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. 2025 Jun;199(2):124-133.
doi: 10.1002/ajmg.c.32136. Epub 2025 Mar 5.

Non-Invasive Prenatal Testing by Cell-Free DNA (cfNIPT) for Detecting Turner Syndrome With Mosaicism and Structural Variants-Prenatal Findings and Postnatal Outcomes

Ivonne Bedei  1   2 , Johanna Bruder  1 , Ida C B Lund  3   4   5 , Simon H Thomsen  3   5 , Ida Vogel  5   6 , Andrea T Maciel-Guerra  7 , Francisco Alvarez-Nava  8   9 , Melissa L Crenshaw  10 , Roland Axt-Fliedner  1 , Claus H Gravholt  2   11   12 , Anne Skakkebæk  2   3   12
Affiliations

Non-Invasive Prenatal Testing by Cell-Free DNA (cfNIPT) for Detecting Turner Syndrome With Mosaicism and Structural Variants-Prenatal Findings and Postnatal Outcomes

Ivonne Bedei et al. Am J Med Genet C Semin Med Genet. 2025 Jun.

Abstract

Turner Syndrome (TS) is a sex chromosomal disorder associated with karyotype heterogeneity. Although TS can be associated with severe prenatal findings, most often linked to the 45, X karyotype, the majority of TS fetuses have no overt phenotype, resulting in delayed diagnosis and management. The objective of this study is to assess the efficacy of non-invasive prenatal testing by cell-free DNA (cfNIPT) in detecting TS fetuses with different TS karyotype variants and to examine the phenotypic variations and clinical outcomes.Data on pregnancies with confirmed or suspected TS from 2000 to 2024 were collected from specialists in fetal ultrasound in Germany. In addition, a small number of Danish cases with 45, X mosaicism in the placenta was included. Data were collected regarding cfNIPT results, karyotypes, prenatal ultrasound findings, and pregnancy outcomes.Of the 114 cases included, 100 (87.7%) had a high-risk cfNIPT result for monosomy X, 53 (46.5%) were true positives (TP), and 47 (41.2%) were false positives (FP). Fourteen (12.3%) were false negatives (FN). No differences in congenital malformation or nuchal translucency were seen between TP and FN. Data on karyotype were available for 67 cases. Fourty (59.7%) had a 45, X karyotype, 16 (23.9%) 45, X mosaicism, and 11 (16.4%) had a structural variant. The 45, X karyotype was associated with a higher prevalence of congenital malformation and increased nuchal translucency (ps ≤ 0.001). The live birth rate was higher in cases with 45, X mosaicism or structural variants compared to cases with a 45, X karyotype (ps ≤ 0.03). Postnatal phenotypes were often mild.cfNIPT represents a valuable tool for the early identification of fetuses with TS karyotype variants, enabling timely intervention and targeted management. However, the high false-positive rate underscores the need for careful counseling.

Keywords: Turner syndrome; Turner syndrome mosaicism; cfNIPT; prenatal phenotype; structural variant.

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References

    1. Álvarez‐Nava, F. , and R. Lanes . 2018. “Epigenetics in Turner Syndrome.” Clinical Epigenetics 10, no. 1: 45.
    1. American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Obstetrics, Committee on Genetics, and Society for Maternal‐Fetal Medicine. 2020. “Screening for Fetal Chromosomal Abnormalities: ACOG Practice Bulletin, Number 226.” Obstetrics & Gynecology 136, no. 4: e48–e69.
    1. Baena, N. , C. De Vigan , E. Cariati , et al. 2004. “Turner Syndrome: Evaluation of Prenatal Diagnosis in 19 European Registries: Prenatal Diagnosis of Turner Syndrome.” American Journal of Medical Genetics 129A, no. 1: 16–20.
    1. Bedei, I. , T. Gehrke , K. Gloning , et al. 2023. “Multicenter Clinical Experience With Non‐Invasive Cell‐Free DNA Screening for Monosomy X and Related X‐Chromosome Variants.” Prenatal Diagnosis 43, no. 2: 192–206. https://doi.org/10.1002/pd.6320.
    1. Bedei, I. , K. Gloning , J. Luc , et al. 2023. “Multicenter Clinical Experience With Non‐Invasive Cell‐Free DNA Screening for Monosomy X and Related X‐Chromosome Variants.” Prenatal Diagnosis: 1–15. https://doi.org/10.1002/pd.6320.

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