Guidance at a glance
The societies' recommendations are summarized as follows:
- Exome sequencing is best done as a trio analysis, with fetal and both parental samples sequenced and analyzed together.
- Extensive pretest education, counseling, and informed consent, as well as posttest counseling, are essential. This should include:
—the types of results to be conveyed (variants that are pathogenic, likely pathogenic, of uncertain significance, likely benign, and benign)
—the possibility that results will not be obtained or may not be available before the birth of the fetus
—realistic expectations regarding the likelihood that a significant result will be obtained
—the timeframe to results
—the option to include or exclude in the results incidental or secondary findings (such as an unexpected childhood disorder, cancer susceptibility genes, adult-onset disorders)
—the possibility of uncovering nonpaternity or consanguinity
—the potential reanalysis of results over time
—how data are stored, who has access, and for what purpose.
- Fetal sequencing may be beneficial in the following scenarios:
—multiple fetal anomalies or a single major anomaly suggestive of a genetic disorder, when the microarray is negative
—no microarray result is available, but the fetus exhibits a pattern of anomalies strongly suggestive of a single-gene disorder
—a prior undiagnosed fetus (or child) with anomalies suggestive of a genetic etiology, and with similar anomalies in the current pregnancy, with normal karyotype or microarray. Providers also can consider sequencing samples from both parents prior to preimplantation genetic testing to check for shared carrier status for autosomal recessive mutations, although obtaining exome sequencing from the prior affected fetus (or child) is ideal.
—history of recurrent stillbirths of unknown etiology, with a recurrent pattern of anomalies in the current pregnancy, with normal karyotype or microarray.
- Interpretation of results should be done using a multidisciplinary team-based approach, including clinical scientists, geneticists, genetic counselors, and experts in prenatal diagnosis.
- Where possible and after informed consent, reanalysis of results should be undertaken if a future pregnancy is planned or ongoing, and a significant amount of time has elapsed since the time the result was last reported.
- Parents should be given a written report of test results.
Three professional societies have convened to issue consensus opinion that includes current indications for prenatal exome sequencing and important factors to include in the consent process. We follow these guidelines in our own practice.
Summary
Exome sequencing is increasingly becoming mainstream in postnatal genetic testing, and it is emerging as the newest diagnostic frontier in prenatal genetic testing. However, there are limitations to prenatal exome sequencing, including issues with consent at a vulnerable time for parents, limited information available regarding the phenotype, and results that may not be available before the birth of a fetus. Providers should be familiar with the indications for testing, the possible results, the limitations of prenatal phenotyping, and the implications for future pregnancies.