Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood

TLDR

The sequencing approach is polymorphism‑independent, making it universally applicable for noninvasive fetal aneuploidy detection. We performed high‑throughput shotgun sequencing of cell‑free DNA from pregnant women's plasma, generating about 5 million tags per sample. The method accurately identified all nine trisomy 21, two trisomy 18, and one trisomy 13 cases in 18 pregnancies, detecting trisomy as early as week 14, and revealed that cell‑free plasma DNA is enriched for nucleosome‑derived sequences.

Abstract

We directly sequenced cell-free DNA with high-throughput shotgun sequencing technology from plasma of pregnant women, obtaining, on average, 5 million sequence tags per patient sample. This enabled us to measure the over- and underrepresentation of chromosomes from an aneuploid fetus. The sequencing approach is polymorphism-independent and therefore universally applicable for the noninvasive detection of fetal aneuploidy. Using this method, we successfully identified all nine cases of trisomy 21 (Down syndrome), two cases of trisomy 18 (Edward syndrome), and one case of trisomy 13 (Patau syndrome) in a cohort of 18 normal and aneuploid pregnancies; trisomy was detected at gestational ages as early as the 14th week. Direct sequencing also allowed us to study the characteristics of cell-free plasma DNA, and we found evidence that this DNA is enriched for sequences from nucleosomes.