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. Author manuscript; available in PMC: 2019 Feb 11.
Published in final edited form as: Prenat Diagn. 2018 Sep 11;38(12):897–903. doi: 10.1002/pd.5353

Ethical and counseling challenges in prenatal exome sequencing

Sarah Harris 2, Kelly Gilmore 1, Emily Hardisty 1, Anne Drapkin Lyerly 3, Neeta L Vora 1
PMCID: PMC6370459  NIHMSID: NIHMS1010428  PMID: 30171820

Abstract

Objective:

Ethical and counseling challenges are expected with the introduction of prenatal whole exome sequencing. In this study, we describe specific challenges identified through the UNC-Chapel Hill Prenatal Exome Sequencing Study.

Methods:

Participants were a subset of women participating in the fetal exome study, which has enrolled 73 mother-father-fetus trios in pregnancies diagnosed with structural anomalies and normal standard genetic testing results. In this descriptive study, cases were reviewed by members of the research team, including a bioethicist, to identify counseling challenges. Illustrative cases were chosen by group consensus.

Results:

Four illustrative cases were identified for further analysis. Challenges included need for adequate counseling and informed consent, challenges in prenatal variant interpretation, performing prenatal diagnosis in subsequent pregnancies, inability to identify a genetic etiology, and identifying parental secondary findings.

Conclusion:

Our study illustrates several challenges identified in an ongoing prenatal exome study. While genomic medicine is a powerful tool for prenatal diagnosis, it is important that clinicians understand the ethical implications and parental perceptions of this testing modality.

1 |. INTRODUCTION

Next generation sequencing, including whole exome sequencing (WES), has revolutionized the field of clinical genetics. While the ethical, legal, and social implications of exome sequencing in children and adults have been studied,1,2 little has been published on challenges unique to prenatal exome sequencing. Concerns regarding the need for appropriate consent, the complexity of genomic data, ongoing need for reanalysis, and challenges of interpreting results in a meaningful way for patients have been raised.3,4

Given the decreasing costs and increasing availability of sequencing combined with case series showing higher diagnostic rates, compared with karyotype and chromosomal microarray analysis (CMA), it is inevitable that WES will become incorporated into the prenatal testing paradigm for anomalous fetuses. In a cohort of 194 fetuses with congenital anomalies and normal karyotype and CMA, 24% (47 of 194) were found to have a causative pathogenic variant with WES.5 Additional case studies of WES in fetuses with congenital anomalies and normal cytogenetic studies have revealed diagnostic rates6 ranging from 6.2% to 80%. It should be noted that these diagnostic rates were reported in case series of fetuses with anomalies. There are no studies of prenatal WES in the absence of fetal abnormalities. Of note, the International Society for Prenatal Diagnosis (ISPD), the Society for Maternal Fetal Medicine (SMFM), and the Perinatal Quality Foundation (PQF) do not recommend the routine use of diagnostic sequencing and suggest that testing should be limited to a research setting or on a case-by-case basis with consultation of genetic experts.7

Careful consideration of the challenges of implementing WES into prenatal clinical practice is needed. Debate continues regarding the appropriate use of this technology, some propose unrestricted testing in which prospective parents have the right to receive results of any variant identified by testing,8 while others feel that prenatal exome sequencing is more strongly justified for severe or life limiting conditions.9 Using case examples from our ongoing fetal exome sequencing project, we will highlight counseling and ethical challenges unique to prenatal WES and discuss recommendations for addressing them.

2 |. METHODS

In this descriptive study, we examined cases from the UNC at Chapel Hill prenatal exome sequencing study to identify ethical and counseling issues. The original study was approved by the UNC at Chapel Hill Institutional Review Board (13–4084). Trios (parents and fetus) were identified prospectively and retrospectively, as reported previously.10 Eligible participants included pregnant women with a singleton fetus diagnosed with a congenital anomaly. Participants were also identified retrospectively by querying the UNC Perinatal Database to identify women with a history of a fetal or neonatal death who had no causative diagnosis and stored fetal cells or extracted DNA. For all participants, standard genetic testing including karyotype, microarray, and any ordered molecular sequencing panel failed to identify a genetic reason for the anomalies. Informed consent was obtained from both parents, including discussion of benefits and limitations of WES. The WES was then performed on the parents and fetus. Qualitative and quantitative data of participants understanding and response to results were collected. To date, the study has enrolled 73 mother-father-fetus trios in pregnancies diagnosed with structural abnormalities. Of these, 41 trios have been fully sequenced with results returned.

