Prenatal Trio Exome Sequencing in Low‐Risk Pregnancies: Diagnostic Yield and Clinical Implications

Prenatal exome sequencing (ES) is increasingly requested in pregnancies without ultrasound‐detected structural anomalies, yet its diagnostic yield and clinical value in this low‐risk setting remain incompletely defined. We reviewed 209 consecutive prenatal trio‐ES cases performed in structurally normal pregnancies over a 3 year period. Variants were classified according to ACMG/AMP guidelines, and reporting was restricted to pathogenic (P) or likely pathogenic (LP) variants associated with childhood‐onset disorders and/or medically actionable secondary findings. P/LP variants were detected in 30 of 211 fetuses (overall P/LP detection rate 14.2%; 95% CI 10.1%–19.6%). After reclassifying three adult‐onset cancer‐predisposition findings ( BRCA2 , MSH6 , SDHD ) as parental secondary findings and excluding them from the reportable set, the diagnostic yield was 27/211 (12.8%; 95% CI 8.9%–18.0%); this reportable definition is used throughout. Inherited variants predominated over de novo events (25/30; 83.3%), and autosomal dominant conditions were the most frequent category. Seven of the 30 positive cases involved genes on the ACMG SF v3.3 list. Pregnancy termination was elected in 2 of 30 positive cases (6.7%). In structurally normal pregnancies, the value of prenatal trio‐ES lies less in detectability than in the nature of its findings mostly inherited, often incompletely penetrant and in their clinical and ethical implications: informing genetic counseling; guiding postnatal surveillance; facilitating familial cascade testing; identifying medically actionable secondary findings; and raising distinct questions of consent and the future child's autonomy.