al. 2017
Wouters and Cornelis 2017
Bell 2018
Johnston, et al. 2018
Clowes Candadai, et al. 2019
Sanderson, et al. 2019
Yu, et al. 2019
Deignan, et al. 2020
Lalonde, et al. 2020
Vears, et al. 2020
Hay, et al. 2021
Clinicians must explain to parents and families the potential for all the types of findings [28].
Potential for results to change over time Burke and Clarke 2016
Deem 2016
Vears, et al. 2020
The potential impact that WGS will have on a newborn’s future medical management complicates the clinician’s task of ensuring that parental consent for testing is properly informed. Parental understanding of how diagnostic results might impact medical management is crucial to informed, responsible decisions about whether a child should receive WGS. Clinicians cannot rule out the possibility that incidental findings will have negative downstream effects on patients’ future medical care. Insofar as understanding the potential risks associated with WGS is a requirement for consent to be truly informed, clinicians who recommend WGS for ill newborns should counsel families not only about how the genomic information will be managed but also about the possibility that this information will have downstream effects on their child’s future options for clinical management. Part of appropriate clinical counseling, then, will involve informing parents that the clinical utility of uncovered variants may change over time, and that one implication of this change could be restriction of their child’s access to scarce medical resources [56].
What does testing entail (needed samples, etc.) Burke and Clarke 2016
Rosell, et al. 2016
Deignan, et al. 2020
Parents felt they needed to know: […] what did the testing entail (i.e. What types of samples were needed and what would be expected from them and their children) [68].
Voluntary nature of the test Burke and Clarke 2016
Malek, et al. 2019
Proposed minimal requirements for consent in whole genome sequencing: […] Voluntary nature of the test [60].
Description of alternative diagnostic tests, if available Burke and Clarke 2016 Proposed minimal requirements for consent in whole genome sequencing: […] Alternative test Description of alternative diagnostic tests, if available [69].
Possibility of refusal at any time, without consequences for care Burke and Clarke 2016 Proposed minimal requirements for consent in whole genome sequencing: […] Possibility of refusal at any time, without consequences for clinical or social care [69].
Clarify parental values Bowdin, et al. 2016
Li, et al. 2016
Wouters and Cornelis 2017
Bell 2018
Werner-Lin, et al. 2018
Gore, et al. 2019
Gyngell, et al. 2019
Malek, et al. 2019
Sanderson, et al. 2019
Smith, et al. 2019
Yu, et al. 2019
Tibben, et al. 2021
Vears 2021
The overall data highlighted the context-dependent nature of decision making for GWS. Participants’ diverse circumstances and other elements such as personality, values, beliefs, and amount of prior knowledge influenced and personalized their decision making and was believed by many participants to be a factor in the amount and type of information they needed. […] It is important for HCPs to assess parents’ individual values, priorities, and informational needs and tailor information accordingly [62].
Privacy and confidentiality considerations Burke and Clarke 2016
Bertier, et al. 2017
McGowan, et al. 2018
Lalonde, et al. 2020
Further, researchers ought to address privacy and confidentiality considerations in the informed consent process, being attentive to the risks of personally identifiable genomic research data making its way into medical, legal, or insurance environments [70].
Potential implications of gathered knowledge for family members Bowdin, et al. 2016
Burke and Clarke 2016
Krabbenborg, et al. 2016
Bertier, et al. 2017
Johnson, et al. 2017
Hart, et al. 2019
Yu, et al. 2019
Hill, et al. 2020
Hay, et al. 2021
Pretest counseling was another unsolved issue identified by technology users in the pediatric setting. Similarly, all three sets of guidelines address this issue, specifying a list of aspects that should be discussed when counseling patients and their families and conducting informed consent prior to WES. This generally includes a discussion of the expected outcomes of testing, outlining the potential benefits and risks of the test, the limitations of such testing, and the implications for family members [28].
Potential effects on parent-child bonding Gyngell, et al. 2019 Therefore, rather than focusing on whether information should be binned, tiered or something else, those obtaining consent to RGT should talk with parents to promote realistic expectations from testing. They should also engage them about the broad goal of the test, clarify parental values and hopes, canvass the possible impact of the test on bonding […] [44].
Emotional preparedness to receive the potential results Rosell, et al. 2016
Malek, et al. 2019
Yu, et al. 2019
Parents also felt it was important for the genetics team to explore with families whether they were ready or if they really wanted the information that may be obtained from the WES and to discuss with them the possibility that a positive result may still result in unanswered questions. Consenting for WES typically focuses on the technical facts (i.e., different types of variants) and likelihood of a diagnosis; findings from these parents suggest that the emotional aspect of the potential outcomes of a diagnosis should be explored as part of the WES consenting process [68].
