Genetic diagnosis provides important information for prenatal decision-making and management. Promising results from exome sequencing (ES) for genetic diagnosis in fetuses with structural anomalies are emerging. The objective of this scoping review was to identify what is known about the use of ES for genetic testing in prenatal cases with known or suspected genetic disease. A rapid scoping review was conducted over a six-week timeframe of English-language peer-reviewed studies. Search strategies for major databases (e.g., Medline) and gray literature were developed, and peer reviewed by information specialists. Identified studies were categorized and charted using tables and diagrams. Twenty-four publications were included from seven countries published between 2014 and 2019. Most commonly reported outcomes were diagnostic yields, which varied widely from 5% to 57%, and prenatal phenotype. Few studies reported clinical outcomes related to impact, decision-making, and clinical utility. Qualitative studies (n = 6) provided useful insights into patient and health-care provider experiences with ES. Findings suggest prenatal ES is beneficial, but more research is needed to better understand the clinical utility, circumstances for ideal use, feasibility, and costs of offering rapid ES as a routine option for prenatal genetic testing.
Approximately 3% of pregnancies will show a fetal structural anomaly during routine prenatal ultrasound screening.1 These findings, which can range from an isolated minor defect to severe multisystem anomalies, can present significant challenges to the medical care team and families, as definitive diagnostic information can be difficult to obtain. The establishment of a timely molecular diagnosis can assist with genetic counseling and has significant value for appropriate prenatal and perinatal medical management.
Genome-wide next-generation sequencing is being increasingly applied as a diagnostic tool in the clinical setting for the diagnosis of suspected monogenic diseases. In particular, exome sequencing (ES), which involves sequencing the protein-coding portions of a genome, has been shown to be a powerful diagnostic test postnatally; tens of thousands of patients have now been reported and the diagnostic yield is around 40%.2 Understandably, there has been increasing interest in the application of this technology in the prenatal setting.
The diagnostic potential for ES in affected pregnancies is most significant for fetuses with structural anomalies identified by sonography, but could also be applied in situations where there is a history of a prior affected and undiagnosed fetus.3 Two large prospective studies4,5 have been recently published in the prenatal setting in which ES technology was used in the diagnostic investigation of malformations identified by sonography. These studies, which comprised over 800 fetuses, identified diagnostic genetic variants in 8.5% and 10% of families, suggesting that prenatal ES may provide clinically relevant information for the management of fetal anomalies identified in pregnancy. Many smaller studies have also generated significant interest in its potential application in the genetic investigation of pregnancies affected with suspected genetic disease.6
Despite these promising results, questions remain for decision makers from funding agencies on how ES should be implemented. These include what studies have found in terms of diagnostic yields for ES in pregnancy, and how they compare with one another; how quickly results can be generated and the ensuing medical benefits of receiving results in pregnancy; whether clinicians value receipt of these results in the context of pregnancy; and whether families want this test to be available during pregnancy. Given the current increased associated costs of performing clinical ES within a limited timeframe, it is important that funders understand these outcomes to best incorporate this testing in their respective health-care systems.
The objective of this systematic scoping review was to examine the question: What is known about the use of ES in prenatal cases with known or suspected genetic disease? A scoping review aims to map key concepts, types of evidence, and gaps in a defined area or field by systematically searching, selecting, and charting available evidence.7 They are ideal for emerging fields and often serve as a preliminary exercise to determine the value of undertaking subsequent studies based on identified evidence gaps. In this case, a scoping review methodology was used to inform guideline development in the province of Ontario for the public funding of ES in pregnancy. The work was undertaken in collaboration with Prenatal Screening Ontario (PSO), the coordinating body for prenatal screening services in the province. PSO is housed within the Better Outcomes Registry and Network (BORN) Ontario. BORN is Ontario’s prescribed registry and provincial perinatal database that collects information on pregnancy and newborn encounters with the health-care system, including laboratory results and birth outcomes (https://www.bornontario.ca/en/index.aspx).
