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

Prenatal trio exome sequencing with reporting restricted to pathogenic or likely pathogenic variants in childhood-onset disorders and medically actionable secondary findings

Two hundred and nine consecutive prenatal trio exome cases, performed over three years in structurally normal pregnancies, were reviewed retrospectively. Pathogenic or likely pathogenic variants were detected in 30 of 211 fetuses (14.2%; 95% CI 10.1-19.6). After reclassifying three adult-onset cancer predisposition findings (BRCA2, MSH6, SDHD) as parental secondary findings, the reportable diagnostic yield was 27 of 211, or 12.8% (95% CI 8.9-18.0). Inherited variants predominated over de novo events (25 of 30; 83.3%), autosomal dominant conditions were the most frequent category, seven of the 30 positive cases involved genes on the ACMG SF v3.3 list, and pregnancy termination was elected in 2 of 30 cases (6.7%).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The 12.8% figure looks high for so-called low-risk pregnancies and largely reflects a broad reporting scope, including inherited variants with incomplete penetrance: this is not a diagnostic yield in the sense of an explained fetal anomaly. As the authors state, the issue is less detectability than the nature of the findings and their consequences for counseling, consent and the future child's autonomy. A retrospective single-pathway series with no reported postnatal follow-up: not to be translated into a routine indication.

Analysis by Dr Thibaut Benquey