(Un) realistic expectations Bowdin, et al. 2016
Burke and Clarke 2016
Rosell, et al. 2016
Bertier, et al. 2017
Johnson, et al. 2017
Wouters and Cornelis 2017
Johnston, et al. 2018
Werner-Lin, et al. 2018
Chassagne, et al. 2019
Gore, et al. 2019
Gyngell, et al. 2019
Lantos 2019 (a)
Malek, et al. 2019
Smith, et al. 2019
Szego, et al. 2019Yu, et al. 2019
Hill, et al. 2020
Lalonde, et al. 2020
Vears, et al. 2020
Concerns have already been raised about the overly positive portrayal of WGS and WES, and the danger of this creating unrealistic expectations among the public. Therefore, rather than focusing on whether information should be binned, tiered or something else, those obtaining consent to RGT should talk with parents to promote realistic expectations from testing [44].
Disclosing policy Abdul-Karim, et al. 2013
Knoppers, Avard et al. 2014
McCullough, et al. 2015
Sénécal, et al. 2015
Burke and Clarke 2016
Bell 2018
Werner-Lin, et al. 2018
Deignan, et al. 2020
Clinician, researchers, and direct-to-consumer provider should describe to potential recipients incidental and secondary findings that are likely to arise or be sought from the tests and procedures conducted. Practitioners should inform potential recipients about their plan for disclosing and managing incidental and secondary findings, including what findings will and will not be returned [71].
Reanalysis policy Knoppers, Avard, et al. 2014
Johnson, et al. 2017
Mandatory reanalysis of genomic raw data is unlikely to occur on a broad scale due to resource limitations and loss of participants to follow-up; however, it may be pursued by individual centers or laboratories. Accordingly, any plan for reanalysis should be disclosed to patients during pretest counseling [54].
Consent to data sharing for research Ayuso, et al. 2015
Oberg, et al. 2015
Burke and Clarke 2016
Bertier, et al. 2017
Yu, et al. 2019
Proposed minimal requirements for consent in whole genome sequencing: […] Destination and potential further use of samples, such as research, retesting with further phenotypical information, retesting as genomic databases become more extensive [60].
Duration of process until reception of results Rosell, et al. 2016 Parents felt they needed to know: […] how long would testing take [68].
ISSUES RELATED TO SEQUENCING, ANALYSIS AND INTERPRETATION
 Challenges regarding infrastructure Risk of inconsistencies and variability due to different bioinformatics pipelines ACMG 2013
Ayuso, et al. 2015
McCullough, et al. 2015
Deem 2016
Green, et al. 2016
Bertier, et al. 2017
Johnson, et al. 2017
Eno, et al. 2018
Vears, et al. 2018
Horton and Lucassen 2019
Yu, et al. 2019
As one example, although an NGS-based test holds the potential to scan the entirety of the exome or genome, the laboratory may not be capable of analyzing all of the sequenced areas due to insufficient coverage of the base pairs in a targeted region. Unfortunately, accepted levels for depths of coverage remain to be determined as do thresholds for calling genetic variants (i.e. quality scores) during analysis of sequencing reads. When considering how specific germline variants are handled across laboratories, the metrics for interpreting, thresholds for classifying, and policies for reporting are not consistent. Although the ACMG has developed a plan for the classification and reporting of germline variants into one of five different categories (i.e. benign, likely benign, variants of uncertain significance, likely pathogenic, or pathogenic), there is an industry-wide lack of standardization in placing variants into one of these five categories. As a result, it is possible for a patient to receive reports with conflicting interpretations of variant pathogenicity from different clinical laboratories [54].
Risk of lengthy turnaround times Editorial 2013
Dimmock and Bick 2014
Krabbenborg, et al. 2016
Bertier, et al. 2017
Werner-Lin, et al. 2018
Smith, et al. 2019
Several parents expressed frustration with the length of time required to receive results, reporting that the length of time was the biggest drawback to their experience overall [72].
Risk of lack of data analysts/ bioinformaticians Beale, et al. 2015 Staffing numbers and training were also considered important by some interviewees, especially regarding the need for more bioinformaticians and genetic counsellors. Limited formal qualification-bearing education and training opportunities are being developed, but these take several years of highly specialised work to complete [46].
Risk of lack of data sharing ACMG 2013
Editorial 2013
Deem 2016
Bertier, et al. 2017
Vears, et al. 2018
Learned, et al. 2019
Technology users highlighted the need for systematic and generalized sharing of variant data from WES to enable the advancement of research and to enhance the detection of genetic causes of disease [28].
Risk of lack of access to high quality databases Deem 2016
Bertier, et al. 2017
Vears, et al. 2018
Learned, et al. 2019
Until there is a clinical-grade general database available to analysts and clinicians, as well as broadly accepted methods for standardizing interpretations of sequence variants, it will remain a challenge to ensure that clinicians are sufficiently familiar with and have ready access to the most recent emerging data about variant-disease associations and their clinical significance [56].
