Non-invasive prenatal diagnosis of fetal chromosomal aneuploidy: State of the art

Current methods for definitive prenatal diagnosis of chromosomal aneuploidy, such as chorionic villus sampling and amniocentesis, are invasive and associated with a risk of fetal miscarriage. In 1997, our group reported the presence of fetal DNA in maternal plasma and offered new possibilities for non-invasive prenatal diagnosis. However, fetal DNA exists as a minor fraction among a high background of maternal DNA. Hence, quantitative perturbations caused by an aneuploid chromosome in the fetal genome, e. g. chromosome 21 for Down syndrome, to the total amount of sequences from that chromosome in maternal plasma would be small. We reasoned that massively parallel genomic sequencing approaches could be applied to the non-invasive prenatal detection of aneuploidies by measuring the relative amounts of sequences from the aneuploid chromosome in maternal plasma. We used the Illumina ‘Solexa’ platform to sequence over 10 million sequence tags per maternal plasma sample. From these data, we quantified chromosome 21 sequences in first and second trimester maternal plasma samples from trisomy 21 and euploid pregnancies. Increased sequenced reads from chromosome 21 was readily identified among the trisomy 21 pregnancies. This work demonstrates the potential of massively parallel plasma DNA sequencing as a strategy for non-invasive fetal aneuploidy detection. The work also affirms the potential of quantitative sequencing by massively parallel approaches as a diagnostic tool.