Performance of prenatal cfDNA screening for sex chromosomes

doi:10.1016/j.gim.2023.100879

Multicenter Study

. 2023 Aug;25(8):100879.

doi: 10.1016/j.gim.2023.100879. Epub 2023 May 5.

Performance of prenatal cfDNA screening for sex chromosomes

Kimberly Martin¹, Pe'er Dar², Cora MacPherson³, Melissa Egbert¹, Zachary Demko¹, Sheetal Parmar¹, Katelyn Hashimoto¹, Sina Haeri⁴, Fergal Malone⁵, Ronald J Wapner⁶, Ashley S Roman⁷, Asma Khalil⁸, Revital Faro⁹, Rajeevi Madankumar¹⁰, Noel Strong¹¹, Robert M Silver¹², Nidhi Vohra¹³, Jon Hyett¹⁴, Matt Rabinowitz¹, Charlly Kao¹⁵, Hakon Hakonarson¹⁵, Bo Jacobsson¹⁶, Mary E Norton¹⁷

Affiliations

¹ Natera Inc., Austin, TX.
² Department of Obstetrics and Gynecology and Women's Health, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY.
³ The Biostatistics Center, George Washington University, Washington, DC.
⁴ Ouma Health, Park City, UT.
⁵ Rotunda Hospital, Royal College of Surgeons in Ireland, Department of Obstetrics and Gynecology, Dublin, Ireland.
⁶ Columbia Presbyterian Medical Center, Department of Obstetrics and Gynecology, New York, NY.
⁷ New York University Langone, Department of Obstetrics and Gynecology, New York, NY.
⁸ St. George's Hospital, University of London, Department of Obstetrics and Gynecology, London, United Kingdom.
⁹ St. Peter's University Hospital, Department of Obstetrics and Gynecology, New Brunswick, NJ.
¹⁰ Long Island Jewish Medical Center, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Department of Obstetrics and Gynecology, New Hyde Park, NY.
¹¹ Icahn School of Medicine at Mount Sinai, Department of Obstetrics and Gynecology, New York, NY.
¹² University of Utah, Department of Obstetrics and Gynecology, Salt Lake City, UT.
¹³ North Shore University Hospital, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Department of Obstetrics and Gynecology, Manhasset, NY.
¹⁴ Western Sydney University, Department of Obstetrics and Gynaecology, Liverpool, NSW, Australia.
¹⁵ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA.
¹⁶ 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.
¹⁷ Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA. Electronic address: nortonm@obgyn.ucsf.edu.

PMID: 37154148
DOI: 10.1016/j.gim.2023.100879

Free article

Multicenter Study

Performance of prenatal cfDNA screening for sex chromosomes

Kimberly Martin et al. Genet Med. 2023 Aug.

Free article

. 2023 Aug;25(8):100879.

doi: 10.1016/j.gim.2023.100879. Epub 2023 May 5.

Authors

Affiliations

¹ Natera Inc., Austin, TX.
² Department of Obstetrics and Gynecology and Women's Health, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY.
³ The Biostatistics Center, George Washington University, Washington, DC.
⁴ Ouma Health, Park City, UT.
⁵ Rotunda Hospital, Royal College of Surgeons in Ireland, Department of Obstetrics and Gynecology, Dublin, Ireland.
⁶ Columbia Presbyterian Medical Center, Department of Obstetrics and Gynecology, New York, NY.
⁷ New York University Langone, Department of Obstetrics and Gynecology, New York, NY.
⁸ St. George's Hospital, University of London, Department of Obstetrics and Gynecology, London, United Kingdom.
⁹ St. Peter's University Hospital, Department of Obstetrics and Gynecology, New Brunswick, NJ.
¹⁰ Long Island Jewish Medical Center, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Department of Obstetrics and Gynecology, New Hyde Park, NY.
¹¹ Icahn School of Medicine at Mount Sinai, Department of Obstetrics and Gynecology, New York, NY.
¹² University of Utah, Department of Obstetrics and Gynecology, Salt Lake City, UT.
¹³ North Shore University Hospital, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Department of Obstetrics and Gynecology, Manhasset, NY.
¹⁴ Western Sydney University, Department of Obstetrics and Gynaecology, Liverpool, NSW, Australia.
¹⁵ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA.
¹⁶ 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.
¹⁷ Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA. Electronic address: nortonm@obgyn.ucsf.edu.

PMID: 37154148
DOI: 10.1016/j.gim.2023.100879

Abstract

Purpose: The aim of this study was to assess the performance of cell-free DNA (cfDNA) screening to detect sex chromosome aneuploidies (SCAs) in an unselected obstetrical population with genetic confirmation.

Methods: This was a planned secondary analysis of the multicenter, prospective SNP-based Microdeletion and Aneuploidy RegisTry (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 (SCT: 47,XXX; 47,XXY; 47,XYY) was determined. Fetal sex concordance between cfDNA and genetic screening was also evaluated in euploid pregnancies.

Results: A total of 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 positive predictive value (PPV) of cfDNA were 83.3%, 99.9%, and 22.7% for MX and 70.4%, 99.9%, and 82.6%, respectively, 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, whereas 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.

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

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Conflict of interest statement

Conflict of Interest All site principal investigators (Pe’er Dar, Bo Jacobsson, Fergal Malone, Ronald J. Wapner, Ashley S. Roman, Asma Khalil, Revital Faro, Rajeevi Madankumar, Sina Haeri, Robert M. Silver, Nidhi Vohra, Jon Hyett, Cora MacPherson, and Mary E. Norton) received institutional research support from the funding sponsor (Natera). Melissa Egbert, Zachary Demko, and Matt Rabinowitz are employed by the study’s funding sponsor (Natera) and hold stock or options to hold stock. Kimberly Martin is a consultant to the funding sponsor (Natera) and holds stock and options to hold stock. Jon Hyett has an ongoing research collaboration that includes financial support for biochemical analytes from Perkin Elmer; has earned honoraria and/or given talks that were not compensated from Natera, Roche, and Canon; and has participated in Asian/Australasian expert consultancies for Natera and Roche. Bo Jacobsson collaborated in the Improving Maternal Pregnancy And Child ouTcomes (IMPACT) study where Roche, Perkin Elmer, and Thermo Fisher provide reagents to Placental Growth Factor (PLGF) analyses. Ronald J. Wapner receives research funding from National Institute of Child Health and Human Development and support from Illumina for research reagents. Mary E. Norton is a consultant to Luna Genetics. All other authors declare no conflicts of interest.

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Performance of prenatal cfDNA screening for sex chromosomes

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Performance of prenatal cfDNA screening for sex chromosomes

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