Clinical outcomes after nondiagnostic prenatal exome sequencing: Need for balancing reassurance and residual risks in genetic counseling

The clinical application of prenatal exome sequencing (pES) for fetal structural anomalies is relatively new. Although a prenatal genetic diagnosis has been shown to have high clinical and personal utility for families, nearly 70% of pregnancies undergoing pES will receive nondiagnostic results. Currently, there is little literature on postnatal outcomes following a nondiagnostic pES result in fetuses with structural anomalies, making it difficult to interpret the postnatal significance of the nondiagnostic result and tailor anticipatory guidance for expectant parents. This retrospective chart review identified trends in clinical outcomes following nondiagnostic pES results for 63 pregnancies and the resulting 61 liveborn children at a specialized maternal and newborn tertiary care hospital. Postnatal clinical outcome measures, including premature delivery (54%), NICU admissions (85%), hospitalizations (52%), surgical interventions (62%), and deaths (20%), highlight the complex care needs of the children in this cohort. However, the clinical outcomes were predominantly predictable, with 69% of the children having clinical care needs as expected based on what was counseled to parents prenatally. The results of this study affirm the assumptions that nondiagnostic pES does not equate to less medical complexity for children with prenatally identified structural anomalies, and that nondiagnostic pES results should not be interpreted as broadly reassuring. Comprehensive post-test counseling is essential and should address the residual risk related to the severity of the identified anomaly or anomalies, the potential for unanticipated or complex clinical outcomes, and the limitations of antenatal ultrasound in capturing the full phenotypic spectrum.