Artifacts, Not Differences in Sex Development, Are the Predominant Cause of Phenotypic Sex Discordance With Prenatal Cell-Free DNA Screening: A Review of 33 Cases.

OBJECTIVE

Although fetal sex chromosome complement prediction by prenatal cell-free DNA (cfDNA) screening is highly accurate, discordance between the cfDNA-inferred chromosomal sex and phenotypic sex observed via ultrasonography or at birth, that is, "fetal sex discordance", does rarely occur. Such discordance may be caused by differences in sex development (DSD) or technical or biological artifacts. This study aims to provide insights into the proportion of fetal sex discordance cases caused by DSD versus non-DSD artifacts.

METHOD: We retrospectively reviewed 122,748 cases that underwent diagnostic testing at the Mayo Clinic Cytogenetics Laboratory between 2015 and 2023. Thirty-three singleton-gestation cases tested for fetal sex discordances were identified.

RESULTS

Fetal sex discordance was attributed to non-DSD artifacts in 24 (73%) of the 33 patients. In these cases, the phenotypic sex matched the chromosomal sex revealed by diagnostic cytogenetic testing. The remaining 9 patients included one with mosaic 46,X,psu idic(Y)(q11.21)/45,X, 5 with 46,XY DSD, and 3 with 46,XX DSD.

CONCLUSION

The majority of fetal sex discordance cases are caused by non-DSD artifacts rather than DSD. Accurate clinical counseling of fetal sex discordance requires distinguishing between DSD and non-DSD causes, emphasizing the need for diagnostic cytogenetic testing.