Diagnosed After Birth—But Detectable Before? A Cohort Study of Prenatal Testing Potential

OBJECTIVE: To evaluate the yield of prenatal genetic testing in infants with a confirmed genetic diagnosis. METHODS: We retrospectively reviewed records of infants with a genetic diagnosis who were evaluated using a standardized genetic consult and testing approach. The predicted yield of various prenatal genetic sceening and diagnostic tools in this cohort was determined and compared. RESULTS: Genome sequencing had the highest predicted diagnostic yield (96.9%), followed by CMA with reflex to exome sequencing (95.5%), exome sequencing alone (93.8%) and CMA alone (43.6%). ACOG-recommended NIPT and carrier screening could have detected 25.4% of diagnoses, while 55.3% were detectable through genome-wide NIPT and a large carrier screening panel. Genome-wide NIPT improved chromosomal abnormality detection by ∼30% compared with ACOG-recommended NIPT. A large commercial carrier screening panel detected 26.1% of single-gene conditions, versus 6.1% with the ACOG-recommended panel. Overall, 62% of single-gene conditions were undetectable with current screening tools. CONCLUSION: Prenatal ES or GS offers high diagnostic yields and a streamlined approach, suggesting that CMA may not be the most appropriate first-line test unless there is strong suspicion of a chromosomal diagnosis. Although prenatal genetic screening is valuable, its ability to identify rare genetic conditions remains limited. Our findings support revising the ACOG/ACMG guidelines to align with postnatal testing recommendations, particularly in high-risk pregnancies.