All completed cases were reviewed by research team members to identify ethical and counseling issues. Illustrative cases were chosen by group consensus and analyzed using available literature and in consultation with a prenatal bioethicist, genetic counselors, and MFM geneticist.

3 |. RESULTS

A summary of the important challenges and illustrative cases are included in Table 1.

TABLE 1.

Summary of challenges identified and recommendations

Challenges Cases Recommendations
Adequate counseling and informed consent All cases • Providers must be familiar with the complexities of genetic testing
• Discussion of the benefits and limitations of testing
• Explore patient’s expectations
• Assess patient’s ability to tolerate uncertainty
• Ongoing need to clearly define what information patients desire and how to tailor counseling
Variant interpretation Case 1 • Discussion of the all possible results including the following:
Case 2  • Variants that very likely explain the fetal phenotype
Case 3  • Variants of uncertain clinical significance (VUS) in genes known to cause an overlapping phenotype
 • No variants identified that are likely to explain the phenotype
• Review the possibility of uncertain results and evaluation of patient’s tolerance of uncertainty
• Discussion of ongoing reinterpretation and need for re-contact if new information becomes available
Lack of an identifiable genetic etiology Case 3 • When multiple affected pregnancies, review of recurrence risk of up to 25%
• Discussion of inability to offer genetic testing in future pregnancies
• Discussion of risk reductions strategies, such as sperm or egg donation, or adoption
• Exploration of individual interpretations of genomic technologies and ability to understand results
• Provide individualized counseling based on patient’s genetic literacy
Prenatal testing in subsequent pregnancies Case 1 • Requires additional counseling and thorough discussion of limitations on a case by case basis
Case 2 • Referral to provider who is comfortable with testing for families interested in this option
Secondary findings Case 4 • Pretest counseling must include a discussion of possibility of secondary findings in the fetus or parents
• Best practice recommendations are needed on how to best manage these results
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3.1 |. Case 1: Reporting two variants of uncertain significance in a gene where the phenotypes significantly overlap that of the proband

A 31-year-old primigravid patient enrolled after second trimester ultrasound revealed multiple fetal anomalies, including fetal growth restriction, structural brain abnormalities (absent septum pellucidum and cerebellar hypoplasia), grossly misshapen calvarium, and hypotelorism. Given concerns for an underlying genetic syndrome with uncertain prognosis, the patient elected pregnancy termination. Microarray analysis results were reported as normal male. The couple indicated they were interested in enrolling in hopes of determining why the anomalies had occurred. They wanted to contribute to scientific understanding, stating altruistic reasons for participating.

Exome sequencing revealed two missense variants (compound heterozygous) of uncertain significance in the RTTN gene. Pathogenic variants in the RTTN gene have been reported in children with micro-cephaly, brain abnormalities, and primordial dwarfism, a phenotype that overlapped with ultrasound findings in our case.11,12

We believed that disclosure of the phenotype-proband overlap was in the best interests of the parents and potentially relevant to future reproductive decisions. The results were reported to the family with highly tailored counseling to explain the uncertainty of the results. In a follow-up interview, the couple stated their understanding of the uncertainty and reported no regret in enrolling in the study and felt strongly it was the right decision.

3.2 |. Cases 2: Reporting only one known pathogenic variant in a gene that causes an autosomal recessive disease overlapping the proband’s phenotype

A 26-year-old primigravid patient enrolled after second trimester ultrasound showed fetal arthrogryposis with upper limb contractures and clubbed feet. The couple enrolled in the study at 27 weeks gestation and indicated they hoped a diagnosis would guide treatment. Umbilical cord blood testing showed a normal male microarray. At birth, the infant was noted to have scoliosis, chordee, bilateral cryptorchidism, inguinal hernia and slow growth (<1%tile). At 8 months of age, the infant was developing normally with no evidence for neurological impairment.

Exome sequencing revealed one pathogenic frameshift variant in the CHRNG gene, which causes autosomal recessive multiple pterygium syndrome, including an Escobar (non-lethal) variant.13 Clinical del/dup testing was recommended to interrogate the second allele in the CHRNG gene, as small deletions and duplications can be missed by exome sequencing.

Results were normal and the family was counseled that this variant in the CHRNG gene is unlikely to be related to the phenotypic findings. The couple indicated they understood the variant did not explain their son’s contractures and are managing his condition expectantly. They are undecided about whether they will pursue future pregnancies.

3.3 |. Case 3: Exome sequencing with a non-specific phenotype

A 36-year-old multigravid patient enrolled after having two consecutive pregnancies with a first trimester cystic hygroma and normal microarray results. Both affected pregnancies were terminated prior to a second trimester ultrasound. At enrollment, the patient stated her primary reason for enrolling was to “find something that may be important in my health”. The couple indicated that they understood there was a 30% expected likelihood of finding an answer.

