Non-Invasive Prenatal Testing Using Cell Free DNA in Maternal Plasma: Recent Developments and Future Prospects

Abstract

Recent advances in molecular genetic technologies have facilitated non-invasive prenatal testing (NIPT) through the analysis of cell-free fetal DNA in maternal plasma. NIPT can be used to identify monogenic disorders including the identification of autosomal recessive disorders where the maternally inherited mutation needs to be identified in the presence of an excess of maternal DNA that contains the same mutation. In the future, simultaneous screening for multiple monogenic disorders is anticipated. Several NIPT methods have been developed to screen for trisomy. These have been shown to be effective for fetal trisomy 21, 18 and 13. Although the testing has been extended to sex chromosome aneuploidy, robust estimates of the efficacy are not yet available and maternal mosaicism for gain or loss of an X-chromosome needs to be considered. Using methods based on the analysis of single nucleotide polymorphisms, diandric triploidy can be identified. NIPT is being developed to identify a number of microdeletion syndromes including α-globin gene deletion. NIPT is a profoundly important development in prenatal care that is substantially advancing the individual patient and public health benefits achieved through conventional prenatal screening and diagnosis.

Non-invasive Prenatal Screening for Fetal Aneuploidy: Comparison with Cytogenetic Results

“…In theory, the SNP-based testing has the advantage of being able to distinguish twin pregnancies and triploidy better than the MPSS approaches. On the other hand, detection of deletions and duplications may be limited by the presence of informative SNPs in the region of interest and, therefore, MPSS may be better suited for this purpose [45].…”

Current status and future perspectives of circulating cell-free DNA methylation in clinical diagnostics

“…The analysis of fetal ccfDNA in maternal blood is an emerging and rapidly growing diagnostic field (reviewed in: [31,32]). Epigenetically caused fetal diseases, i.e.…”

Aneuploidy Screening: The Ongoing Role of First-Trimester Ultrasound

“…The MPSS approach could be used for detection of all aneuploidies, although clinical trials have only yet validated testing for nonmosaic chromosomes 21, 18, 13, and monosomy X. A related strategy known as targeted massively parallel sequencing (t-MPS) differs in that it selectively amplifi es only the chromosomal regions of interest (i.e., 21, 13, 18) and then determines whether there is an excess of one chromosome relative to another [ 81 ].…”

“…However, sample sizes in these studies were small and may have included ascertainment bias through preferential inclusion of nonviable cases and those with abnormal serum and/or ultrasound fi ndings [ 81 ]. Observed detection rates for 45,X ranged from 75 % [ 16 ] to 91.5 % [ 83 ] using MPS methodology.…”

“…However, the total number of aneuploidy cases included in the SNP-based studies was smaller (124 total cases) compared to that of the studies using t-MPS (274 total cases) or MPSS (680 total cases) approach. All three methodologies achieved low false-positive rates for the common aneuploidies, ranging from 0 to 0.32 % [ 81 ]. The positive predictive value (PPV) of a high-risk NIDS result was evaluated as part of the Comparison of Aneuploidy Risk Evaluations (CARE) study, a prospective, blinded, multicenter observational study comparing results of NIDS (performed by MPSS) with those of conventional screening for trisomy 21 and 18 in a general obstetrical population .…”