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Review
, 3 (2), 537-65

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

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Review

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

Peter Benn. J Clin Med.

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.

Keywords: Down syndrome; aneuploidy; cell-free DNA; monogenic disorders; non-invasive prenatal testing; prenatal diagnosis; prenatal screening; sequencing; sex chromosome abnormalities.

Figures

Figure 1
Figure 1
Illustration of SNP analysis in fetal DNA. Dark brown and light brown heavy lines indicate two homologs present in fetal DNA. Thin dark brown and light brown lines represent DNA fragments that may contain SNPs and map uniquely to their corresponding chromosome while thin grey lines are DNA fragments that can map to either homolog. 1–20 refers to representative positions along each chromosome, some of which are the sites of SNPs (bold, underlined bases). Analysis of the fragments present, comparison with the parent’s SNPs, and mapping to reference genome sequences allows construction of the fetal haplotypes. The analysis potentially allows identification of inherited disease causing mutations (e.g., position 5, G boxed) either through identification of the specific fragments with the mutation or through closely linked SNPs.
Figure 2
Figure 2
Segregation of an autosomal recessive disorder. Blue indicates paternal chromosomes and red maternal chromosomes. Upper shows the haplotypes for the parents and the lower shows the four different segregation possibilities. X denotes a disease mutation. The identification of the boxed G SNP in the maternal plasma would indicate that the paternal haplotype that carries the mutation was present in the fetus. An excess of the circled C and A SNPs in the maternal plasma (relative to the A and C) would indicate the maternal haplotype with the mutation was present in the fetus.
Figure 3
Figure 3
Use of SNPs to detect trisomy 21. Red denotes fetal DNA, black denotes maternal DNA. Left: In this example, for a normal pregnancy, the father is genotyped and known to be GG and the mother GA. The fetus inherited a G allele from the father and A allele from the mother. For a normal pregnancy, the G/A DNA fragment ratio is 1.0 regardless of the fetal fraction percentage. Right: Trisomy 21 is present due to a maternal non-disjunction resulting in a fetal genotype AGG. The G/A fragment ratio will be dependent on the fetal fraction. For example, if the fetal fraction is 20%, the G/A ratio will be approximately ((20% × 2) + (80% × 1))/((20% × 1) + (80% × 1)) = 1.2. The departure from the normal ratio, 1.0, provides evidence for trisomy 21.
Figure 4
Figure 4
Summary detection rates and false-positive rates for (a) Down syndrome; (b) trisomy 18; (c) trisomy 13; and (d) all three trisomies combined for the three NIPT methods.
Figure 5
Figure 5
(A) Detection of a paternally inherited balanced translocation; (B) Detection of a maternally inherited balanced translocation.

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