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Digital fetal aneuploidy diagnosis by next-generation sequencing.

Since the identification of fetal lymphocytes in maternal blood in 1969, investigators have endeavored to develop genetics-based noninvasive prenatal diagnostics (NIPD)1 (1). A robust noninvasive approach would augment or potentially supplant amniocentesis and chorionic villus sampling, which, although gold standards, carry a risk of fetal loss. Despite considerable efforts, the use of fetal cells for NIPD has never reached clinical implementation because of their paucity (on the order of a few cells per milliliter of maternal blood) and concerns of fetal cell persistence in the maternal circulation between pregnancies (2). A new avenue was opened in 1997 by the discovery of circulating cell-free fetal DNA in maternal blood (3). Cell-free fetal DNA constitutes between 5% and 10% of the total DNA in maternal plasma and increases during gestation. It rapidly clears from the circulation postpartum, a feature that enhances its attractiveness as a per-pregnancy–specific analyte. Several clinical applications based on the analysis of cell-free fetal DNA have been developed. These assays include determining fetal Rh D status in Rh D-negative women (4), sex in sex-linked disorders (3)(5), and detection of paternally inherited autosomal recessive and dominant mutations (6). In the context of these successes, however, there remains the outstanding challenge of the use of cell-free fetal DNA for the detection of chromosomal aneuploidy, in particular trisomies 21, 18, and 13.

A cell-free fetal DNA–based approach for chromosomal aneuploidy must overcome several technical hurdles. By virtue of being cell free, fetal DNA in the maternal plasma cannot be easily analyzed by traditional visualization methods such as fluorescence in situ hybridization. The high “background” of maternal DNA (cell free or from residual cells) further complicates analysis by diluting the fetal genetic information. To address these issues, investigators have worked to identify fetal-specific molecular markers. The origin of circulating cell-free …