Is cell-free fetal DNA from maternal blood finally ready for prime time?

H prenatal genetic diagnosis for numeric chromosomal abnormalities (trisomy 21) at last reached its desired goal of becoming a definitive test (not a screen)? Can we relegate our invasive diagnostic procedures— chorionic villus sampling (CVS) and amniocentesis—to the museum? The contributions of Bianchi et al1 (see p. 890) and others earlier this year2,3 take us a considerable distance. Of course, a few steps remain before declaring victory. Definitive noninvasive fetal diagnosis long has been considered tantalizingly close, first through analysis of intact fetal cells in maternal blood and, more recently, through cell-free fetal DNA. The first detection of fetal trisomy (trisomy 18) from maternal blood was made in 1991, based on recovery of nucleated fetal red blood cells and analysis by fluorescence in situ hybridization.4 Subsequent confirmation was made by several other groups, and successful cases accrued.5,6 A multicenter National Institute of Child Health and Human Development collaborative study was begun, with its 2002 report showing 74% detection of trisomy 21 cases with no false positives.7 Recovery of intact fetal cells at that time was considered proven; however, the method was laborious and it was hindered by inconsistent recovery. It had been known previously that cell-free DNA was present in the plasma of adults with cancer, but, in 1997, Lo’s discovery of cell-free fetal DNA in maternal blood opened the door for its application to noninvasive prenatal genetic diagnosis.8 In fact, earlier reports of the presence of paternal -thalassemia mutations in maternal blood9 (and, hence, obligatorily of fetal origin) may have been the result of cell-free fetal DNA in maternal plasma rather than intact fetal cells, as was generally assumed at the time. Approximately 5% of cell-free DNA in maternal plasma is believed to be fetal in origin. Distinguishing trisomic from nontrisomic pregnancies can be based on quantifying the total number of chromosome 21 transcripts in maternal blood using a technique called massive parallel genomic sequencing. A pregnancy with a fetus with trisomy 21 will have more chromosome 21 transcripts than one carrying a fetus without trisomy 21 because the trisomic fetus has three 21 chromosomes rather than the usual two. If 5% of cell-free DNA in maternal blood were of fetal origin, a mother carrying a fetus with trisomy 21 should have 2.5% more chromosome 21 transcripts than if her fetus were not trisomic. The study of Bianchi and colleagues collected samples prospectively.1 Later analysis of 2,882 samples yielded 127 without informative results, but in the remaining samples all 89 trisomy 21 cases were detected; one false-positive result occurred. Other groups have published salutary results, all involving biotech teams with academic partners. Chiu et al studied plasma of 576 samples.2 Of all samples, 1.7% “did not meet See related article on page 890.