Rare autosomal trisomies: comparison of detection through cell‐free DNA analysis and direct chromosome preparation of chorionic villus samples

Abstract

Objectives Direct chromosome preparations of chorionic villus samples (CVS) and cell‐free (cf) DNA testing both involve analysis of the trophoblastic cell lineage. We compared the spectrum of rare autosomal trisomies (RATs) detected by these two approaches and assessed the available information on their clinical significance. Methods Data from 10 reports on genome‐wide cfDNA testing were pooled to determine which chromosomes were most frequently involved and pregnancy outcome information was reviewed. CVS information was drawn from an updated database of 76,102 consecutive CVS analyses where trophoblastic and mesenchymal layers were analyzed and amniotic fluid (AF) cell analysis was recommended for RAT‐positive cases. Chromosomes involved, confined placental mosaicism, true fetal mosaicism, and uniparental disomy (UPD) for imprinted chromosomes was assessed. RAT involvement was also compared to those present in spontaneous abortions. Results RATs were present in 634 of 196,662 (0.32%) cfDNA samples and 237 of 57,539 (0.41% CVS trophoblast samples (P<0.01). Rates for cfDNA varied over 8‐fold between reports. Confirmation of abnormality through amniocentesis was more likely when RATs were ascertained through cfDNA (15 of 237, 9.8%) compared to CVS trophoblasts (7 of 237, 3%) (P<0.01). cfDNA ascertained cases contained proportionately more trisomy 16, 15 and 22 which are associated with fetal loss. Of 153 cf‐DNA RAT cases with outcome information, 41.2% were normal livebirths, 26.8% were fetal losses, 7.2% had phenotypic abnormality detected through ultrasound or other follow‐up evaluation, 2.0% with a clinically significant UPD and 21% with fetal growth restriction/low birth weight. Conclusions Although there are strong parallels between RATs ascertained through these two methods, caution is needed in applying conclusions from CVS analysis to cfDNA testing, and vice versa. RATs identified through genome‐wide cf‐DNA tests have uncertain risks for fetal loss, growth restriction, or fetal abnormality.