Discrepancies Between Sex Prediction and Fetal Sex After Prenatal Noninvasive Cell-Free DNA Screening

Selma F Witchel, Aleksandar Rajkovic, Svetlana A Yatsenko
Journal of the Endocrine Society, Volume 9, Issue 2, February 2025, bvaf007
https://doi.org/10.1210/jendso/bvaf007

Abstract

In the last 10 years the field of prenatal diagnosis has been significantly reshaped followed by the implementation of noninvasive prenatal cell-free DNA (cfDNA) testing methodologies in clinical practice. Based on a superior performance and higher sensitivity and specificity than the former practice of biochemical markers screening, the American College of Obstetricians and Gynecologists and American College of Medical Genetics and Genomics recommend noninvasive prenatal cfDNA screening for trisomy 21, 18, 13, and sex chromosome aneuploidy to all pregnant people. While cfDNA screening is helpful in risk assessment for the most common autosomal trisomies, cfDNA also provides information about fetal sex chromosomes. Prediction of fetal sex is highly desired by the parents and also useful to healthcare providers for management of pregnancies that are at-risk for X-linked conditions. In fact, utilization of cfDNA screening has resulted in a significant number of referrals to evaluate discordant results for cfDNA sex prediction and appearance of fetal genitalia by prenatal ultrasound scan or at birth raising concerns about the fetus/infant atypical sex development known as a difference in sex development (DSD). In this mini-review, we outline principles and limitations of cfDNA technology, summarize recent findings related to cfDNA test performance in prediction of sex chromosome abnormalities and DSD conditions, define the technical and biological causes of discrepant results, provide recommendations to consolidate efforts by prenatal and clinical management teams in challenging situations, and discuss ethical considerations associated with fetal sex prediction and prenatal DSD diagnosis.

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