MATERIALS AND METHODS
Literature search and study selection process
An information specialist developed the search strategy in consultation with the review team. Seven databases were searched using the Ovid platform: MEDLINE®, Embase Classic + Embase, the NHS Economic Evaluation Database, and the Cochrane Library, which includes the Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, and the Health Technology Assessment Database. Another senior information specialist peer reviewed the search strategy using the Peer-Review of Electronic Search Strategies (PRESS) Checklist (see S1, Supplementary Materials).10 The final search was run on 8 April 2019 (see S2, Supplementary Materials).
Animal-only studies, opinion pieces, and abstracts were removed from the search results, where possible. Gray literature searching was limited to searching 14 relevant organizational websites and reference lists of included studies; ClinicalTrials.gov and the World Health Organization’s International Clinical Trials Registry Platform were searched for ongoing studies (see S3, Supplementary Materials).
Citations were collated and de-duplicated in Reference Manager (Thomson Reuters). In consultation with PSO, case reports were removed from the search results by title and keyword searching for “case report” publication type imported into these respective fields within Reference Manager, and by identifying any record published in specific journals known to only publish case reports.
DistillerSR Software® (Evidence Partners, Ottawa, Canada) was used to facilitate screening. Pilot testing of screening questions was completed prior to implementation. Titles and abstracts were screened by independent reviewers (M.T., M.P., L.E.) using a liberal accelerated method whereby only one reviewer is needed to assess an abstract as eligible but requires two reviewers to exclude a citation.11 Full-text reports were reviewed independently in duplicate (M.T., M.P., L.E.) for eligibility with disagreements solved through consensus if needed. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram summarized the review selection process.12
Study selection criteria
We included English-language primary studies published from 2012 onward. This date was chosen as prenatal ES testing has been driven by recent technological advances in the last seven years. We considered various study designs including systematic reviews, randomized controlled trials, nonrandomized studies, cohorts, case–controls, cross-sectional studies, case series (if ≥5 cases), mixed-methods, and qualitative studies. We excluded narrative reviews, editorials, letters, commentaries, opinion pieces, conference abstracts, and case reports.
Studies were included if the study population had undergone genetic testing by use of ES including prenatal ES for fetuses (proband-only or proband–biological parental samples) with an unknown or suspected genetic disease. We excluded studies if ES had been performed to assess a specific disease or condition and did not address a broader prenatal population, or if postnatal examination had provided a diagnosis prior to ES being performed. We also excluded studies where ES was performed by proxy (meaning only parental samples were used in place of proband samples) or where ES data was analyzed using a targeted (e.g., “slice” or “virtual gene panel”) approach associated with a specific phenotype (e.g., skeletal dysplasia, microcephaly).
Virtual gene panels were excluded based on our intent to inform funders about research most relevant to the clinical ES tests that are most widely available commercially. Individual panels are difficult to compare and contrast given their extreme variability in number of genes offered. One exception to these criteria was the inclusion of Lord et al.,4 which used a very large gene panel (~1600 genes) comprising genes associated with fetal phenotypes. In this case, the virtual gene panel likely represents a close estimation (if not a slight underestimation) to the diagnostic yield that would result from a full exome analysis.
Given the lack of consensus on definitions of fetal anomalies and the consistency of grouping anomalies, specific fetal anomalies were not considered in a study’s eligibility criteria as part of our study selection, as a scoping review aims to broadly map a body of literature.
All data was collected in a predeveloped form using Microsoft Excel software and was pilot tested on three studies by two team members. One reviewer (M.P. or M.T.) extracted all data (see S4, Supplementary Materials), and the other reviewer performed full verification of all data. Disagreements were resolved by consensus, if necessary.
A risk of bias assessment of the individual studies is not commonly undertaken for scoping reviews, as the purpose is not to evaluate the risk of bias of studies, but rather to identify existing research.7,8 Therefore, this was not completed.
Data charting and visualization
In general, a formal synthesis of data is not required for a scoping review. However, we believed it was important to map and describe the data in detail, especially as it pertained to the main outcome of diagnostic yields. Results were summarized by study design for each population/condition and presented in tables or charts as appropriate with a descriptive summary to describe and support tabular and diagrammatic results.
