Genome-wide sequencing is increasingly being conducted on fetal tissues, either as whole exome sequencing (WES), whole genome sequencing (WGS), or targeted analysis that uses clinical panels. These kinds of prenatal sequencing are sometimes done when more standard genetic tests have not yielded helpful results to explain structural anomalies, or if a specific genetic condition is suspected that would not be detected through other prenatal tests. While such sequencing is more likely to yield a positive result, it comes with its own set of risks and challenges – for instance, it is more likely to detect variants of unknown significance and other results that lead to excessive testing and stress on parents without significant benefit.
The International Society of Prenatal Diagnosis (ISPD), in conjunction with the Society of Maternal Fetal Medicine (SMFM) and the Perinatal Quality Foundation (PQF), just issued a joint position statement on the use of genome-wide sequencing for fetal diagnosis. While they recognize that sequencing can be useful in some instances, they generally take a cautionary approach. Based on “lessons learned from existing prenatal testing,” along with currently available literature and a panel discussion at the most recent annual ISPD meetings, their consensus opinion includes the following points.
The primary point of the consensus statement is that they do not recommend prenatal sequencing for routine use as a diagnostic test:
“The routine use of prenatal sequencing as a diagnostic test cannot currently be supported due to insufficient validation data and knowledge about its benefits and pitfalls. … Currently, it is ideally done in the setting of a research protocol. Alternatively, sequencing may be performed outside a research setting on a case-by-case basis when a genetic disorder is suspected for which a confirmatory genetic diagnosis can be obtained more quickly and accurately by sequencing.”
They go on to emphasize the importance of “expert guidance” in such cases, including “multidisciplinary” teams that can guide the use of these new techniques in the prenatal setting. Later in the statement, they note the complexity of prenatal sequencing interpretation and post-test counseling, and again emphasize the need for a multidisciplinary team approach with expertise in these areas.
Other “points to consider” include a recommendation that fetal diagnostic sequencing be conducted as a “trio” analysis, which includes fetal and both parental samples. They also emphasize the inherent uncertainties of prenatal sequencing, due to our limited knowledge of the relationship of gene variants to physical fetal characteristics.
The consensus statement also notes the necessity of “extensive” pre- and post-test counseling, pre-test education, and informed consent for the complex genetic information that prenatal sequencing offers. At minimum, they recommend these should include:
- Pre-test education and counseling for both parents, “individualized” to their particular situation;
- Assessing the effectiveness of any “alternative patient education tools” (think videos, tele-counseling, interactive internet presentations, etc.) before using them instead of, or in addition to, individual in-person genetic counseling;
- Getting consent from both biological parents for fetal sequencing if at all possible – but recognizing that the mother’s consent for the procedure is essential;
- Getting separate consent from each parent in the case of trio sequencing;
- Explaining to parents the importance of data sharing and getting informed consent from them when sharing is planned; and
- Including the following elements in pre-test counseling and informed consent for each sample to be analyzed:
- what kinds of results they may get,
- the realistic chances that they will get a clinically significant result,
- how long it will take to get results,
- the fact that sequencing may not yield a result,
- whether results will include incidental or secondary findings for the parents or future child (including variants unrelated to the suspected fetal condition, adult-onset conditions for the fetus, results related to potential conditions for the parents, and results that reveal non-paternity or other family relationships among the parents), and
- the fact that knowledge about genes is necessarily incomplete and will likely change over time.
Finally, the consensus statement includes more detailed information about when fetal diagnostic sequencing may be indicated, and how labs should handle samples, variant interpretation, and returning results. They also note that in light of rapidly changing technologies, these guidelines will need to be updated frequently, and that emphasis should be placed – including funding priorities – on educating health professionals and on clinical and translational research.
For more information, see the official press release for the consensus statement, which includes a link to the full text.
Prenatal Information Research Consortium 