Sequencing Cell Free DNA in the Maternal Circulation to Screen for Down Syndrome and Other Common Aneuploidies

Abstract

Currently, an estimated 72 % of all pregnancies in the USA receive first and/or second trimester screening for Down syndrome based on combinations of maternal age, biochemical markers, and ultrasound findings. The current “best” test can identify about 90 % of cases at a 2 % false positive rate. In 1997, circulating cell free DNA from the fetus was reported to constitute up to 10 % of all circulating cell free DNA in maternal plasma, after 10 weeks of gestation. Since that time, four commercial laboratories in the USA have performed external validation studies documenting the performance of laboratory developed next-generation sequencing tests for maternal plasma aimed at identifying Down syndrome and other common trisomies. Overall, the sensitivity for Down syndrome is higher (99 % or more), with fewer false positive results (0.2 % or less). In addition, some of these tests can reliably identify trisomy 18 and trisomy 13, along with select sex chromosome abnormalities. Testing occasionally (1–5 %) fails to provide a clinically useful result. This chapter also discusses potential future developments, such as the identification of large deletion/duplication syndromes, and current implementation issues (testing in twins and pregnancies conceived using assisted reproductive technologies).