Genome-Wide Noninvasive Prenatal Genetic Testing Uncovers Additional Findings Beyond Common Trisomies

About 1 in every 275 women who opted for genome-wide noninvasive prenatal genetic testing had an additional finding beyond the common trisomies, according to data from the Dutch TRIDENT-2 study.

While developed to detect the common aneuploidy conditions of trisomy 21, trisomy 18, and trisomy 13, noninvasive prenatal testing has also been adapted and expanded to detect additional chromosomal aneuploidies including rare autosomal trisomies and structural chromosomal aberrations, both of fetal and maternal origins.

Through the TRIDENT-2 (Trial by Dutch Laboratories for Evaluation of Noninvasive Prenatal Testing-2) study, the Dutch NIPT Consortium aimed to assess NIPT as a first-tier screening test for common aneuploidies among a general-risk population. Participants in it could then opt for either targeted screening for trisomies 21, 18, and 13, or genome-wide NIPT, which would report other chromosomal anomalies as well. As the team reported in the American Journal of Human Genetics on Thursday, additional findings — most of which had a clinical impact — were detected in nearly 0.4 percent of pregnancies for which GW-NIPT was sought.

"Based on the known prevalence of severe chromosomal aberrations in pregnancies, we were expecting to detect pathogenic fetal chromosomal aberrations other than the common trisomies," senior author Robert-Jan Galjaard from Erasmus Medical Center wrote in an email.

The TRIDENT-2 study launched in 2017 with funding from the Dutch Ministry of Health to offer NIPT to all pregnant women in the Netherlands — the previous TRIDENT-1 study had focused on NIPT for high-risk pregnancies. In TRIDENT-2, women could choose to undergo NIPT for a €175 (US $190) fee and further decide whether to undergo targeted testing for the common trisomies or GW-NIPT.

More than 43 percent of women chose to undergo NIPT, and, of those, nearly three-quarters opted for GW-NIPT.

Overall, a common aneuploidy was found among 0.49 percent of individuals who underwent any type of NIPT screening. But an additional finding was uncovered within 0.36 percent of individuals who underwent GW-NIPT, meaning that 1 in every 275 women who chose GW-NIPT had a result indicating an additional finding.

For about 10 percent of those cases, the researchers could not determine the origin of the additional chromosomal aberration. But of the remainder, nearly a quarter were fetal in origin, while just more than a quarter were maternal in origin and about half were due to placental mosaicism.

Of the fetal origin chromosomal aberrations, 77.2 percent were pathogenic. These aberrations included a handful of rare autosomal trisomies, but most were structural chromosomal aberrations. Parents chose terminations in 86.9 percent of cases.

A mosaic placental origin was confirmed or assumed for 52.8 percent of cases and these typically were rare autosomal trisomies. About half of these cases were associated with adverse perinatal outcomes, including increased risk of preeclampsia, preterm birth, and low birth weight, among others. These correlations held, the researchers noted, even when they excluded trisomy 16 cases, which had previously been tied to adverse outcomes. This finding suggested to them that individuals with these findings should be offered tailored perinatal obstetric care.

Meanwhile, about two-thirds of the chromosomal aberrations of maternal origin were acquired chromosomal aberrations, though others were constitutional CNVs. More than half the women with constitutional chromosomal aberrations had disease-related symptoms that had not previously been diagnosed, the researchers noted. Additionally, 12 of the 15 chromosomal aberrations of maternal origin that were complex aberrations were due to a maternal malignancy.

These findings suggested to the researchers that most of the additional findings uncovered by GW-NIPT have a clinical impact.

"For certain we see the added value of the additional pathogenic fetal aberrations that are detected with GW-NIPT. The prevalence of these findings is about the same as trisomy 13 and 18, for which prenatal screening is widely accepted," Galjaard said. He cautioned, though, that there are challenges to address, as many of the additional findings they detected are not of fetal origin but are derived from the placenta.

According to Galjaard, TRIDENT-2 is additionally examining the validity of GW-NIPT for twin pregnancies, the psychological impact of additional findings, and the long-term health consequences of confined placental mosaicism for children. The study has also been collecting additional years of data, which will expand its current dataset.