A genetic etiology was not identified through exome sequencing. The family was counseled that the risk of recurrence may be up to 25%. This is one of seven cases to date where families have enrolled after experiencing multiple pregnancies affected with a similar phenotype and exome sequencing was unable to identify a genetic etiology.

3.4 |. Case 4: Identifying secondary findings in a parent

A 31-year-old primigravid patient enrolled in the study after second trimester ultrasound revealed fixed, flexed lower extremities in the fetus, concerning for fetal akinesia. Microarray revealed normal male chromosome complement. The patient elected to have an induction of labor at 20 weeks gestation. Autopsy confirmed ultrasound findings and did not show additional anomalies. The couple indicated that their reason for enrolling was to find “something identifiable” for accurate recurrence risk and prenatal testing options in future pregnancies.

No molecular etiology was identified for the fetal findings. However, a variant in the BRIP1 gene, which predisposes to ovarian cancer14, was identified in the maternal sample. Results were disclosed to the patient. This was consistent with pretest counseling in which we indicated such medically actionable findings would be disclosed.15

The patient reported a family history of ovarian cancer in a maternal aunt. She was counseled not to delay reproduction and the potential benefits of bilateral oophorectomy after child bearing was complete was discussed. She was referred to a cancer geneticist for further discussion of medical management. In the follow-up interview, the patient reported she was grateful for the knowledge and reported no regrets in having exome sequencing and felt strongly that it was the right decision.

4 |. DISCUSSION

In our ongoing prenatal exome sequencing study, we identified several complex ethical and counseling issues that will increasingly present challenges with the expanding use of these technologies in the prenatal setting. While ethical issues around prenatal testing and counseling tend to focus on the relationship between counseling and decisions regarding pregnancy termination, we identified a wider range of challenges that future guidelines should address.

4.1 |. Challenge and recommendations: adequate counseling and informed consent (all cases)

In order to make informed decisions, and out of respect for a patient’s reproductive autonomy, all patients diagnosed with a fetal anomaly should be offered genetic counseling and the option of genetic testing.16 Counseling for prenatal WES requires clear communication with detailed pretest and posttest counseling.3 Nondirective counseling is central to the prenatal genetic counseling process as providers aim to provide information to allow their patients to make decision based on their own set of beliefs, values, and goals.17 De Jong et al argue that providing nondirective counseling for prenatal genomic testing may not be adequate and suggest using the “interpretive model” in which a provider informs a patient of her choices and helps her clarify her values and goals to decide which testing is best.18 Jonhston et al argue that given the volume of data available from testing, clinicians need to help patients “parse the distinction between empowering and disempowering information.”19

Traditionally, informed consent for prenatal genetic testing has included a discussion of the suspected genetic condition and a review of risks, benefits, and limitations of testing. This methodology may not be adequate for genomic medicine, given the vast data generated, the possibility of secondary findings, and the expectation of uncertain results.2 Further, even in the context of ostensibly valid consent, data suggest that women may not appreciate in advance the effect that uncertain results have on their well-being, sense of identity, or relationship to their pregnancy and/or child.20 In a qualitative study, prospective parents indicated that having clear information about expected results from prenatal WES is extremely important.21

Some have argued that advance discussions about the potential for results to introduce “pivotal decisions about ending or continuing their pregnancy” are an “ethical responsibility.”19 Such discussions may need to take into account concerns of disability rights advocates that “prenatal tests to select against disabling traits express a harmful attitude about and send a hurtful message to people who live with these traits.”22 While it is not clear that prenatal diagnosis has had this effect,9 creating space for informed choice while avoiding these “expressivist” harms remains an important clinical and ethical challenge.

Consent must be obtained by professionals familiar with the complexities of genetic testing who are trained to provide information clearly while exploring patient’s expectations.3 Given the likelihood of uncertain and potentially distressing results, counseling should include enhanced discussion of the limitations and uncertainties associated with this technology. Assessing a patient’s tolerance for uncertainty may be an important part of the informed consent process.20 Additional studies are needed to determine the long-term effects that genomic information has on prospective parents. We are actively collecting data on participants psychological adaptation to results in our study.

4.2 |. Challenge and recommendations: variant interpretation (cases 1, 2, and 3)

Variant analysis provides a challenge for any use of genomic technology as it is highly dependent on phenotypic information and the likelihood that the genetic variant in question is responsible for the clinical findings. Descriptive features for genetic syndromes are based on postnatal phenotypes and developmental information gathered over the lifespan. Prenatal variant interpretation is uniquely constrained by limitations in knowledge of prenatal presentations.23 As illustrated in case 1, prenatal findings overlapped those seen in primordial microcephaly dwarfism syndrome; however, this condition had not previously been reported prenatally, resulting in less certainty that the heterozygous variants identified through WES were causative.

