Beyond the Negative: Insights From Postnatal Medical Genetics Follow-Up After Nondiagnostic Prenatal Exome Sequencing.

OBJECTIVE: To evaluate postnatal medical genetic reassessment and reinterpretation of prenatal exome sequencing (pES) in liveborn children with prenatally identified structural anomalies and nondiagnostic prenatal genetic testing. METHOD: We performed a retrospective chart review of 61 liveborn children with fetal structural anomalies who had nondiagnostic chromosomal studies and pES at a tertiary care center in British Columbia, Canada (2016-2022). We assessed postnatal medical genetics reassessment, clinical drivers of reassessment, and outcomes of selective pES reinterpretation. RESULTS: Postnatal medical genetics reassessment occurred in 41% (25/61) of children. Most reassessments occurred in the neonatal intensive care unit within the first week of life (68%, 17/25) and were prompted by postnatal phenotype modifications in 44% (11/25). Additional clinical drivers prompting reassessment included prenatally identified variants of uncertain significance and prenatal phenotypes of multisystem structural anomalies or unexplained hydrops. Of the children reassessed postnatally, 44% (11/25) underwent pES reinterpretation. Explanatory genetic diagnoses following reassessment and pES reinterpretation were made in 27% (3/11), representing 12% (3/25) of those reassessed and 5% (3/61) of the cohort. One additional postnatal genetic diagnosis was made, which explained a portion of the postnatal phenotype but was not considered explanatory for the prenatal findings. CONCLUSION: Postnatal pES reinterpretation identified genetic diagnoses in carefully selected cases following medical genetics reassessment of children with nondiagnostic prenatal testing for fetal structural anomalies, supporting a structured, clinically guided approach to postnatal follow-up.