Non-Invasive Prenatal Testing for Sex Chromosome Aneuploidy in Routine Clinical Practice

Abstract

Objectives: To assess the accuracy of non-invasive prenatal testing (NIPT) for sex chromosome aneuploidy (SCA) in routine clinical practice and to review counselling and sonographic issues arising in SCA cases. Methods: Three specialist Australian obstetric ultrasound and prenatal diagnosis practices offering NIPT after 10 weeks' gestation participated in this study. NIPT was reported for chromosomes 21, 18, 13, X, and Y. Results: NIPT screening was performed in 5,267 singleton pregnancies. The odds of being affected given a positive screening result (OAPR) was lowest for SCAs, most notably for monosomy X (20%). Fewer women underwent invasive prenatal testing when counselled regarding a high risk for SCA (65.5%) compared with those who had a high risk for another aneuploidy (85%). The positive screening rate of NIPT including SCA was 2.3%, but 1.2% if only the autosomal trisomies were included in the panel. Conclusion: The addition of SCA testing to NIPT doubles the positive screening rate. The OAPR for SCAs (most notably for monosomy X) is reduced compared with the autosomal trisomies. Clinicians need a more extensive discussion with women prior to the inclusion of the X and Y chromosomes in the NIPT panel, given the complexity in counselling regarding further management and the additional anxiety that these abnormal results may cause. A benefit of sex chromosome analysis is an improvement in antenatal diagnosis of some disorders of sexual development.

A comment on “clinical experience with sex chromosome aneuploidies detected by noninvasive prenatal testing (NIPT): Accuracy and patient decision‐making”

“…All these findings highlight the critical need for comprehensive pretest and posttest counseling provided by a multidisciplinary team having specific knowledge about the detailed features of each syndrome, as suggested by multiple studies . Medical geneticist have a central role not only for counseling about prenatal diagnosis but also for postnatal follow‐up.…”

Clinical experience with sex chromosome aneuploidies detected by noninvasive prenatal testing (NIPT): Accuracy and patient decision‐making

“…While SCAs as a group are as common as autosomal aneuploidies in low‐risk populations, NIPT performance is not as good for SCAs as compared to trisomies 21, 18, and 13 because of fetal mosaicism, confined placental mosaicism, underlying maternal X chromosome variation, and/or fetal aneuploidy diagnoses outside the scope of NIPT validation . The majority of the published data regarding positive and negative predictive values comes from commercial labs in addition to a few retrospective studies from clinical practices . These prior case series have shown that inclusion of SCAs on NIPT platforms doubles the overall positive screening rate and increases the false positive rate .…”

“…The majority of the published data regarding positive and negative predictive values comes from commercial labs in addition to a few retrospective studies from clinical practices . These prior case series have shown that inclusion of SCAs on NIPT platforms doubles the overall positive screening rate and increases the false positive rate . The true positive rate for monosomy X especially is much lower as compared to autosomal trisomies most likely because of maternal and placental mosaicism …”

“…While NIPT position statements published by the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, and Society for Maternal Fetal Medicine recommend that all pregnant women be informed about the availability of NIPT for SCAs, the importance of confirming any positive NIPT results via diagnostic testing is emphasized . While previous case series have shown that the majority of women with positive NIPT results for a SCA do elect prenatal diagnosis, uptake is lower as compared to positive NIPT results for other aneuploidies …”

PREFACE: In silico pipeline for accurate cell‐free fetal DNA fraction prediction

“…Gonosomal aberrations are theoretically exposed during NIPT in a similar way as any other aneuploidy. Nevertheless, the specificity is reported to be much lower in comparison with traditional screening of chromosomes 13, 18, and 21, especially for monosomy X . Ethical issues on reporting these sometimes nonsevere abnormalities aside, the incorporation of FF in statistical outcome—which is generally not done with, eg, the popular z ‐score approach—does improve performance .…”