 Challenge to determine how broad/targeted analysis   Bunnik, et al. 2013
Clayton, et al. 2014
Berg and Powell 2015
Botkin, et al. 2015
Botkin 2016
Thornock 2016
Bertier, et al. 2017
Johnson, et al. 2017
Vears, et al. 2018
Holm, et al. 2019
Ross and Clayton 2019
Deignan, et al. 2020
One way to avoid the need to deal with most incidental findings is by only examining genes that have a high likelihood of being associated with a child’s clinical condition. […] In order to increase the clinical and economic efficiency of sequencing, geneticists may analyze only those portions of the genome that have a high likelihood—based on prior studies—of being associated with the particular symptoms of the newborn. Though the entire genome is sequenced, the sequence is filtered so that only those variants related to a newborn’s symptoms are fully analyzed and returned to the treating physician. This approach only generates information about specific genes and as such it is less likely than a more comprehensive analysis of the genome to reveal unsought information. This approach will not avoid every incidental finding since there may be some incidental findings in the specific genes that are analyzed. But it will decrease the number of such findings. It will not, however, eliminate the need for difficult ethical choices [57].
 Challenge to decide whether it should be actively searched for a certain list of disease-associated genes in every genome-wide sequencing   Bush 2014
Clayton, et al. 2014
Knoppers, Avard, et al. 2014
Anderson, et al. 2015
Botkin, et al. 2015
Clayton 2015
Levenson 2015
Sénécal, et al. 2015
Bowdin, et al. 2016
Burke and Clarke 2016
Johnson, et al. 2017
Wouters and Cornelis 2017
Vears, et al. 2018
Cornelis and Wouters 2019
Hart, et al. 2019
Holm, et al. 2019
Ormond, et al. 2019
Szego, et al. 2019
Ross and Clayton 2019
Wong, et al. 2019
De Wert, et al. 2021
Miller, et al. 2021
Wouldstra, et al. 2021
Based on the capability of NGS approaches to simultaneously sequence multiple genes at the same time, in 2013, the American College of Medical Genetics and Genomics (ACMG) recommended that clinical labor atories performing this testing analyze and report back on pathogenic variants for a panel of 56 disease-associated genes regardless of the original indication for ordering the testing. These genes were selected for analysis and reporting because it was felt that early identification of the associated diseases followed by intervention were likely to prevent serious morbidity and mortality. These recommendations were criticized for not allowing individuals to opt out of receiving these genetic results. Significant ethical concerns were also raised due to the potential to identify adult-onset conditions in children. There was also fear that an obligatory analysis of an additional 56 genes would significantly increase the time and resources required for testing. In response, the ACMG has revised this policy in 2014, relaxing their position around the mandatory nature of analysis and reporting on this prespecified list of genes. Recommendations for analysis and reporting are changing rapidly and in 2016, the ACMG again revised their position where the gene list now includes 59 genes. Currently, individual clinical laboratories determine the scope of tests that each offers, and many use a tiered informed consent that allows patients to choose which of these so-called ‘ACMG genes’ they would like to have tested [54].
 Challenges for the interpretation of variants Risk due to the gap between amount of data which are generated and knowledge to use them in a clinical context Lunshof 2012
Editorial 2013
Knoppers, Sénécal, et al. 2014 [b]
Landau, et al. 2014
Hens and Dierickx 2015
Howard, et al. 2015
McCullough, et al. 2015
Petrikin, et al. 2015
Reinstein 2015
Bowdin, et al. 2016
Deem 2016
Lantos 2016
Newson and Schonstein 2016
Rosell, et al. 2016
Friedman, et al. 2017
Iskrov, et al. 2017
Johnson, et al. 2017
Johnston, et al. 2018
Horton and Lucassen 2019
Lantos 2019(a)
Lantos 2019(b)
Szego, et al. 2019
In both sequencing approaches (WGS and WES), however, differentiating disease-related mutations from variations of unknown clinical significance is a major problem, even in the known coding regions of genes. In WGS this represents an even greater challenge in the non-coding parts of the genome where function is not yet clearly defined for many sequences. Thus, the clinical significance of thousands of genomic and exomic variants detected by NGS cannot presently be interpreted with complete certainty, preventing evidence-based decisions being made to guide treatment and clinical surveillance [73].
Risk to miss scientific developments Deem 2016
Lantos 2016
Newson and Schonstein 2016
Lantos 2019(a)
Lantos 2019(b)
Odgis, et al. 2021
It is difficult to maintain up-to-date information on every known genetic disease. No centrally maintained repository of all rare and disease-associated variants currently exist [74].
Risks due to limited ethnic diversity within the sequencing content of reference databases Green, et al. 2016
Johnson, et al. 2017
Rotz and Kodish 2018
Chaudhari, et al. 2020
Odgis, et al. 2021
Racial and ethnic differences may play a role in the heterogeneity of cancer biology. Differences in research participation may lead to future disparities in our fundamental understanding of malignancy and our ability to offer precision treatment approaches. For example, as part of the National Institutes of Health–sponsored Cancer Genome Atlas project, white patients were overrepresented, and Asian and Hispanic patients were underrepresented, compared with the entire United States population. Due to decreased research participation with less background data, individuals from minority groups are at a higher risk for false-positive and false-negative genomic testing results. Increasing the availability of genomic tests to historically underserved populations is critical to the amelioration of health disparities and ensuring distributive justice [59].