Deviation from protocol
Although not originally planned, we attempted to contact authors for more information on the identified data to try and expand information reported in the included articles. No additional data was received. After examining the diagnostic genetic variant (DGV) rates reported in the included studies, and in consultation with PSO clinical experts, we chose to focus on DGV rates in phenotypic subgroups for studies with a sample size ≥100. We chose larger studies for several reasons: because smaller studies tended to focus on specific system types, to reduce bias associated with smaller case series, and because the studies with larger sample sizes (which combined, covered >75% of total cases in this review) reported a wide range of structural anomalies stratified by system type.
The study selection process is summarized as a PRISMA flow diagram in Fig. 1. For a list of excluded studies and possibly relevant case reports see S6 in the Supplementary Materials. The search identified a total of 3720 unique titles and abstracts, of which 20 were located through the gray literature search. Following title and abstract screening, 330 reports were reviewed for relevancy at full text. Of these, a total of 24 studies were included in our analysis.
Characteristics of included studies
There were 24 studies, of which 154,5,14,15,16,17,18,19,20,21,22,23,24,25,26 were cohort studies (prospective [n = 8], retrospective [n = 5], both prospective and retrospective [n = 2]) (see Table S7, Supplementary Materials). Three studies were described as case series,27,28,29 and six studies used qualitative methods.30,31,32,33,34,35
Overall, 11 studies were performed in the United States,5,14,18,22,26,28,29,30,33,34,35 5 in the United Kingdom,4,23,25,31,32 3 in China,17,19,20 and the remaining studies in Canada (n = 1),16 Europe (n = 2),24,27 and Israel (n = 1).15 Most studies received funding from nonprofit, academic, or government sources (see Table S7, Supplementary Materials).
Cohorts and case series
Sample sizes ranged from 7 to 610 participants (median = 30, interquartile range [IQR] = 81). Fifteen studies included fetuses with at least one structural anomaly.4,5,15,16,17,18,19,21,23,24,25,26,27,29,30 Three studies looked at specific phenotypes such as congenital anomalies of the kidney and urinary tract (CAKUT) with or without other structural anomalies,19 central nervous system abnormalities,21 and severe cardiac defects or syndromic congenital heart defects (CHDs).27
All but one study29 outlined the ES procedure and laboratory process. Studies analyzed more than one type of ES sample, with almost all studies including trio (proband–parents) samples (see Fig. S10, Supplementary Materials). Only two studies did not report which type of sample was used.24,29 Eight studies used both fetal-only and trio samples.4,14,15,16,17,19,23,27 Several studies included a small number of dyad (one parent–fetus)4,15,20,26,27 or quad (parent–twins) samples.4,20,25,26,27 All studies collected various types of DNA samples, with most studies using DNA extracted from chorionic villi or amniotic fluid.
The turnaround time was reported in eight studies,5,14,15,17,18,19,24,28 with five studies14,15,17,18,24 offering rapid ES (defined as a turnaround time of 2 to 5 weeks)28 for at least some of the included patients (see Table S11, Supplementary Materials). How authors reported time varied across studies, and was not reported in ten studies.4,16,20,21,22,23,25,26,27,29 In one of those studies, authors stated that results were not available in pregnancy,23 and in another, results were not available before pregnancy termination, fetal demise, or delivery.29
Mapping of reported outcomes
We mapped studies according to the categorization of the results and outcomes reported (Fig. 2). Diagnostic yields (overall) and by phenotype were the most commonly reported outcomes. Subgroups were reported in nine of the studies, and included single versus multiple anomalies,4,5,14,16,17,26 prenatal phenotype,4,14,15,16,17,19,26 ES testing strategy (proband-only versus trio),14,15,19,23 and groups defined by the stage of pregnancy and legality of termination24 (see Table S9A & B, Supplementary Materials).
