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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].