Performance of prenatal cfDNA screening for sex chromosomes

Kimberly Martin, Natera Inc., Austin, TX, USA.
Pe'er Dar, Department of Obstetrics and Gynecology and Women's Health, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
Cora MacPherson, The Biostatistics Center, George Washington University, Washington, DC, USA.
Melissa Egbert, Natera Inc., Austin, TX, USA.
Zachary Demko, Natera Inc., Austin, TX, USA.
Sheetal Parmar, Natera Inc., Austin, TX, USA.
Katelyn Hashimoto, Natera Inc., Austin, TX, USA.
Sina Haeri, Ouma Health, Park City, UT, USA.
Fergal Malone, Rotunda Hospital, Royal College of Surgeons in Ireland, Department of Obstetrics and Gynecology, Dublin, Ireland.
Ronald J. Wapner, Columbia Presbyterian Medical Center, Department of Obstetrics and Gynecology, New York, NY, 10032, USA.
Ashley S. Roman, New York University Langone, Department of Obstetrics and Gynecology, New York, NY, USA.
Asma Khalil, St. George's Hospital, University of London, Department of Obstetrics and Gynecology, London, SW17 0RE, United Kingdom.
Revital Faro, St. Peter's University Hospital, Department of Obstetrics and Gynecology, New Brunswick, NJ, USA.
Rajeevi Madankumar, Long Island Jewish Medical Center, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Department of Obstetrics and Gynecology, New Hyde Park, NY, USA.
Noel Strong, Icahn School of Medicine at Mount Sinai, Department of Obstetrics and Gynecology, New York, NY, USA.
Robert M. Silver, University of Utah, Department of Obstetrics and Gynecology, Salt Lake City, UT 84112, USA.
Nidhi Vohra, North Shore University Hospital, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Department of Obstetrics and Gynecology, Manhasset, NY, USA.
Jon Hyett, Western Sydney University, Department of Obstetrics and Gynaecology, Liverpool NSW 2170, Australia.
Matt Rabinowitz, Natera Inc., Austin, TX, USA.
Charlly Kao, Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Hakon Hakonarson, Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Bo Jacobsson, Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Gothenburg, Sweden.
Mary E. Norton, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA. Electronic address: NortonM@obgyn.ucsf.edu.

Document Type

Journal Article

Publication Date

5-5-2023

Journal

Genetics in medicine : official journal of the American College of Medical Genetics

DOI

10.1016/j.gim.2023.100879

Keywords

Cell-free DNA; Fetal sex; Monosomy X; Sex chromosome aneuploidies; Sex chromosome trisomies

Abstract

PURPOSE: To assess the performance of cell-free DNA (cfDNA) screening to detect sex chromosome aneuploidies (SCA) in an unselected obstetrical population with genetic confirmation. METHODS: This was a planned secondary analysis of the multicenter, prospective SMART study. Patients receiving cfDNA results for autosomal aneuploidies and who had confirmatory genetic results for the relevant sex chromosomal aneuploidies were included. Screening performance for SCAs, including monosomy X (MX) and the sex chromosome trisomies (SCTs; 47,XXX; 47,XXY; 47,XYY) was determined. Fetal sex concordance between cfDNA and genetic screening was also evaluated in euploid pregnancies. RESULTS: 17,538 cases met inclusion criteria. Performance of cfDNA for MX, SCTs and fetal sex was determined in 17,297, 10,333 and 14,486 pregnancies, respectively. Sensitivity, specificity, and PPV of cfDNA were 83.3%, 99.9%, and 22.7% for MX, and 70.4%, 99.9%, and 82.6% for the combined SCTs. The accuracy of fetal sex prediction by cfDNA was 100%. CONCLUSION: Screening performance of cfDNA for SCAs is comparable to that reported in other studies. The PPV for the SCTs was similar to the autosomal trisomies, while the PPV for MX was substantially lower. No discordance in fetal sex was observed between cfDNA and postnatal genetic screening in euploid pregnancies. These data will assist interpretation and counseling for cfDNA results for sex chromosomes.

Department

Epidemiology

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