DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study

TLDR

The study aimed to assess whether maternal plasma cell‑free DNA sequencing can accurately detect trisomy 18 and trisomy 13. The authors performed a laboratory‑developed next‑generation sequencing assay on plasma cfDNA from 62 trisomy‑18, 12 trisomy‑13, and matched euploid pregnancies, adjusting for GC bias during result interpretation. The assay achieved 100 % detection of trisomy 18 and 91.7 % of trisomy 13 with false‑positive rates of 0.28 % and 0.97 %, respectively, and an overall detection rate of 98.9 % for common aneuploidies at a 0.1 % false‑positive rate, suggesting cfDNA sequencing could reduce invasive procedures by up to 95 %.

Abstract

To determine whether maternal plasma cell-free DNA sequencing can effectively identify trisomy 18 and 13.Sixty-two pregnancies with trisomy 18 and 12 with trisomy 13 were selected from a cohort of 4,664 pregnancies along with matched euploid controls (including 212 additional Down syndrome and matched controls already reported), and their samples tested using a laboratory-developed, next-generation sequencing test. Interpretation of the results for chromosome 18 and 13 included adjustment for CG content bias.Among the 99.1% of samples interpreted (1,971/1,988), observed trisomy 18 and 13 detection rates were 100% (59/59) and 91.7% (11/12) at false-positive rates of 0.28% and 0.97%, respectively. Among the 17 samples without an interpretation, three were trisomy 18. If z-score cutoffs for trisomy 18 and 13 were raised slightly, the overall false-positive rates for the three aneuploidies could be as low as 0.1% (2/1,688) at an overall detection rate of 98.9% (280/283) for common aneuploidies. An independent academic laboratory confirmed performance in a subset.Among high-risk pregnancies, sequencing circulating cell-free DNA detects nearly all cases of Down syndrome, trisomy 18, and trisomy 13, at a low false-positive rate. This can potentially reduce invasive diagnostic procedures and related fetal losses by 95%. Evidence supports clinical testing for these aneuploidies.