Ethical Implications of Rapid Whole-Genome Sequencing in Neonates

Whole-Genome Sequencing

Whole-genome sequencing is a technique in which the order of all nucleotides in one’s DNA is determined, demonstrating variation in any part of the genome. ⁶ Recall that a nucleotide is a base, adenine, thymine, guanine, or cytosine attached to a sugar molecule and a phosphate molecule in DNA. ⁷ Because of advances in technology, rapid WGS can return results in as little as 26 hours with high precision and sensitivity. ⁸

The newborn screening program in the United States has been very successful in identifying over 5,000 newborns per year with treatable genetic diseases. ⁸ Limitations to the newborn screening program include time to results, usually ten days; equivocal or negative results; and screening that is available for only approximately 60 genetic diseases. The actual number and type of screening varies by state. ⁸

Newborns with congenital anomalies and inherited diseases often undergo extensive, prolonged, and costly testing, sometimes without discovery of a final diagnosis. ² As technology improves and becomes more widely available, WGS or whole-exome sequencing (WES) can provide more rapid, less expensive, pinpoint diagnosis of monogenetic causes of disease and congenital anomalies in newborns. Managing newborns without a specific diagnosis often leads to more pain and suffering, exacerbating symptoms rather than improving them. ² Whole-genome sequencing has the potential to revolutionize the care of newborns with diseases of genetic origin by allowingprecise, individualized treatment plans. Additionally, in cases of fatal defects, rapid WGS allows for refocusing of ineffective and often painful neonatal care to comfort care with the goals of decreasing suffering and supporting the grieving family. ²

Ethical Implications

Whole-genome sequencing may reveal secondary findings, such as genetic diseases with adult-onset or genetic risk factors for diseases that do not manifest in infants or children. In 2013, the American College of Medical Genetics and Genomics (ACMG) issued a recommendation that laboratories performing WES or WGS, for any indication, include specific analysis of 56 genes for which there is clinical evidence that disease-causing variants may result in severe disease preventable if identified before the onset of symptoms. ⁹ That same year, the Presidential Commission for the Study of Bioethical Issues released a report making recommendations for the ethical management of secondary findings, including findings related to WGS. ¹⁰ There are three contexts in which secondary findings are revealed: in research, in clinical practice, and with direct-to-consumer products such as 23 and Me or Ancestry DNA. For this discussion, research is the most relevant context, and broader clinical application of WGS is likely on the horizon. Regardless of the situation in which testing is done, the overarching recommendation of the Presidential Commission is

Specific to research, the Presidential Commission made the following recommendation,

In the clinical context, the Presidential Commission recommended,

After discussion informed by this report by the Presidential Commission for the Study of Bioethical Issues, the ACMG updated its recommendation regarding secondary findings to “. . . patients [and parents of minors] should be able to opt out of the analysis of genes unrelated to the indication for testing, and the decision should be made during the informed consent before testing.” ^{9 (p68)} Researchers have addressed this concern by returning only those results that directly impact the nominating symptoms that lead to participation in WGS. ⁴

The Presidential Committee examined ethical considerations of incidental and secondary findings in both the research and clinical context across three basic ethical principles: respect for person, beneficence, and justice and fairness. ¹⁰ An essential element of informed consent for WGS research is informing parents about the possibility of uncovering incidental or secondary findings and determining the parents’ preference for wanting to know or not to know about these findings. Additionally, under some circumstances secondary findings might not be disclosed. Being informed of this fact may play a role in the decision of whether to participate in research. Similarly, in the clinical setting, there is tension between the requirement to disclose all findings and the potential harm or anxiety that may be caused by such disclosures. Therefore, clinicians must balance the best interest of the infant and parents with the parents' expressed wishes, using judgment to provide the information necessary for the family to participate in medical care decision making. ¹⁰

In the research arena, the ethical principle beneficence , to do good, and its complement principle nonmaleficence, to do no harm, must be balanced in relation to managing incidental and secondary findings of WGS. ¹⁰ In other words, does the benefit of disclosing a finding outweigh the risk of harm of disclosure? A relevant example is misattributed paternity. ¹⁰ In the clinical setting beneficence requires the clinician to provide care, even when doing so is burdensome. Additionally, potential benefits of care must be viewed in relation to potential risks to meet the requirements of nonmaleficence. ¹⁰

Justice and fairness are related to equitable distribution of benefits and burdens. To disclose incidental and secondary findings in research, time and resources must be allocated for interpretation, assessment, and disclosure. Utilization of research time and resources may overburden the research initiative, slowing the process of bringing forth generalizable knowledge. ¹⁰ If health concerns are revealed through disclosure, some participants may benefit if they have resources to address these concerns, while for others without necessary resources, disclosure becomes a burden. Such disclosure may reveal health disparities. ¹⁰ Clinically, justice and fairness require equitable distribution of benefits and burdens across society. Incidental and secondary findings require that patients receive health care resources to meet their needs while also taking into account all of society's health care priorities. Thus, judicious use of laboratory tests and procedures must be considered. ¹⁰

In his discussion of ethical challenges of WGS in the NICU, Deem cautions about the portrayal of WGS as a means for determining whether to continue aggressive medical care or to withdraw care and transition to palliative care in reinforcing negative social attitudes toward disability. ¹¹ First and foremost, WGS should be described as a diagnostic tool to inform and guide clinical management of critically ill newborns. Palliative care is appropriate clinical management for infants in which a lethal diagnosis is returned and continued aggressive care would result in ongoing pain and suffering. However, if WGS is specifically linked to palliative care or serves as a more cost-effective means of moving more rapidly to palliative care compared with the often-prolonged diagnostic testing and procedures many neonates endure in search of a diagnosis, there is the risk that disability is viewed by health care professionals as a drain on both medical and societal resources. Many genetic diseases are not lethal. Whole-genome sequencing may return a novel genetic variation for which the phenotypic expression and potential degree of disability are not known. ¹¹ Additionally, many clinicians are misinformed and biased about disability and quality of life for both the child and the family. ¹¹

Institutional review boards wrestle with these ethical principles during the review and approval process for research studies. As technologies such as WGS move into the clinical arena, it is incumbent upon all clinicians to wrestle with these ethical concerns as well.

The future is now and it not only holds so much promise for our tiny patients and their families, but it also commands great thought and responsibility regarding benefit, harm, and equity.