Overall diagnostic yields were reported across 16 primary studies, with two additional studies that describe diagnostic genetic variants, but do not report a total proportion of diagnoses for their cohort.21,24 Collectively, diagnostic yields ranged from 5% to 57% (see Table S9A & B, Supplementary Materials). When these rates were mapped according to sample size, studies with higher sample sizes were observed to report lower diagnostic yields while the inverse was noted for the smaller-scaled studies (Fig. 3). The two largest cohorts4,5 included fetuses with a wide range of structural anomalies, while smaller cohorts21,23 and case series27 tended to include anomalies related to a specific organ system.21,27 There were also studies where the study population only included pregnancies resulting in a fetal demise or termination,16,18,26,28 which may lead to an overall higher diagnostic yield (due to potential bias in the severity of phenotype and better phenotyping on postmortem examination). One such study had a diagnostic genetic variant rate of 19% in a cohort of 101 fetuses. This study included fetuses (from terminated pregnancies) and stillborns that either had two or more structural malformations, severe ventriculomegaly or a structural brain malformation, or an anomaly associated with a high risk of perinatal lethality.16
In addition, postnatal examination or autopsy can help to refine the phenotype and adds confidence to the diagnosis when pathogenic variants are identified.18 In two studies with high diagnostic yields, it was unclear whether autopsies had been performed on some or all of the included fetuses, but both were retrospective in design and included some fetuses after termination or fetal demise.14,29
Diagnostic yields by fetal phenotype
Of the 18 studies that reported diagnostic genetic variants, all provided some amount of information regarding fetal phenotype. There was significant heterogeneity in the number and definitions of fetal phenotypes, and in the manner in which the data was reported. As described in the methods, those studies with sample sizes >100 were examined further to assess variability in diagnostic yields according to fetal phenotype (see Table 1). These five studies4,5,14,16,17 represented >75% of reported fetuses receiving ES (1287 fetuses of 1698 total) and overall diagnostic yields ranged from 8.5% to 32%. The rate of variants of unknown significance (VUS) ranged from 3.9% to 20%,4,5,17 and were not reported in two of the studies.14,16
We first examined the diagnostic yields based on the number (isolated vs. multisystem) of organ systems affected within the fetuses. The diagnostic yields for multisystem anomalies were reported in all five studies and ranged from 15.4% to 30.8%. By comparison, the diagnostic yields for fetuses with isolated anomalies were reported in four of the five studies and ranged from 6% to 22%.4,5,14,17 It should be noted that in all four of these studies the reported diagnostic yield was higher in the multisystem cases compared with those with isolated anomalies.
Next, we attempted to capture the reported diagnostic yields by specific organ system. Our examination of these diagnostic yields was limited, as the studies used different criteria to classify their cases and did not provide enough information to analyze the diagnostic yield by isolated anomaly type alone (see Table S9A & B, Supplementary Materials). Two of the five studies reported the diagnostic yield for anomalies isolated to a single system; however, the types of structural anomalies in each single system varied between the two studies.4,17 The remaining three studies in Table 1 reported diagnostic yields by single system type, but these cases may have been reported as one of multiple congenital anomalies.5,14,16 Thus a fetus with more than one anomaly may have been counted several times across different organ systems, confounding the ability to analyze for isolated anomalies. For more details on the classification of anomalies into phenotypic group by study, see S12, Supplementary Materials. Detailed DGV rates for these three studies can be found in Table 2.
The qualitative studies included prenatal patients undergoing ES as part of fetal genetic evaluation,30,32,34 health professionals31 involved in one of the included cohorts,4 those with expertise in reproductive or genomic medicine,33 and genetic counselors.35 All studies sought to explore issues, attitudes/perspectives, and experiences of individuals directly affected by or involved with prenatal ES. Sample sizes ranged from 12 to 498 participants, and methods included semistructured interviews (n = 4)30,31,32,33 and surveys (n = 2).34,35 Descriptive and comparative statistics were used to analyze the data in both surveys, while the reports using interview methodology followed thematic analysis31,32,33 and a constructivist grounded theory approach.30
Mapping of results of qualitative studies
A common theme across studies that included pregnant women and their families was the desire for more information. Kalynchuk et al. surveyed parental attitudes toward ES and found that half felt that prenatal ES should be offered for a fetus or baby with a medical problem, and 34.6% stated that they would want prenatal ES even if there was no indication of a medical problem.34
