Diagnostic Yield After Postnatal Reanalysis of Prenatal Exome Sequencing Results

Kate Swanson; Ugur Hodoglugil; Teresa N Sparks; Billie R Lianoglou; Anne M Slavotinek; Mary E Norton

doi:10.1002/pd.6886

Diagnostic Yield After Postnatal Reanalysis of Prenatal Exome Sequencing Results

Prenat Diagn. 2025 Sep 11:10.1002/pd.6886. doi: 10.1002/pd.6886. Online ahead of print.

Authors

Kate Swanson^{1

2

3}, Ugur Hodoglugil⁴, Teresa N Sparks^{1

3

5}, Billie R Lianoglou³, Anne M Slavotinek⁶, Mary E Norton^{1

2

3

5}

Affiliations

¹ Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Maternal-Fetal Medicine, University of California, San Francisco, San Francisco, California, USA.
² Department of Pediatrics, Division of Medical Genetics, University of California, San Francisco, San Francisco, California, USA.
³ Center for Maternal-Fetal Precision Medicine, University of California, San Francisco, San Francisco, California, USA.
⁴ Genomics Medicine Laboratory, University of California, San Francisco, San Francisco, California, USA.
⁵ Institute for Human Genetics, University of California, San Francisco, San Francisco, California, USA.
⁶ Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.

PMID: 40935603
PMCID: PMC12722113 (available on 2026-09-11)
DOI: 10.1002/pd.6886

Abstract

Objective: Analysis of exome sequencing (ES) relies on correlation with phenotypic features, but fetal phenotyping is often incomplete. The additional yield of postnatal follow-up in cases with negative or inconclusive prenatal ES has not been demonstrated. Our objective was to assess the incremental diagnostic yield of ES reanalysis after initially negative prenatal ES for congenital anomalies incorporating features identified postnatally.

Methods: This was a secondary analysis of two prospective cohort studies of ES for fetal anomalies. We included cases in which initial ES utilizing the prenatal phenotype was not diagnostic. The primary outcome was incremental diagnostic yield of ES when incorporating postnatal findings.

Results: Eighty-seven cases with negative or inconclusive prenatal ES and postnatal follow-up available were included. Of those, 56 (64%) had new findings postnatally. There was an incremental yield of 2% in the entire cohort, and 7% in those with new postnatal findings. In two additional cases, postnatal evaluation suggested a specific genetic diagnosis that was not detectable with ES.

Conclusion: Among pregnancies with fetal anomalies and no clear diagnosis identified by prenatal ES, postnatal follow-up is recommended. Reanalysis of ES results can result in a genetic diagnosis in 7% of cases with new findings.

Abstract

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