Implications of fetoplacental mosaicism on cell‐free DNA testing for sex chromosome aneuploidies

• Published in: Prenatal diagnosis Vol. 37; no. 10; pp. 1017 - 1027
• Main Authors: Grati, Francesca Romana, Bajaj, Komal, Zanatta, Valentina, Malvestiti, Francesca, Malvestiti, Barbara, Marcato, Livia, Grimi, Beatrice, Maggi, Federico, Simoni, Giuseppe, Gross, Susan J., Ferreira, Jose
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.10.2017
• Subjects: Abnormalities; Amniocentesis; Aneuploidy; Anomalies; Cell-Free Nucleic Acids - blood; Chorionic Villi Sampling; Chromosome aberrations; Chromosomes; Chromosomes, Human, X - genetics; Congenital Abnormalities - diagnostic imaging; Congenital Abnormalities - genetics; Data collection; Deoxyribonucleic acid; Disjunction; DNA; DNA testing; False Negative Reactions; Female; Fetus; Fetuses; Genetic testing; Humans; Karyotypes; Karyotyping; Lymphangioma, Cystic - genetics; Monosomy; Mosaicism; Mosaicism - embryology; Nuchal Translucency Measurement; Placenta; Pregnancy; Recombination; Retrospective Studies; Sex; Sex chromosomes; Sexual behavior; Ultrasonic imaging; Ultrasonography, Prenatal; Ultrasound; Villus
• ISSN: 0197-3851; 1097-0223
• DOI: 10.1002/pd.5138

Objective The unique biological behavior of sex chromosomes has implications for cell‐free DNA (cfDNA) testing. Our purpose is to predict the (1) false positive/negative rates of cfDNA testing consequent to fetoplacental mosaicism for any sex chromosome aneuploidies (SCA) and (2) positive predictive value (PPV) and negative predictive values of a high‐risk and low‐risk cfDNA result for any SCA. Method This is a retrospective analysis of 67 030 chorionic villus sampling karyotypes, including fetoplacental mosaicism cases. Results Non‐mosaic 45, X is associated with cystic hygroma/increased nuchal translucency and fetal anomalies. The false positive rate consequent to confined placental mosaicism is predicted to be 0.05%. The estimated false negative rate is in the range of 0% to 5.7% for all non‐mosaic SCAs; it is 70% for mosaic 45, X with normal ultrasound. The predicted PPV on amniocytes is very high for most SCAs (94.4–99.4%). However, the stratified analysis shows that the PPV is much lower for 45, X without ultrasound anomalies compared with 45, X with abnormal scan (51% or 71%, vs 99%, respectively). Conclusion Mosaicism is a major issue for SCA cfDNA testing, and prenatal confirmation, preferentially with amniocentesis if there are no ultrasound anomalies, remains important in counseling. As PPV varies on the basis of the presence of an ultrasound anomaly, skilled evaluation is critical. © 2017 John Wiley & Sons, Ltd. What is already known about this topic? Sex chromosomes are prone to non‐disjunction and recombination errors because of their particular structure and gene content. Previous studies have demonstrated that monosomy X is the single chromosome abnormality most frequently involved in fetoplacental mosaicism. Despite established false positive cell‐free DNA results for sex chromosome aneuploidies, it has been difficult to determine false negative characteristics because sex chromosome aneuploidies have variable phenotype, making complete data collection difficult. What does this study add? We present predicted false positive and false negative rates of cell‐free DNA testing, because of a fetoplacental mosaicism, for all sex chromosome abnormalities, stratified on the presence or absence of an ultrasound abnormality. A robust prenatal cytogenetic dataset can be used as a proxy to calculate the likely positive predictive value and negative predictive value of cell‐free DNA testing for sex chromosome abnormalities. Such models are of benefit because these test characteristics are difficult to ascertain prospectively for sex chromosome aneuploidies, particularly as the phenotypes are often variable and mild.