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CME Credit Offered
CME Credit Offered
Abstract Award
Abstract Award
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Poster Session 4

(1001) Detecting maternal mosaicism in fetal sex chromosome aneuploidy screening

Friday, January 31, 2025
4:00 PM – 6:00 PM  
Objective: Sex chromosome anomalies (SCA) are a common class of fetal aneuploidy,
but cell-free DNA (cfDNA) screening assays have relatively low positive predictive value (PPV) for SCA calls. False positives are caused by factors including statistical error, confined placental mosaicism, and maternal mosaicism. To compare the impact of these factors and improve SCA screening PPV, we developed a new "depth trajectory" method that identifies mosaic maternal aneuploidy by analyzing covariation in read depth and DNA fragment size.

Study Design: We screened 728 prenatal cfDNA samples for fetal SCA with a whole-genome sequencing (WGS) assay and a new targeted sequencing assay. The targeted assay uses in silico size selection to measure how chromosome dosage varies with fetal fraction within each sample’s sequencing reads. Maternal mosaic loss of X is identified when X chromosome dosage is depressed but increases along with fetal fraction. The cohort included 25 patients screening positive for monosomy X and 36 patients screening positive for other SCAs on the WGS assay. Fetal diagnosis via amniocentesis or postnatal karyotype was obtained for 12 monosomy X screen-positive patients.

Results: 59 of 61 patients screening positive for fetal SCA in the WGS assay were also positive in the targeted assay prior to maternal anomaly calling. PPV of monosomy X calls in the WGS assay was 42% (5/12). One fetal mosaic true positive was not detected and 3 of 7 false positives were identified as maternal anomalies in the targeted assay, improving PPV to 50% (4/8). Remaining false positives had an average 61% degree of mosaicism in the targeted assay, consistent with placental mosaicism.

Conclusion: Depth trajectory analysis successfully identifies maternal X chromosome mosaicism and improves PPV in fetal sex chromosome anomaly screening. We observed high confirmation rates in re-tested samples, suggesting that statistical error is a relatively minor contributor to SCA false positives, which are primarily explained by confined placental mosaicism and maternal mosaicism.