In case 2, only one pathogenic variant was identified in a gene associated with an autosomal recessive condition that overlapped the phenotype of the affected fetus. When a second variant is not found through additional testing, appropriate counseling is needed to help parents understand that the gene in question likely not causative. This can be difficult once a particular gene or syndrome has already been discussed and reflects the importance of appropriately framing discussions about possible diagnoses as well as the chance that a variant may not be clinically significant.24

Case 3 illustrates a cystic hygroma in multiple pregnancies, which increases the likelihood of an autosomal recessive genetic etiology. However, like many ultrasound findings, a cystic hygroma is a nonspecific feature of multiple conditions.25 A prenatal phenotype based solely on ultrasound anomalies is often not specific for a single genetic condition and is limited by factors including gestational age, fetal presentation, and maternal body habitus. Interpreting the significance of rare variants presents a challenge in the absence of additional phenotypic information.

Variants of uncertain significance (VUS) are an expected challenge with prenatal exome sequencing. From an ethical perspective, clinicians must balance respect for autonomy and non-maleficence when considering variant reporting for individual patients. The duty to provide patients with a clear and accurate description of findings, including those that may or may not provide a genetic etiology for the anomalies identified, must be considered in light of the potential psychological harms of receiving results of uncertain signficance.26 Women who received VUS results with prenatal chromosomal micro-array reported increased anxiety throughout the remainder of their pregnancies.20 The importance of discussing uncertain results in the initial consent process cannot be overemphasized. It has been demonstrated that individuals who view uncertainty of genomic results as an expected outcome find the ambiguity more tolerable.1

When a VUS in a gene related to the phenotype is identified, there is a need to reevaluate the clinical significance of the variant over time. Parents should be informed that they may be re-contacted should additional information become available. Consideration should be given to limiting this window to a defined future time period, for both the family and the research team. This also requires that the family remain connected with the research team.

4.3 |. Challenge and recommendations: prenatal testing in future pregnancies (cases 1 and 2)

When WES is able to identify causative variants, patients can be provided with accurate recurrence risk counseling and the option or prenatal testing in future pregnancies. However, in situations like cases 1 and 2, the role of testing in future pregnancies is less clear. Identifying ways to accurately communicate the relevance of WES findings to future reproductive decisions is an important challenge in these contexts.

In the case where only one pathogenic variant is identified for an autosomal recessive condition, parents may desire testing for the single variant in subsequent pregnancies. While there is very little published regarding this practice, it is a request that we have encountered in clinical practice. Patients who desire this testing require detailed counseling to discuss the value and limitation of testing for a single variant. Additional options for reducing the risk of an affected fetus may also be discussed, such as sperm or egg donation and adoption.

Testing for the recurrence of VUS in early pregnancy or in a structurally normal appearing fetus is not clinically recommended27 and needs to be thoroughly discussed with parents who may be interested in testing. It is necessary to make clear that testing in this way may result in falsely diagnosing an unaffected fetus or in not identifying an affected fetus. In our clinical experience, patients have requested prenatal testing for a VUS that was identified in a prior affected child, despite appropriate counseling regarding the uncertainty of the variant. We anticipate that as the use of clinical WES becomes more widespread, these requests will increase. While it is important that patients understand that it is technically possible to test for a VUS in future pregnancies, providers must also account for the possibility that discussing the relevance of findings to future pregnancies may be understood as a recommendation to test, even where care is taken to discuss limitations of clinical applicability.

Providing VUS information to families may lead to pregnancy management decisions, such as termination that may make some providers feel uncomfortable. Where discomfort stems from a belief that decisions are being made without a full understanding of findings, efforts should be made to enhance informed decision-making. However, where discomfort stems from divergence in values, respect for the autonomy of parents as they make decisions regarding future reproduction is critical and should take priority.19 If accurate disclosure might lead to a decision a provider finds morally objectionable, accurate provision of information is nevertheless critical; withholding such information cannot be justified on the basis of conscience.28 Reproductive decision-making is based on patient’s own cultural, social, familial, and religious values.

