The clinical utility of systematic reporting of secondary findings in prenatal diagnosis.

Abstract

Secondary findings (SFs) identified through genomic sequencing are results unrelated to the primary indication but with potential clinical utility. Although genomic technologies are increasingly used in perinatal diagnosis, the clinical implications of SFs remain insufficiently explored. We evaluated the detection rates, phenotypic concordance, and clinical implications of SFs in a prenatal cohort undergoing trio exome sequencing (trio-ES). This was a single-center cohort study of 424 consecutive families who underwent prenatal trio-ES at a tertiary maternal-fetal medicine center from January 2019 to December 2023. SFs were classified using a 3-category framework (medically actionable risks, childhood-onset diseases, and carrier status) and analyzed via a stepwise protocol, including validation by a specialized clinical review panel. Among 1272 individuals, SFs were identified in 2.9% (37/1272), including 2.1% of fetuses (9/424) and 3.3% of parents (28/848). SF-related phenotypes were observed in 1 fetus and 3 adults. SFs prompted medical management changes in 27.0% (10/37) of cases, including 1 pregnancy termination, 7 adults initiating medical evaluations, and 2 couples committing to prenatal diagnosis/neonatal screening in subsequent pregnancies. Systematic SF reporting in prenatal diagnosis has demonstrated clinical value by facilitating pregnancy decisions, informing parental health risks, and enabling preventive reproductive strategies.