Performance of prenatal cfDNA screening for sex chromosomes

Kimberly Martin; Pe'er Dar; Cora MacPherson; Melissa Egbert; Zachary Demko; Sheetal Parmar; Katelyn Hashimoto; Sina Haeri; Fergal Malone; Ronald J Wapner; Ashley S Roman; Asma Khalil; Revital Faro; Rajeevi Madankumar; Noel Strong; Robert M Silver; Nidhi Vohra; Jon Hyett; Matt Rabinowitz; Charlly Kao; Hakon Hakonarson; Bo Jacobsson; Mary E Norton

doi:10.1016/j.gim.2023.100879

Performance of prenatal cfDNA screening for sex chromosomes

Genet Med. 2023 Aug;25(8):100879. doi: 10.1016/j.gim.2023.100879. Epub 2023 May 5.

Authors

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

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.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Aneuploidy
Cell-Free Nucleic Acids* / genetics
Chromosome Disorders* / diagnosis
Chromosome Disorders* / genetics
Female
Humans
Noninvasive Prenatal Testing*
Pregnancy
Prenatal Diagnosis / methods
Prospective Studies
Sex Chromosome Aberrations
Sex Chromosomes / genetics
Trisomy / diagnosis
Trisomy / genetics
Turner Syndrome*

Substances

Cell-Free Nucleic Acids