Although Wou et al. found that participants’ lived experiences of ES were similar to those of other prenatal genetic diagnostic tests, in hypothetical scenarios, participants desired more information than was provided, including information relating to uncertain results or secondary findings.30 The authors reported that “most participants stated that they could accept uncertainty if it is clearly explained to them and would find uncertain results useful, especially if they are actionable” (p. 807).30
In interviews with participants, Quinlan-Jones et al. identified patients’ desire for more information on test processes and results, but also found that information needed to be repeated and provided in various formats.32 Interactive resources were reported as most helpful, including direct questions to the medical team, peer support and support groups, and printed information. One participant suggested “…a workshop held by the hospital or midwife that is solely dedicated to this as part of their job, where they would have all the knowledge and can educate families and where parents can come together and share their experiences” (p. 1230).32
A patients’ desire for more information, however, presents a challenge for health professionals who need to interpret results. In the prenatal context, genetic variants may not match well with the phenotypic findings identified prenatally, and hence introduce a level of uncertainty that health professionals must communicate to patients.33 Horn et al. found that health professionals (midwives, genetic consultants, and some of the research staff involved in the PAGE cohort study) struggled with achieving informed consent when having to communicate complex genomic information to parents after the emotional stress of finding out their babies have a congenital anomaly.31 One participant argued that informed consent should be an ongoing process: “I think it’s repetition as well. You know, if they’re able to talk to a few people about it and ask questions, and have an ongoing opportunity to ask questions, they always have my contact number and things so I think that kind of can help with continuing to develop their understanding” (p. 5).31
Brew et al. found that genetic professionals’ opinions on “…the return of VUS findings from prenatal ES differed depending on whether or not they were related to the presenting phenotype, with the majority only supporting the return of related VUS results” (p. 236).35 The participants were concerned about increased anxiety and harm to parents when receiving uncertain information. The authors concluded there was a need for specific recommendations when ES is used in a prenatal context, as current guidelines are focused on children and adult-onset conditions. The need for updated guidelines was recommended in all three qualitative studies exploring health professionals’ perspectives on ES.
In this scoping review, we identified 24 peer-reviewed and published studies, 18 quantitative and 6 qualitative, related to the use of ES in pregnancy. Upon mapping data from these identified publications, it was determined that most studies were conducted in North America, used either cohort or case series designs, had wide-ranging sample sizes, and included heterogeneous populations, settings, and phenotypes. The turnaround time for reporting results ranged widely and was underreported in the studies that were identified.
Diagnostic yields for the application of ES in pregnancy, the most commonly reported outcome, were variable across studies (5–57%). These yields could not be combined into an overall diagnostic yield given the discrepancies in eligibility criteria among publications. Regardless, these yields are in keeping with postnatal diagnostic yields for ES, which can also vary significantly depending on the phenotype of the affected patient and sequencing strategy. Of note, one of the limitations of this scoping review was that most cases came from the two largest prospective cohort studies that have been done to date. In examining the use of ES in the diagnostic assessment of structural anomalies identified by ultrasound, the diagnostic yields in these studies were 8.5% and 10%. These lower yields likely reflect a number of the challenges related to the use of ES in prenatal, rather than postnatal, context. First, the cohort of patients receiving postnatal ES is possibly enriched for true monogenic diseases, being more likely to have had a full clinical assessment by a clinical geneticist.36 Second, there is greater imprecision in prenatal versus postnatal phenotyping.37 Finally, the paucity of literature related to prenatal genotypes and phenotypes.38
A select number of studies stratified diagnostic yields by single system anomalies, which may help to determine under which clinical circumstances ES may be most useful. However, our ability to examine systematically the performance of different single system anomalies was limited by the fact that classification was study dependent and isolated anomalies were reported within multiple congenital anomalies, confounding the ability to tease out specific diagnostic rates. In addition, care should be taken when drawing firm conclusions as bias may exist in choice of patient or sample potentially skewing single anomaly diagnostic yields. Further studies will need to determine how single system anomalies are commonly defined and greater case numbers for each single anomaly system will better inform diagnostic rates. It is likely that certain isolated findings/anomalies (e.g., hydrops) will prove in time to have higher diagnostic rates than others.
