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Oral Concurrent Session 6 - Ultrasound and Genetics

Oral Concurrent Sessions

Oral Concurrent Session 6 - Ultrasound and Genetics

(72) Incremental diagnostic yield of genome sequencing for nonimmune hydrops fetalis spectrum disorders

Thursday, February 12, 2026

3:00 PM - 3:15 PM

Location: Summit 218 - 221

Submitting Author and Presenting Author(s)

Rozlyn C.T Boutin, MD, PhD (she/her/hers)

Postdoctoral Fellow & Medical Genetics and Genomics Resident Doctor
University of California, San Francisco
San Francisco, California, United States

Coauthor(s)

Billie R. Lianoglou, MS (she/her/hers)

Genetic Counselor
University of California, San Francisco
San Francisco, California, United States
NS

Nuriye Sahin-Hodoglugil, MD, PhD

Program Manager
University of California, San Francisco
San Francisco, California, United States
KT

Katie Tick, MPH

University of California, San Francisco
San Francisco, California, United States
Carmen M.A Santoli, MD (she/her/hers)

Maternal Fetal Medicine / Medical Genetics and Genomics Fellow
University of California, San Francisco
University of California, San Francisco, California, United States
JV

Jessica Van Ziffle, PhD

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

Patrick Devine, MD, PhD

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

Ugur Hodoglugil, MD, PhD

University of California, San Francisco
San Fraincisco, California, United States
PM

Pierre Martin, PhD

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

Professor of Obstetrics, Gynecology & Reproductive Sciences
University of California, San Francisco
San Francisco, California, United States
Teresa N. Sparks, MD, MS (she/her/hers)

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

Objective:
Exome sequencing (ES) detects a monogenic disorder underlying approximately 1/3 of unexplained nonimmune hydrops fetalis (NIHF) spectrum cases, i.e. those with NIHF or single pathologic fetal fluid collections. Because genome sequencing (GS) can identify additional rare genetic variants not detectable by ES, we sought to determine the incremental diagnostic yield of GS following nondiagnostic ES for NIHF spectrum.

Study Design:
Retrospective cohort study of pregnancies affected by NIHF spectrum with nondiagnostic karyotype and/or chromosomal microarray (CMA) and ES. Eligible fetal fluid collections included: ascites, pleural or pericardial effusions, skin edema, cystic hygroma, and/or nuchal translucency ≥ 3.5mm. Sequencing was performed in a CLIA-approved laboratory and genetic variants were classified according to the American College of Medical Genetics and Genomics guidelines. Primary outcome was the incremental diagnostic yield of GS for detecting pathogenic or likely pathogenic (P/LP) variants not reported on prior ES and resulting in a new diagnosis. Secondary outcome was the type of variants detected by GS.

Results:
Overall, 118 fetal samples underwent GS following negative (n=110) or inconclusive (n=8) ES. Cohort characteristics by type of fetal fluid collection are described in Table 1. GS had an incremental diagnostic yield of 2.5% (3/118), identifying four P/LP copy number variants (CNVs, i.e. small deletions or duplications) previously undetected on CMA and ES in three pregnancies that led to a clear genetic diagnosis. Details of the new genetic diagnoses revealed with GS are shown in Table 2. Two new secondary findings and four variants of uncertain significance were also identified with GS in five different pregnancies.

Conclusion:
GS has a small but clinically relevant diagnostic yield over ES and can identify genetic causes of NIHF spectrum not detectable by ES, particularly CNVs. As interpretation of noncoding regions and complex genomic variations improves, the incremental diagnostic yield of GS over ES is expected to further increase.