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Association of Copy Number Variants With Specific Ultrasonographically Detected Fetal Anomalies

Donnelly, Jennifer C. MD; Platt, Lawrence D. MD; Rebarber, Andrei MD; Zachary, Julia; Grobman, William A. MD, MBA; Wapner, Ronald J. MD

doi: 10.1097/AOG.0000000000000336
Contents: Original Research

OBJECTIVE: To evaluate the association of other-than-common benign copy number variants with specific fetal abnormalities detected by ultrasonogram.

METHODS: Fetuses with structural anomalies were compared with fetuses without detected abnormalities for the frequency of other-than-common benign copy number variants. This is a secondary analysis from the previously published National Institute of Child Health and Human Development microarray trial. Ultrasound reports were reviewed and details of structural anomalies were entered into a nonhierarchical web-based database. The frequency of other-than-common benign copy number variants (ie, either pathogenic or variants of uncertain significance) not detected by karyotype was calculated for each anomaly in isolation and in the presence of other anomalies and compared with the frequency in fetuses without detected abnormalities.

RESULTS: Of 1,082 fetuses with anomalies detected on ultrasound scan, 752 had a normal karyotype. Other-than-common benign copy number variants were present in 61 (8.1%) of these euploid fetuses. Fetuses with anomalies in more than one system had a 13.0% frequency of other-than-common benign copy number variants, which was significantly higher (P<.001) than the frequency (3.6%) in fetuses without anomalies (n=1,966). Specific organ systems in which isolated anomalies were nominally significantly associated with other-than-common benign copy number variants were the renal (P=.036) and cardiac systems (P=.012) but did not meet significance after the adjustment.

CONCLUSIONS: When a fetal anomaly is detected on ultrasonogram, chromosomal microarray offers additional information over karyotype, the degree of which depends on the organ system involved.

LEVEL OF EVIDENCE: II

When a fetal anomaly is detected on ultrasonogram, chromosomal microarray offers additional information over karyotype, the degree of which depends on the organ system involved.Supplemental Digital Content is Available in the Text.

Department of Obstetrics and Gynecology, Columbia University Medical Center, and Maternal Fetal Medicine Associates PLLC and the Department of Obstetrics, Gynecology, and Reproductive Science, Icahn School of Medicine, Mount Sinai School, New York, New York; the Center for Fetal Medicine and Women's Ultrasound and the Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; the George Washington University Biostatistics Center, Rockville, Maryland; and the Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

Corresponding author: Ronald J. Wapner, MD, Department of Obstetrics and Gynecology, Columbia University Medical Center/New York Presbyterian Hospital, 622 W 168th Street, New York, NY 10032; e-mail: rw2191@cumc.columbia.edu.

Secondary analysis of primary research supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD05565101, R01HD055651-03S1, and RC2HD064525).

The authors thank Cartagenia for the use of their web-based software, the Cartagenia BENCH™ database; Michelle DiVito (Columbia University Medical Center), Anthony Johnson (Texas Fetal Center, UT-Health), and Melissa Savage for their help in data gathering and in preparation of this manuscript; Nicolasa H. Chavez, Jessica Feinberg, and Andrea M. Murad for their coordination and recruitment efforts; Elizabeth Thom, PhD, and Vinay Bhandaru (the George Washington University Biostatistics Center) for providing leadership and conducting the statistical analysis at the Data Coordinating Center; the laboratory technologists, including Emily Carron from Columbia University, Vanessa Jump from Emory University, Caron Glotzbach from Signature Genomic Laboratories, PerkinElmer, and Patricia Hixson at Baylor College of Medicine; and the participants and the North American Fetal Therapy Network for their support of the study. The authors also thank the participant recruitment sites, a full listing of which can be found in Appendix 1, available online at http://links.lww.com/AOG/A519.

Presented at the International Society for Prenatal Diagnosis, June 2–5, 2013, Lisbon, Portugal.

Financial Disclosure Dr. Platt is on the Clinical Advisory Board and a Consultant to Illumina. Dr. Rebarber has served on the advisory board for Natera and is on the speakers’ list for Alere. Dr. Wapner is a Principal Investigator on studies funded by Natera, Ariosia, Sequenom, and Illumina and has been a speaker for Natera and Ariosia. The other authors did not report any potential conflicts of interest.

© 2014 by The American College of Obstetricians and Gynecologists.