Genome-wide NIPT: implications for pregnancy outcomes and clinical practice

Genome-wide sequencing of cell-free DNA (cfDNA) from maternal plasma enables non-invasive prenatal testing (NIPT) of all 23 pairs of chromosomes. The primary advantage of a genome-wide approach is the potential to identify pathogenic copy number changes that would go unrecognized using standard methods of cfDNA-based NIPT. Importantly, these additional pathogenic changes account for up to 25% of readily detectable chromosome abnormalities encountered during routine cytogenetic prenatal diagnosis.

Genome-wide cfDNA screening can identify both whole chromosome and segmental chromosomal imbalances, which involve partial duplications and/or deletions of chromosomal material. Our own experience of using genome-wide NIPT at 10-12 weeks of gestational age, on more than 50,000 pregnancies, indicates that rare autosomal aneuploidies (RAAs; autosomes other than 13, 18 and 21) are often associated with pregnancy complications that include miscarriage, true fetal mosaicism, uniparental disomy (UPD), fetal growth restriction (FGR) and preterm birth. High frequencies of rare autosomal trisomy mosaicism in the placenta can be predicted from the bioinformatics data. These pregnancies are at greatest risk of true fetal mosaicism and UPD following trisomy correction. We have documented UPD in 16/68 (24%) of on-going pregnancies involving RAAs, including pathogenic cases of maternal UPD14 (Temple syndrome) and maternal UPD15 (Prader-Willi syndrome). Other chromosomes, such as chromosomes 2 and 16, show a strong correlation with severe FGR and preterm birth and may benefit from increased fetal surveillance.

Copy number abnormalities involving larger (>5-10 Mb) partial duplications and deletions of chromosomal material also contribute to pathogenic disease. However, accurate screening for these abnormalities can be confounded by both placental and maternal mosaicism. This reduces the sensitivity and specificity of CNV screening, although in our experience, the benefits outweigh the challenges for those couples seeking an expanded non-invasive screening test. I will also present data on novel applications of genome-wide NIPT, including screening pregnancies at risk of inherited unbalanced chromosomal rearrangements.