Risks of uncertainties and failures in the classification of variants Tarini and Goldenberg 2012
ACMG 2013
Editorial 2013
Holm, et al. 2014
Landau, et al. 2014
Petrikin, et al. 2015
Reinstein 2015
Sénécal, et al. 2015
Bowdin, et al. 2016
Deem 2016
Kesserwan, et al. 2016
Newson and Schonstein 2016
Friedman, et al. 2017
Johnson, et al. 2017
Newson 2017
Johnston, et al. 2018
Rotz and Kodish 2018
Vears, et al. 2018
Lantos 2019(b)
Gyngell, et al. 2019
Horton and Lucassen 2019
Our understanding of the clinical significance of any given sequence variant falls along a gradient, ranging from those in which the variant is almost certainly pathogenic for a disorder to those that are almost certainly benign.” To classify genetic variants along this spectrum, interpreters must take into consideration population data on the frequency of the allele in question, computational and predictive data (“in silico models”) in which a deleterious effect from the variant is suggested, functional studies, family history, and studies revealing that people with the variant have the disease and those without the variant do not. It is a laborious process that can be considered as much an art as a science. The art requires value judgments about the risks of “calling” a variant as pathogenic. There are risks to both false-positives and false-negatives [49].
Risk of information overload Lunshof 2012
Botkin and Rothwell 2016
Joseph, et al. 2016
Lantos 2016
Sabatello and Appelbaum 2016
Johnston, et al. 2018
Lantos 2019(a)
Biesecker recognized the problems of information overload, saying, “A whole-genome or whole- exome result is overwhelming for both the clinician and the patient … [because] variants from [the] genome or exome range from those that are extremely likely to cause disease to those that are nearly certain to be benign and every gradation between these 2 extremes.” [74]
ISSUES RELATING TO COMMUNICATING RESULTS
 Challenges for reporting results from lab to clinician/participant/patients/parents Risks due to inconsistencies in guidelines and IRB decisions which results to report Sénécal, et al. 2015
Eno, et al. 2018
Vears, et al. 2018
Vears 2021
Although NGS technologies are well-embedded in the clinical setting for identification of genetic causes of disease, guidelines issued by professional bodies are inconsistent regarding some aspects of reporting results. Most recommendations do not give detailed guidance about whether variants of uncertain significance (VUS) should be reported by laboratory personnel to clinicians, and give conflicting messages regarding whether unsolicited findings (UF) should be reported [75].
The management and disclosure of incidental pediatric genomic research findings are increasingly pressing issues. Investigators are looking to IRBs and research ethics consultants for guidance, yet disagreements persist about this complicated set of issues. As NGS becomes increasingly widespread, excessive IRB variation may lead to decisional inconsistencies. More uniform guidelines on how to address the disclosure of incidental findings can serve as a framework to guide IRB decisions, and additional investigation is needed [16].
Risk of ineffective communication between lab and ordering physician Abdul-Karim, et al. 2013
Eno, et al. 2018
Vears, et al. 2018
In order for a targeted approach to be effective, using either targeted gene-capture or exome sequencing with bioinformatic filtering, the laboratory must have a clear idea of the clinical question that is being asked. Therefore, detailed and accurate information about the clinical phenotype of the patient is required to determine which genes should be included in the analysis. Detailed phenotypic information is also crucial for deciding which variants to report. Although laboratories can contact the referring clinician after sequencing takes place to get more details about the patient’s phenotype, and how this relates to the variants identified, this additional step can be time consuming and would be unnecessary if more information was provided at the time of the request. We suggest it is not good clinical practice for laboratories to perform exome or large panel sequencing until sufficient clinical information is received from the clinician [75].
Challenge to decide whether results should be made directly available to patients/ participants (incl. Raw data) ACMG 2013
Editorial 2013
Johnson, et al. 2017
Eno, et al. 2018
Grebe, et al. 2020
Beauvais, et al. 2021
Laboratory tests are ordered by clinicians based on the medical needs of their patients, and the results are typically returned to the referring clinician. Only recently have laboratories been either encouraged or required to make results directly available to patients. Patients who seek out their laboratory test results independent of their health-care providers have made their own choice about learning these results [14].
Challenge to determine where to stop knowledge in different steps of information pipeline Bunnik, et al. 2013
Hufnagel, et al. 2016
Friedman, et al. 2017
Eno, et al. 2018
Vears, et al. 2018
Holm, et al. 2019
Deignan, et al. 2020
Highlighted in this case is also the ethical dilemma that occurs when laboratory personnel are privy to information that would be relevant to an individual but are unable to act on it. Some feel that if laboratory personnel have knowledge of clinically important information about a patient or participant or even a family member whose biological specimen was submitted for validation testing, they ought to disclose it or at least discuss it with the ordering physician or researcher [21].
 Challenges for Post-test-counselling Risks due to varying degrees of genetic literacy among clinicians Howard, et al. 2014
Deem 2016
Johnson, et al. 2017
Vears, et al. 2018
Werner-Lin, et al. 2018
Chaudhari, et al. 2020
Deuitch, et al. 2020
Vears, et al. 2020
The working group discussed whether part of the role of the referring clinician is to filter the variants that are reported to them and to decide which of those variants it is appropriate to report to the patient. This is likely to be particularly challenging when the referring specialist does not have specific training in genetics. It is unrealistic to expect laboratories to tailor their reports to the experience of the referring clinician [52].
