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