Routine cell-free DNA prenatal screening identifies pregnancies at high risk for cystic fibrosis that may benefit from fetal therapy

Recent improvements in cell-free DNA technology have enabled non-invasive prenatal testing (NIPT) to screen for fetal single-gene autosomal recessive conditions from maternal blood as early as the first trimester. This technique can determine the fetal risk for cystic fibrosis (CF) with a single blood sample from a pregnant person without the need for a partner sample, which is required for traditional carrier screening. A retrospective review of 100,106 consecutive general-risk pregnant patients who underwent CF carrier screening was completed. All positive CF carriers underwent cell-free DNA testing, which reported a risk of the fetus being affected with CF. Pregnancies with at least a 1 in 4 risk were classified as high risk. Results of confirmatory testing were solicited from all high-risk cases, and a random sample of 50 % of low-risk cases were used to compute test performance analytics. The study cohort included 2,587 CF carriers and 20 cases with high-risk cell-free DNA results where the CF-affected status of the fetus/neonate was known, of which 13 were affected. All cases (n = 8) with a 9 in 10 cell-free DNA estimated risk were affected. The assay correctly identified all known affected fetuses as high risk (sensitivity of 100 %). Of the 13 affected, 12 cases had at least one CFTR variant eligible for CFTR modulator therapy. Additionally, 75 % of all cell-free DNA fetal risk results were returned before 18.5 weeks gestation, providing ample time for diagnostic testing and initiation of in utero treatment if indicated. Carrier screening with reflex to cell-free DNA analysis provides a personalized fetal risk assessment and efficient turnaround times at an early gestational age, without the need for a partner sample for a general risk population. This screening method can precisely guide prenatal diagnostic testing to identify CF-affected fetuses that may benefit from in utero therapy.