Risk of overestimating genetic results Dimmock and Bick 2014
Howard, et al. 2014
Reinstein 2015
Burke and Clarke 2016
Johnston, et al. 2018
Gyngell, et al. 2019
An ethical consideration is what life is best worth living. Do we support genetic determinism in which all information is present at the beginning with a clear path and destiny and no ultimate freedom of choice? [73]
Challenge to deal with “genotype only” situations McCullough, et al. 2015
Johnston, et al. 2018
Horton and Lucassen 2019
Lantos 2019(b)
Szego, et al. 2019
With our current imperfect state of knowledge, it may be hard to know whether a finding of a pathogenic variant in an asymptomatic patient ought to be considered a false-positive test result or whether, instead, such a test result should be considered a warning flag indicating a higher-than-average probability that the person will develop disease in the future. Some have referred to people in this situation as “patients- in-waiting.” I would like to suggest, in a manner only partially tongue-in- cheek, that such a situation could also be characterized as a “false-negative phenotype.” With either label, the implications are that the patient will be treated as if they were at risk for developing disease in the future. This may lead to increased anxiety, extra diagnostic testing, and, in some cases, even treatment of disease that may or may not ever occur […] Such testing leads to questions about how to think about the concept of “molecular diagnoses” in apparently healthy people. Given a genomic variant that would be classified as likely pathologic in an apparently healthy person, there are 2 possibilities. The tests could be wrong. Or the people could, in fact, have disease but have not yet developed phenotypic manifestations of illness [49].
Risk of therapeutic uncertainty despite diagnosis Tarini and Goldenberg 2012
McCullough, et al. 2015
Chassagne, et al. 2019
Szego, et al. 2019
The downside is that in some instances, technology creates a “therapeutic gap” by making it possible to screen for a disorder before effective treatments are available. The imminence of financially feasible whole-genome sequencing (WGS) is likely to transform this gap into a chasm [76].
Challenge to decide to whom report: parents or children/adolescents or together? Sénécal, et al. 2015
Sabatello and Appelbaum 2016
Sundby, et al. 2018
Werner-Lin, et al. 2018
We recommend providers disclose findings to adolescents and parents together, and in each stage offer the opportunity for parents and adolescents to meet separately to discuss concerns, questions, and next steps. Separating family members to discuss these issues will minimize protective buffering, enhance informed consent, and support long term care of the identified patient. A significant feature distinguishing pediatric from adult care is the role of parents in directing the care of their children and providing consent on behalf of the child. Beliefs, emotions, or concerns revealed in separate conversations may also alert providers to the presence of red flags for depression or anxiety, and enable a referral to family counseling. In some families, it might be appropriate to first return results to the parents, and then discuss results with the parents and child together, and then with the child separately [72].
Risk of negative impact of diagnosis on parent-child bonding ACMG 2013
Holm 2014
Allain 2015
Berg and Powell 2015
Bowdin, et al. 2016
Burke and Clarke 2016
Johnson, et al. 2017
Johnston, et al. 2018
Gyngell, et al. 2019
Hill, et al. 2020
One consideration that parents may not appreciate when they agree to testing is the potential for WGS and WES in the newborn period to interfere with family dynamics by influencing parent-child bonding. These concerns could be exacerbated in the cases of RGT in the NICU, given the short turnaround time. While parent-child bonding starts during pregnancy, it intensifies in the months after birth. This means that RGT in the NICU will often return genomic results very early in the bonding process, whereas traditional (slower) testing in unwell infants will return results when bonding is established [44].
Challenge to identify when a prognosis is sufficiently poor that treatment may be withheld Gyngell, et al. 2019
Horton and Lucassen 2019
RGT also raises significant ethical challenges. Some of these are shared with other prognostic tests and technologies, and some are shared with perennial questions around the care of very unwell newborns.19 These include normative uncertainty, and the challenge of identifying when a prognosis is sufficiently poor that treatment may be withheld, or sufficiently good that it must not be [44].
Risks regarding variants of unknown significance ACMG 2013
Ayuso, et al. 2015
Oberg, et al. 2015
Deem 2016
Joseph, et al. 2016
Lantos 2016
Rosell, et al. 2016
Bertier, et al. 2017
Friedman, et al. 2017
Johnson, et al. 2017
Vears, et al. 2018
Werner-Lin, et al. 2018
Gore, et al. 2019
Gyngell, et al. 2019
Scollon, et al. 2019
Szego, et al. 2019
Vears, et al. 2020
Hay, et al. 2021
Because a VUS cannot be confirmed as benign and may therefore be related to the patient’s condition, they can generate anxiety in patients. The assessment of their pathogenicity may require testing of other family members, or additional investigations that may be costly and time consuming for patients and their families […] Indeed, the status of such VUS is likely to change as research in genomics advances. Jiang and colleagues suggested that this reevaluation should be offered to patients as part of comprehensive care and patient follow- up. However, Biesecker and Green explained that the potential for a “negative result” to become “positive” or clinically relevant could complicate the post-counseling process [28].
