Noninvasive prenatal diagnosis empowered by high‐throughput sequencing

Abstract

Noninvasive prenatal diagnosis of fetal Down syndrome using direct nucleic acid analysis was once an elusive goal. The presence of cell-free fetal DNA in maternal plasma was discovered in 1997 and offered a new noninvasive source of fetal genetic material. A number of approaches have since been developed for the assessment of fetal chromosome dosage based on cellfree fetal DNA analysis. The most effective approach developed to date is based on massively parallel sequencing of maternal plasma DNA molecules for the detection of an increased representation of chromosome 21 DNA molecules in the plasma of women pregnant with trisomy 21 fetuses when compared with euploid pregnancies. A number of multicenter studies have since been conducted to evaluate the diagnostic efficacy of the sequencing-based method. To date, the literature contains results for the analysis of a total of 305 trisomy 21 pregnancies and 2061 euploid pregnancies. The overall diagnostic sensitivity and specificity were both 99%. Besides trisomy 21, massively parallel maternal plasma DNA sequencing has also been applied to the noninvasive detection of trisomy 18, trisomy 13 and fetal genetic sequences across the genome.