4.4 |. Challenge and recommendations: lack of an identifiable genetic etiology (case 3)

An important aim of prenatal testing is to establish a genetic diagnosis, which allows for accurate counseling of recurrence risks and testing options for future pregnancies. However, as described in case 3, WES may not identify any pathogenic variants, even when one is highly suspected. It is important to stress to patient that negative WES results do not rule out the possibility of a genetic condition in the tested individual.24 We counsel patients with two or more similarly affected pregnancies of a recurrence risk of up to 25%. It is important to note that although a genetic etiology remains possible, screening for future pregnancies would be limited to ultrasound. These families in particular may experience more psychological distress related to uncertainty and have greater difficulty with family planning.

We previously reported that despite informing families that WES is only able to provide a diagnosis in 30% of cases, many patients remain more hopeful and optimistic that testing will provide an answer.10 Several reasons for discrepancies between potential and expected benefit of studies have been identified and may include selective attendance to hopeful messages, susceptibility to communication that reinforces this hope,29 as well as communication challenges due to lower health literacy.30 Counseling should be carefully tailored to an individual’s level of health literacy. Additional studies should explore the role that physicians, counselors, and other contextual factors have in shaping expectations and adequately communicating the limitations of these new technologies.

4.5 |. Challenge and recommendations: secondary findings (case 4)

Secondary findings describe a result that was not the primary indication for testing but that was analyzed based on recommendations from expert consensus.31 In the case of prenatal testing, WES is pursued to determine the cause of a congenital anomaly. However, results may reveal unrelated genetic conditions, including adult onset conditions. Traditionally, predictive genetic testing for adult onset diseases in children has not been recommended, but a shift in these policies has been made with the introduction of genomic medicine.32 Identification of adult onset conditions in the prenatal period raises deep ethical questions about providing results before birth, including the future child’s right to decide whether they want to know their carrier status and the heterogeneous nature of adult onset conditions, which make it difficult to predict quality of life.33 While these questions continue to be debated in the context of pediatric testing,34 this knowledge raises particular more complexities in the prenatal context, particularly where such findings might lead to pregnancy termination.

In an attempt in increase informative findings, prenatal WES is typically performed with trio sequencing of the parents and the fetus. This may result in the identification of non-paternity, unsuspected consanguinity, and unidentified genetic conditions in the parent. We agree that it is imperative that patients be informed of the possibility of these results before consenting.35

In our study, all parental samples were tested for a subset of “medically actionable” genes, per the American College of Medical Genetics and Genomics (ACMG) guidelines.15 However, there remains debate on reporting these variants, and some argue that patients have the option to opt out of receiving secondary results.36 This may be especially true in the prenatal setting, where testing is initiated for fetal anomalies during a time of stress; further, testing is done for reasons not directly related to the parents’ health. Case 4 involved discussing an increased risk of ovarian cancer, which could significantly affect family planning in the setting of a recent fetal loss with no known etiology. The dual psychological burden of these two results may be great, but the relevance of these findings to health care decisions is also significant.

Based on data from >6000 genomes from the National Heart, Lung, and Blood Institute Exome Sequencing Project, it is estimated that 0.7% of adults with European ancestry and 0.5% of adults with African ancestry will have a pathogenic variant in one of the ACMG recommended genes.37 As sequencing of parents is used to filter out uninformative variants, it is critical to develop best practices regarding return of results.

5 |. CONCLUSIONS

While genomic medicine is a powerful tool for prenatal diagnosis, it is important to critically analyze this new testing modality to ensure that it is incorporated into practice in a meaningful way. Further, this testing brings with it new ethical complexities, including how to address possible requests for pregnancy termination for adult onset conditions or VUS, and what it means to respect autonomy and ensure informed consent beyond the detailed provision of information. Additional research is needed on patient perspectives of the consent process, challenges to effective and appropriate communication of uncertainty, how results are returned, and how results will be reinterpreted over time. There is little doubt that the integration of new genetic technologies will further expand our understanding of fetal development. It is critical that clinicians and researchers equally attend to the social and ethical implications as this testing shifts into the clinical realm.

What’s already known about this topic?

  • Next generation sequencing, including whole exome sequencing, is revolutionizing the field of clinical genetics. Many unique challenges are expected as this technology becomes more widespread in the prenatal setting.

What does this study add?

  • We highlight ethically complex counseling challenges identified through an ongoing fetal exome sequencing study, including the need for adequate counseling and informed consent, counseling challenges related to return of uncertain results, prenatal testing in future pregnancies, and identification of secondary findings.

FUNDING INFORMATION

Eunice Kennedy Shriver National Institute of Child Health and Human Development BIRCWH grants K12 HD001441 (Dr. Vora) and K23 HD088742 (Dr. Vora).

Footnotes

CONFLICTS OF INTEREST

The authors do not report any conflict of interest.

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