Risk to undermine right not to know with obligatory disclosure of UFs ACMG 2013
Borry, et al. 2014
Holm, et al. 2014
Knoppers, Avard, et al. 2014
Zawati, et al. 2014
Anderson, et al. 2015
Blackburn, et al. 2015
Botkin, et al. 2015
Levenson, 2015
Botkin 2016
Bowdin, et al. 2016
Burke and Clarke 2016
Bertier, et al. 2017
Ormond, et al. 2019
Ross and Clayton 2019
Benedetti and Marron 2021
Vears 2021
Parents should be able to decline secondary findings in advance of testing, but clinicians should disclose those findings if they indicate a serious health risk and “effective action can be taken to mitigate that threat,” the statement recommends. “We said it’s OK not to look for secondary findings, but if a lab does find something with serious implications, the clinician must disclose it,” says Jeffrey Botkin, MD, MPH, first author of the ASHG position statement. […] ASHG clearly states that a clinician has a fiduciary duty to override parent preferences to not receive secondary results when genomic sequencing reveals a serious risk to children’s health and medical action can mitigate the threat, Dr. Biesecker notes. “I think this is correct and a significant advance in the thinking on this topic,” he adds [15].
Risk to undermine child’s future autonomy with disclosure of UFS of adult onset conditions and carrier status Lunshof, 2012
ACMG 2013
Borry, et al. 2014
Holm 2014
Holm, et al. 2014
Allain 2015
Anderson, et al. 2015
Blackburn, et al. 2015
Knoppers, Avard, et al. 2014
Levenson 2015
McCullough, et al. 2015
Sénécal, et al. 2015
Bowdin, et al. 2016
Burke and Clarke 2016
Kesserwan, et al. 2016
Lantos 2016
Sabatello and Appelbaum 2016
Bertier, et al. 2017
Johnson, et al. 2017
Johnston, et al. 2018
Garrett, et al. 2019
Lantos 2019(a)
Ormond, et al. 2019
Ross and Clayton 2019
Wong, et al. 2019
Savatt, et al. 2020
Sofer 2020
De Wert, et al. 2021
Dondorp, et al. 2021
Miller, et al. 2021
Tibben, et al. 2021
Uveges and Holm 2021
Whereas guidelines from the British Medical Association‍ and the American Academy of Pediatrics‍ recommended that carrier status results obtained incidentally should be conveyed to parents, the American Medical Association‍ and the German Society of Human Genetics recommended that this information should not be disclosed to parents or other third parties. Miller et al.‍. write, “The provision of carrier or predictive genetic testing is seen to infringe on the child’s autonomy and right to confidentiality because it forecloses on the child’s right to decide whether to seek this information and to whom it should be disclosed.” [74]
Challenge to balance the best interests of the child with the best interests of the family regarding the disclosure of UFs Abdul-Karim, et al. 2013
ACMG 2013
Borry, et al. 2014
Bush 2014
Clayton, et al. 2014
Holm 2014
Holm, et al. 2014
Knoppers, Avard, et al. 2014
Zawati, et al. 2014 Anderson, et al. 2015
Berg and Powell 2015
Clayton 2015
McCullough, et al. 2015
Sénécal, et al. 2015
Botkin 2016
Botkin and Rothwell 2016
Bowdin, et al. 2016
Burke and Clarke 2016
Kesserwan, et al. 2016
Newson and Schonstein 2016
Bertier, et al. 2017
Friedman, et al. 2017
Johnson, et al. 2017
Johnston, et al. 2018
Vears, et al. 2018
Cornelis and Wouters 2019
Garrett, et al. 2019
Holm, et al. 2019
Horton and Lucassen 2019
Ross and Clayton 2019
Szego, et al. 2019
Wong, et al. 2019
Chaudhari, et al. 2020
Savatt, et al. 2020
Sofer 2020
De Wert, et al. 2021
Miller, et al. 2021
Uveges and Holm 2021
A counter argument to ‘respect for an open future’ considers that genomic testing of the child in the present may be the only way to identify familial genetic risks; an argument that considers present day interests of the family over the child’s future interests and autonomy. If the child does not survive to adulthood to make an autonomous decision to undergo testing, then he or she does not benefit from being allowed an open future. The family, however, is potentially harmed through the failure to identify an inherited genetic predisposition that would only be identified through testing of the child. Given the possibility to reveal information about genetic risk in family members, whose best interests should prevail? Should the child’s immediate medical well-being [i.e. his or her self-regarding or present day interests] be weighed over the benefits that the family would receive through the child’s test results? […] Children exist within a family unit; therefore, some argue that best interest evaluations should occur within the context of overall family interests [54].
