Confirmation rate of cell free DNA screening for sex chromosomal abnormalities according to the method of confirmatory testing

Abstract

Objective To examine the positive predictive value (PPV) of cfDNA screening for sex chromosome aneuploidies (SCA) in a large series of over 90 000 patients. Methods Retrospective study based on samples that were sent to Cenata, a private laboratory which uses the Harmony Prenatal Test. The SCA high‐risk results were stratified according to the method of diagnostic testing and according to karyotype result. Results The study population consisted of 144 cases. The CfDNA test indicated monosomy X, XXX, XXY, and XYY in 62, 37, 40, and 5 cases, respectively. The overall PPV was 38.9% (30.9‐47.4), 29.0% (18.2‐42.9) for monosomy X, 29.7% (15.9‐47.9) for 47,XXX, 57.5% (40.9‐73.0) for 47,XXY, and 80.0% (28.4‐99.5) for 47,XYY). A total of 112 (77.8%) women with a high‐risk result for SCAs opted for prenatal karyotyping. In this group, there were significant differences in the PPV if the karyotype was assessed by amniocentesis or by CVS: 29.5% vs 50.0%. This significant difference was driven by the monosomy X result which shows a significantly higher PPV in CVS (54.6% (23.4‐83.3) vs 17.1% (6.6‐33.6)). For the other SCAs, the differences were not significant. Conclusion PPV of an abnormal cfDNA test for SCAs is low, particularly for monosomy X. The confirmation rate depends on the type of confirmatory test.

Cell-Based NIPT Detects 47,XXY Genotype in a Twin Pregnancy

“…The positive predictive value (PPV) for cell-free NIPT for SCAs is low (overall PPV for SCAs is 38.9%) compared to the PPV for common trisomies and false positive results may lead to unnecessary invasive testing ( Lüthgens et al, 2021 ). Klinefelter syndrome is the most common SCA in males affecting in 500 live male births ( Kanakis and Nieschlag, 20182018 ) and the PPV for cell-free NIPT finding of 47,XXY has been estimated to range between 70 and 90% in singleton pregnancies (Wang et al, ; Samango-Sprouse et al, 2017 ).…”

“…While cell-free NIPT detects the common trisomies with high accuracy, the test performance is significantly lower for the other chromosomal alterations. In general, cell-free NIPT results must be interpreted with caution because maternal factors such as copy number variants (CNVs), sex chromosomal anomalies (SCAs) and benign- or malignant tumors may interfere with the data interpretation ( Lenaerts et al, 2019 ; Lüthgens et al, 2021 ).…”

Non‐invasive prenatal testing 10 years on

“…who demonstrate the low positive predictive value (PPV) more generally for sex chromosome abnormalities 12 . These authors also show how the PPV is higher when using CVS to confirm a high‐risk NIPT result than with amniocentesis, particularly for monosomy X, indicating that CVS may confirm CPM rather than the true fetal karyotype 12 …”

Antenatal screening for chromosomal abnormalities

“…Since the study excludes unreported cases, a lower detection rate must be assumed. Lüthgens et al investigated the confirmation rate of sex chromosomal defects suspected based on cfDNA screening [ 41 ]. The overall PPV was 38.9% and was 29.0% for monosomy X, 29.7% for 47, XXX, 57.5% for 47, XXY and 80.0% for 47, XYY.…”