The proof-of-principle of diagnosing fetal aneuploidy by shotgun sequencing cell-free DNA from maternal blood was demonstrated independently by two groups in 2008.(1,2) The strength of the initial approach was the fact that it was genome-wide by design, yet it was exclusively or mainly limited in scope to the detection of trisomy 21 (T21). Follow-up studies then substantiated the lower sensitivity of the approach for autosomal trisomies other than T21. This article is protected by copyright. All rights reserved.