Factors influencing inconclusive sex chromosomal aneuploidies results on non-invasive prenatal testing

Non-invasive prenatal testing (NIPT) has been gaining wider acceptance as the preferred screening test for detecting common fetal chromosomal aneuploidies. In addition, NIPT can also screen for sex chromosomal aneuploidies (SCAs), namely Turner syndrome (45,X), Klinefelter syndrome (47,XXY), Triple X syndrome (47,XXX), and Jacobs syndrome (47,XYY). Recently, the American College of Medical Genetics and Genomics 2022 guidelines recommend that NIPT should be offered to screen for SCAs in pregnant women with singleton pregnancies. In our experience, in 99.8% of pregnant women, the NIPT gave a conclusive result i.e. either low-risk or high-risk for SCAs. However, in the remaining 0.2%, an inconclusive result was released as the test parameters did not fall within the expected low-risk or high-risk score. In such cases, detailed ultrasound and further diagnostic testing with appropriate genetic counselling are recommended. In 30 of 183 samples with an inconclusive result, follow-up information from a diagnostic test was obtained. In most cases, i.e., in 40% (12/30), the diagnostic results did not reveal any abnormal findings. About 30% (9/30) of the cases presented with a history of vanishing twin. In about 10% (3/30) of the cases, the fetus had sex chromosomal abnormality (Monosomy X, 20% Mosaic XXX and XXY). In addition, in about 10% (3/30) of cases, the maternal biological background was confounding the NIPT result for the fetus, i.e., the pregnant woman was identified to have an SCA (2 XXX and Mosaic MX). Adverse outcomes such as intrauterine fetal demise and spontaneous miscarriage were observed in 6.7% (2/30) of cases (the reason for the adverse outcome could not be ascertained) and pregnancy was continued without any further investigations in 3.3% (1/30) of the cases. In conclusion, this study highlights the importance of careful analysis of NIPT results when reporting SCAs. While NIPT offers superior sensitivity (99.6%) and specificity (99.8%) for screening SCAs, it is critical that pregnant women receive appropriate pre-test and post-test counseling to understand the clinical implications of inconclusive results, and the importance of further investigations to determine the fetus’s chromosomal status and in some cases of the mother.