(797) Genome sequencing versus exome sequencing for fetal anomalies

Friday, January 31, 2025

10:30 AM – 12:30 PM

Submitting Author and Presenting Author(s)

Kate Swanson, MD (she/her/hers)

Assistant Professor
University of California, San Francisco
San Francisco, California, United States

Coauthor(s)

Teresa N. Sparks, MD, MS (she/her/hers)

Associate Professor, Maternal-Fetal Medicine and Clinical Genetics
Center for Maternal-Fetal Precision Medicine, University of California San Francisco
San Francisco, California, United States
NS

Nuriye Sahin-Hodoglugil, PhD

Program Manager
University of California, San Francisco
San Francisco, California, United States
Billie R. Lianoglou, MS (she/her/hers)

Genetic Counselor
Center for Maternal-Fetal Precision Medicine, University of California San Francisco
San Francisco, California, United States
KT

Katie Tick

University of California, San Francisco
San Francisco, California, United States
PD

Patrick Devine, MD, PhD

Genomic Medicine Laboratory, University of California, San Francisco
San Francisco, California, United States
Mary E. Norton, MD (she/her/hers)

Professor of Obstetrics, Gynecology & Reproductive Sciences
Center for Maternal-Fetal Precision Medicine, University of California San Francisco
San Francisco, California, United States

Objective: Genomic sequencing is increasingly recommended when fetal anomalies are detected. Exome (ES) and genome sequencing (GS) are both options; there are limited data comparing the two technologies. Our laboratory transitioned from ES to GS in July 2023; our objective was to compare ES versus GS in the setting of fetal anomalies.

Study Design: Prospective study of pregnancies with fetal anomalies undergoing ES or GS after non-diagnostic microarray. ES was performed in our laboratory from 1/2018 to 7/2023, and GS from 7/2023 to 7/2024. Rapid testing was performed in ongoing pregnancies to prioritize turnaround time (TAT) when management might be impacted. The primary outcome was diagnostic yield, defined as a pathogenic or likely pathogenic variant consistent with the presentation. Secondary outcomes were TAT, diagnostic yield in cases of multiple vs single anomalies, and frequency of variants of uncertain significance (VUS) and secondary findings.

Results: A total of 384 patients underwent fetal sequencing, 54 with multiple anomalies and 330 with a single anomaly. In all, 294 had ES and 90 had GS. Patients undergoing ES were more likely to undergo trio sequencing (69% vs 42%; p< 0.01). Multiple anomalies were present in 15% undergoing ES and 10% of GS cases (p=0.21). Diagnostic yield was higher with multiple versus a single anomaly (31% vs 12%; p< 0.01) but did not differ by sequencing approach (14% for trio, 15% for duo or proband first; p=0.7). The diagnostic yield was 16% with ES versus 10% with GS (p=0.16). TAT with rapid sequencing was 30 days for ES vs 13 days for GS and was 51 vs 25 days for ES vs GS with routine (p < 0.01). The detection rate of VUS and secondary findings did not differ (Table).

Conclusion: GS for fetal anomalies was not associated with higher diagnostic yield or more VUS results when compared to ES, but was associated with shorter TAT. When decision making and care plans may be impacted by results, GS may be preferred for this reason.