Challenge to define “actionable” UFs Abdul-Karim, et al. 2013
Holm, et al. 2014
Hens and Dierickx 2015
Green, et al. 2016
Kesserwan, et al. 2016
Ormond, et al. 2019
Especially in the case of minors, questions regarding what is actionable and what is not remain. For example, the finding of an extra X chromosome in males (Klinefelter syndrome) may on the one hand be significant in that it is related to an increased chance of learning problems or autism. On the other hand, the only constant in Klinefelter syndrome is infertility. Is this enough to warrant inclusion of sex chromosome screening in the panel? Knowledge of infertility may avoid medical odysseys later in life, but may also be part of the genetic privacy of the child that needs safeguarding. What about mutations or copy number variants that are linked with an increased risk of autism? [65]
Challenge to deal with UF of misattributed parentage Holm, et al. 2014
Botkin, et al. 2015
Johnson, et al. 2017
Bell 2018
Eno, et al. 2019
Deignan, et al. 2020
Another potential harm is the possibility of disrupting family relationships with unanticipated genetic information. One example involves the identification of nonpaternity (i.e. the person claiming to be the father of the child is not the biological father). It can be difficult to decide whether and how to release this result to the patient and family and currently, there is not a consensus within the ethics literature as how best to proceed [54].
Challenge to deal with UF of consanguinity Botkin, et 1 l. 2015 The ASHG recommends that laboratories adopt data standards and analytical methods that allow reliable detection of incest. Practitioners should develop procedures for case management when genetic laboratory results are consistent with incest involving a minor. Practitioners have a duty to report suspected child abuse. Health-care providers do not have a responsibility to report incest involving consenting adults, even though this might be illegal in their jurisdiction [45].
Challenge for parents to understand and deal with the results Bowdin, et al. 2016
Rosell, et al. 2016
Lantos 2016
Rogers and Zhang 2016
Bertier, et al. 2017
Johnson, et al. 2017
Werner-Lin, et al. 2018
Lantos 2019(a)
Malek, et al. 2019Scollon, et al. 2019
Vears, et al. 2020
CGES findings may present difficulties for families and patients due to poor genome- based health literacy, lack of tolerance for ambiguity or uncertainty, or the emotional demand and future implications of testing in the context of a child’s ongoing and intensive clinical care [72].
Need for good relationship between parents and clinicians Rosell, et al. 2016
Werner-Lin, et al. 2018
Scollon, et al. 2019
We also found that post-test genetic counseling and clinical follow-up are critically important. The clinical relationship, based on trust, respect, and open communication was key to how many parents perceived the process of WES and parents both with and without reportable findings wanted closer contact with the clinicians [68].
Need for thoughtful communication of results Goldenberg and Sharp 2012
Abdul-Karim, et al. 2013
Holm, et al. 2014
Blackburn, et al. 2015
Krabbenborg, et al. 2016
McCullough, et al. 2015
Sénécal, et al. 2015
Bowdin, et al. 2016
Deem 2016
Rosell, et al. 2016
Sabatello and Appelbaum 2016
Werner-Lin, et al. 2018
Chassagne, et al. 2019
Gyngell, et al. 2019
Lantos 2019(a)
Malek, et al. 2019
Scollon, et al. 2019
Smith, et al. 2019
Odgis, et al. 2021
Sachdev, et al. 2021
There should be designated supports for communication of information that may be disappointing or concerning for participants while respecting participant preferences to receive such information [77].
 Risk of legal liability for disclosure/non-disclosure of findings   Green, et al. 2016
Bertier, et al. 2017
CSER investigators have also conducted important legal and regulatory analyses relevant to clinical sequencing, including the legal liability for disclosure or non-disclosure of findings to patients, research participants, and family members [78].
 Risk of lacking post-test strategies and resources (access to genetic counselling, clinical follow-up, treatment options required etc.)   Jenkins, et al. 2008
Abdul-Karim, et al. 2013
Holm, et al. 2014
Ayuso, et al. 2015
Sénécal, et al. 2015
Bowdin, et al. 2016
Joseph, et al. 2016
Kesserwan, et al. 2016
Krabbenborg, et al. 2016
Rosell, et al. 2016
Bertier, et al. 2017
Johnson, et al. 2017
Bell 2018
Werner-Lin, et al. 2018
Chassagne, et al. 2019
Holm, et al. 2019
Deuitch, et al. 2020
Hitchcock, et al. 2020
Cabello, et al. 2021
There must be a process of immediate follow-up and querying of participants, combined with an offer of genetic counselor involvement for further questions or concerns [77].
ISSUES RELATED TO FUTURE USE OF DATA
 Challenges of data sharing, storage and governance Challenge to determine data ownership Lunshof 2012
Editorial 2013
Botkin, et al. 2015
Clayton 2015
Sabatello and Appelbaum 2016
Other issues relate to genomic data-sharing by professionals, especially in the context of new informational technologies. One such issue is the increasing incorporation of genomic data in electronic medical records. This development has been intensely debated, given that these records may optimize personalized care, but their “multi-owner and multi-user nature” may increase the risks of privacy breaches and misuses of genomic data. […] Studies regarding pediatric genomic SFs show that although parents often worry that their children’s participation in research will lead to loss of privacy [and possible stigma and discrimination], they do not view their own access to their children’s genomic information as a privacy concern. Many parents in fact disclose genetic data about their children to extended family members, friends, neighbors, and others, suggesting a sense of ownership [41].
