58 - Postnatal phenotyping after negative prenatal exome sequencing for fetal anomalies

Friday, February 10, 2023

3:15 PM – 3:30 PM

Location: Room 3022, Moscone West, Level 3

Objective: Exome sequencing (ES) is a phenotype driven process. In the setting of fetal anomalies, ES yield may be lower due to the limitations of prenatal phenotyping. The value of postnatal follow up in cases with negative prenatal ES is not clear. Our objective was to assess the frequency of identification of new phenotypic features on postnatal evaluation, and the impact on ES yield, in patients with fetal anomalies and negative prenatal ES.

Study Design: This is a secondary analysis of a prospective cohort study. In the primary study, patients with fetal anomalies underwent prenatal trio ES (or in rare cases, duo ES) and results were returned to participants. In this study, all cases in which ES utilizing the prenatal phenotype was not diagnostic, and in which postnatal follow up was performed (including examination, imaging, laboratory test results, and autopsy) were included. The primary outcome was identification of new phenotypes. Secondary outcomes were the incremental yield of ES with the addition of postnatal phenotype, and frequency of new findings by organ system. Moon (Invitae), the HPO-based ranking software, was utilized to prioritize gene variants

Results: A total of 329 prenatal ES cases were reviewed. Eighty-six (26%) had a genetic diagnosis utilizing the prenatal phenotype. Of the remaining 243, 87 (36%) had postnatal follow up. A majority of participants (56/87, 64%) had new findings in the postnatal setting. These were most frequently neurologic, present in 30% of participants (Table 1). ES reanalysis yielded a suspicious gene variant in 4 cases (5%). In an additional 2 cases, postnatal evaluation suggested a specific genetic diagnosis that could not be made with ES, but was confirmed using other genetic tests, such that postnatal evaluation contributed to a genetic diagnosis in 7% of cases (Table 2).

Conclusion: When ES is negative in the setting of fetal anomalies, postnatal follow up frequently results in identification of new phenotypes. In our cohort, this resulted in a genetic diagnosis in 7% of cases.

Primary & Presenting Author(s)

Kate Swanson, MD (she/her/hers)

Physician
NorthShore University Health System
Evanston, Illinois, United States

Coauthor(s)

UH

Ugur Hodoglugil, MD, PhD

University of California, San Francisco
San Francisco, CA, United States
Teresa N. Sparks, MD, MAS

Maternal-Fetal Medicine and Clinical Genetics
University of California, San Francisco
San Francisco, California, United States
Billie R. Lianoglou, MS

Genetic Counselor
University of California, San Francisco
San Francisco, California, United States
Mary E. Norton, MD (she/her/hers)

Professor, Dept of Obstetrics, Gynecology & Reproductive Sciences
University of California, San Francisco
San Francisco, CA, United States