Exploring the Issues Surrounding Clinical Exome Sequencing in the Prenatal Setting

Abstract

Exome sequencing is a clinical diagnostic test offered primarily for children and adults with suspected genetic conditions. The purpose of this study was to explore issues related to exome sequencing in a reproductive clinical setting. This was a qualitative study using semi-structured interviews. Participants were professionals drawn from four key stakeholder groups-healthcare providers, laboratory/industry, ethics, and government. Transcribed interviews were analyzed for emergent themes. Most participants saw potential clinical utility in offering prenatal exome sequencing for diagnostic purposes as opposed to screening. Participants expressed similar challenges already encountered with using exome sequencing in a pediatric setting, such as difficulty interpreting results and voiced many of the same concerns posed by prenatal testing, such as adequate pretest counseling. While previously reported issues and challenges were mentioned, participants agreed those difficulties are anticipated to be much greater with prenatal exome sequencing because of the scope of testing and the option for pregnancy decision-making. The results of this study help gain a better understanding of the implications of using exome sequencing in a prenatal setting. Development of guidelines is also warranted to aid clinical practice and laboratory standards for reporting prenatal results.

Impact of prenatal exome sequencing for fetal genetic diagnosis on maternal psychological outcomes and decisional conflict in a prospective cohort

“…7 In particular, prior studies have identified the conflict between respect for patient autonomy and the potential harms of uncertainty and unquantifiable risk, ultimately resulting in outcomes that are discordant with robustly autonomous medical decision making. 29 Prior studies have suggested that use of evidence-based counseling methods, guidelines on most applicable clinical scenarios for trio-ES, and standardization of reporting of results may improve patient autonomy in decision making 27 Our study has many strengths. It is a large, prospective cohort with longitudinal data.…”

“…The issues surrounding pre and post-test counseling, including interpretation of results and potential patient harms associated with anxiety, uncertainty, and missed parental expectations are in line with previously noted challenges of incorporating trio-ES into the prenatal fold. 27 28 Previous work from our group discussed specific examples of ethical counseling challenges that have risen from this ongoing prospective cohort, identifying the importance of effective and appropriate communication of uncertainty and how it may impact long-term parental decisions. 7 In particular, prior studies have identified the conflict between respect for patient autonomy and the potential harms of uncertainty and unquantifiable risk, ultimately resulting in outcomes that are discordant with robustly autonomous medical decision making.…”

Dealing with uncertain results from chromosomal microarray and exome sequencing in the prenatal setting: An international cross‐sectional study with healthcare professionals

“…A body of evidence has been published over recent years looking at healthcare professionals (HPs) experiences and attitudes towards returning uncertain results following prenatal CMA, and more recently ES. These studies have been conducted in countries including the Netherlands, 12 United States of America (USA), 13–15 United Kingdom (UK), 16–18 Hong Kong 19 and Australia 20,21 . The findings have highlighted differences in opinions and practice both across and within countries, regarding the management of uncertain results 22 .…”

Beyond diagnostic yield: prenatal exome sequencing results in maternal, neonatal, and familial clinical management changes

“…Surveys of clinicians and parents have reported that most believe that pES will have clinical utility related to diagnosing genetic conditions, impacting pregnancy management, facilitating decisions about pregnancy termination, preparing for childhoodonset conditions, and informing reproductive planning. 22,24,[30][31][32][33] In stark contrast, a study of 14 US health-care insurance payers reported that none believed that decisions about TOP, withdrawal of intensive care, provision of palliative care, family planning, or directing families to disease-specific resources (e.g., support groups, research) were aspects of clinical utility of pES, and only a minority agreed that referral to a tertiary center for specialized care was an aspect of clinical utility. 28 Therefore, it will be challenging to reconcile the different perspectives of the various pES stakeholders to establish its clinical utility.…”

“…21 Most genetics providers believe that pES will have clinical utility. [22][23][24][25] Previous studies of pES indicate that results can impact decision-making about continuation or termination, pre-or postnatal medical management, delivery planning, recurrence risk counseling, reproductive planning, and parental medical management. [8][9][10]13,18,20,26 However, there are also risks and limitations of pES that must be considered.…”