It is of use to consider the diagnostic utility of fetal exome compared with that of chromosomal microarray in the diagnosis of fetuses with anomalies. Chromosomal microarray is supported by numerous publications and recommended by professional bodies as a diagnostic tool in the investigation of fetuses with structural anomalies.39,40,41,42 The diagnostic yield reported for chromosomal microarray is in the range of 4–10% in fetuses with one or more structural anomalies, and 1.7% in phenotypically normal fetuses.41,43,44,45 The diagnostic rate of chromosomal microarray for individual structural anomalies varies by report and by the approach to case definitions.39 While further data are required to better understand the clinical presentations for which fetal exome has the highest diagnostic yield, the rates reported from the largest studies, i.e., 8.5% and 10%, are in a similar range to that reported for chromosomal microarray. Comparatively, a meta-analysis in the postnatal setting reported that the diagnostic utility of ES (and genome sequencing) was qualitatively greater than chromosomal microarray.2 There is currently more clinical experience with microarray in the prenatal setting, and as the literature evolves, more lessons will be learned about the utility of fetal exome. In time, the use of chromosomal microarray and ES in prenatal diagnosis may gradually diminish once the ability to reliably detect copy-number variants improves from genome sequencing.
While no studies reported “clinical utility” as an outcome, several studies did report outcomes related to clinical impact. Clinical impact was not well defined but appeared to address management outcomes including medical management, reproductive planning, and recurrence risk estimates.14,29 Clinical utility in genetics is broadly defined as the ability of a test to “prevent or ameliorate adverse health outcomes such as mortality, morbidity or disability through the adoption of efficacious treatments conditioned on test results.”46 However, researchers argue that the definition of clinical utility needs to be broadened beyond clinical endpoints to encompass emotional, social, ethical, and legal benefits. Within the field of genetic testing, there is a clear need for standardized reporting of core outcomes, which will help improve the strength of future studies.47
Overall, studies concluded that ES can increase the diagnostic yield in fetuses with structural anomalies, but that there are limitations to this testing in the prenatal setting. Several limitations were noted among the studies including turnaround time and the reporting and interpretation of secondary and inconclusive findings. Cost was also considered to be a barrier to ES;18 however, none of the studies reported economic or costing data. In addition, the potential for incomplete phenotypic information, which limits the genotype–phenotype evaluation, is a particular challenge in the prenatal setting. Many studies concluded that more research was needed in this area, along with the development of prenatal ES guidelines that highlight the need for implementation under the guidance of experienced, multidisciplinary teams. A full systematic review would be useful as more data become available.
In addition, a cursory review of the qualitative studies suggests that patients desire access to information from a variety of mediums, and that there are challenges for health-care providers in achieving informed consent and in how information is interpreted. A vast number of variants can be identified in any patient's genome, and interpretation and disclosure of secondary findings may increase uncertainty and patient anxiety. Balancing patients’ desires for more information with the need for only the most clinically relevant information is difficult to achieve but must be considered as genome-wide testing becomes a more prevalent prenatal test.
Although evidence is not formally synthesized for clinical decision-making in a scoping review, it is a useful tool that aims to map key concepts underpinning a research area, and the main sources and types of evidence available. As such, the present scoping review provides insight into the current state of the evidence with regard to offering ES as a genetic diagnostic test in the context of prenatal care.
Overall, from the evidence identified, the use of ES in the prenatal context is clearly an emerging field that requires further evaluation. Research is needed to determine for which clinical indications ES would be most beneficial, and to highlight in which context ES would lead to a low diagnostic yield. The need to evaluate the clinical utility of findings (keeping in mind costs and patient values and preferences) is a significant hurdle facing this diagnostic technology. Therefore, the community should work toward producing high-quality evidence needed to inform clear guidelines for patient care, including recommendations for pre- and post-test counseling and the disclosure of results.
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This report was funded by Better Outcomes Registry Network (BORN) Ontario. The content is solely the responsibility of the authors and does not necessarily represent the official views of BORN. Members of BORN assisted in drafting of the research question, eligibility criteria, and provided feedback on the final list of included studies.
The authors declare no conflicts of interest.
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Pratt, M., Garritty, C., Thuku, M. et al. Application of exome sequencing for prenatal diagnosis: a rapid scoping review. Genet Med 22, 1925–1934 (2020). https://doi.org/10.1038/s41436-020-0918-y
- exome sequencing
- prenatal genetic diagnosis
- congenital anomalies
- scoping review
- systematic review
Clinical efficiency of simultaneous CNV-seq and whole-exome sequencing for testing fetal structural anomalies
Journal of Translational Medicine (2022)
European Journal of Human Genetics (2021)