Risk to privacy Lunshof 2012
Wilfond and Diekema 2012
Editorial 2013
Knoppers, Avard, et al. 2014
Clayton 2015
Howard, et al. 2015
Oberg, et al. 2015
Sabatello and Appelbaum 2015
Bowdin, et al. 2016
Joseph, et al. 2016
Rogers and Zhang 2016
Sabatello and Appelbaum 2016
Bertier, et al. 2017
Friedman, et al. 2017
Seidel 2017
Johnston, et al. 2018
Vears, et al. 2018
Zacharias, et al. 2018
Lantos 2019(a)
Lewis, et al. 2020
Beauvais, et al. 2021
Benedetti and Marron 2021
However, data sharing can be ethically challenging, particularly with regards to issues of privacy and confidentiality. Although data may be anonymised or deidentified, the nature of genomic information means that it is potentially reidentifiable, particularly in patients with rare diseases. In these cases, linking phenotypic data with genomic data is crucial for determining whether a variant is causative. However, this makes these patients more easily identifiable [75].
Risk of discrimination Dimmock and Bick 2014
Knoppers, Sénécal, et al. 2014
Allain 2015
Oberg, et al. 2015
Bowdin, et al. 2016
Deem 2016
Joseph, et al. 2016
Rogers and Zhang 2016
Sabatello and Appelbaum 2016
Bertier, et al. 2017
Friedman, et al. 2017
Johnson, et al. 2017
Johnston, et al. 2018
Zacharias, et al. 2018
Graf, et al. 2019
Szego, et al. 2019
Chaudhari, et al. 2020
Grebe, et al. 2020
Savatt, et al. 2020
Sofer 2020
Benedetti and Marron 2021
Miller, et al. 2021
Sachdev, et al. 2021
Other important challenges to returning secondary WES/WGS findings are the imperfect confidentiality of genetic information and uneven regulation of the use of personal genetic data by employers, insurers, corporations and governments. While many countries and jurisdictions legally constrain discrimination on the basis of genetic pre-disposition to disease (e.g. the Genetic Information Nondiscrimination Act (GINA) in the United States), other countries lack specific laws [e.g. Canada] and existing legal protections may fall short of covering every situation in which confidentiality is breeched or genetic information used to deny employment and/or insurance [53].
Risk irresponsible parental data sharing Allain 2015
Clayton 2015
Sabatello and Appelbaum 2015
Sabatello and Appelbaum 2016
Beauvais, et al. 2021
There is evidence that the concept of genetic privacy is applied asymmetrically within families. Whereas many parents disclose genetic data about their children to extended family members, friends, neighbors, and others, studies of adults who have undergone predictive testing show that they are wary of disclosing their own genetic results [66].
Challenge to determine whose responsibility it is to initiate reanalysis, provide access and recontact patients/parents/participants Abdul-Karim, et al. 2013
Knoppers, Avard, et al. 2014
Ayuso, et al. 2015
Botkin, et al. 2015
Levenson 2015
McCullough, et al. 2015
Sénécal, et al. 2015
Bowdin, et al. 2016
Burke and Clarke 2016
Kesserwan, et al. 2016
Thornock, 2016
Bertier, et al. 2017
Johnson, et al. 2017
Vears, et al. 2018
Cornelis and Wouters 2019
Chaudhari, et al. 2020
It has been argued that clinicians have a responibility to recontact patients when new information, regarding the interpretation of genetic information, becomes available. No consensus currently exists about how this should be managed, and addressing such concerns is likely to be particularly challenging in the paediatric setting: how should information be communicated to children gaining competency and autonomy with regard to their own health? Any duty to recontact children in adulthood, to ensure the appropriate communication of results or to reconsider the significance of variants of unknown significance in the light of new information, would be challenging from logistical, economic and legal perspectives [60].
Challenge to gain re-consent of children when they reach majority Wilfond and Diekema 2012
Knoppers, Avard, et al. 2014
Howard, et al. 2015
Lantos 2016
Bertier, et al. 2017
Lantos 2019(a)
Wong, et al. 2019
Finally, the issue of when (if ever) to seek reconsent from people who were enrolled as minors but have now reached the age of majority is only beginning to be addressed. Some argue that parents should never be able to consent for the enrollment of minors.‍ Others suggest that a robust process of recontact and reconsent at the age of majority will be sufficient.‍ Given the rapid pace of change in the field, it is difficult to anticipate what we may be doing 5, 10, or 18 years from now both in terms of genomics and in terms of our ability to stay in touch with research subjects [74].
Risk of storage costs being higher than sequencing again in the future Knoppers, Sénécal, et al. 2014
Howard, et al. 2015
Friedman, et al. 2017
Others argue that the cost of secure storage and stewardship of these data over the lifetime of the child may exceed the cost of repeating the genomic testing in the future if the information becomes necessary [79].
 Challenge to determine which type of data should be included in the medical record   Botkin, et al. 2015
Oberg, et al. 2015
Chaudhari, et al. 2020
Deignan, et al. 2020
Grebe, et al. 2020
Recent federal regulations provide for laboratory results to be the property of the patient, raising questions about how much genomic information should be placed in the medical record, particularly in the case of genetic variation that does not have well-established clinical implications [45].