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ACMG Presenter Highlights Effect of Rare Autosomal Trisomy on NIPT Outcomes

PHOENIX, AZ (GenomeWeb) – Rare autosomal trisomies (RATs) may explain many of the false positive or inconclusive results obtained with whole-genome sequencing-based non-invasive prenatal screening tests, according to preliminary research presented at the American College of Medical Genetics and Genomics meeting on Thursday.

As part of the opening plenary session, Eunice Kennedy Shriver National Institute of Child Health and Human Development Director Diana Bianchi outlined findings from her team's effort to visually review whole-genome sequence data from nearly 90,000 Verinata/Illumina NIPT tests. In a few hundred tests with unusual results, the group found that almost half of test failures seemed to stem from RAT-related reads, including reads associated with trisomies that apparently led to pregnancy loss.

In an article published in the journal Prenatal Diagnosis in January, Bianchi noted that "bioinformatics algorithms applied to interpret the results of raw, massively parallel sequencing data use non-target reference chromosomes as a denominator for the most common target chromosomes (chromosomes 13, 18, 21, X, and Y)."

Consequently, alterations such as RATs that affect the level of the non-targeted reference chromosomes can skew the interpretation of reads generated for circulating fetal DNA representing the chromosomes that are targeted — somewhat similar to the discordant or false-positive NIPT results that Bianchi and her colleagues observed in expectant mothers with cancer for a 2015 study in the Journal of the American Medical Association.

There is an ongoing debate over the potential harms or benefits of returning RAT results after to individuals who receive NIPT testing, Bianchi explained. Still, she noted that making genome sequence data on circulating fetal DNA more freely available might clarify some confusing or inconclusive NIPT results, while offering improved insights into the natural history of fetuses and the RATs that affect pregnancy outcomes, including miscarriage.

During her ACMG presentation, Bianchi highlighted early results from systematic visual re-analyses on circulating genomic DNA-based prenatal tests for more than 89,800 women in cohorts in Australia and California.

Based on the reference chromosome sequence patterns in these data, Bianchi and her team uncovered hundreds of apparent RATs, particularly fetal trisomies involving chromosomes 7, 15, and 16. Twenty-three miscarriages occurred not long after blood draw in the 51 fetuses with detectable RATs for which outcomes data were available, Bianchi said, though fetal outcomes varied depending on the affected chromosome.

The team's analyses also led to examples of maternal mosaicism for rare chromosome 8 trisomies, as well as fetal mosaicism for some RATs that did not appear to affect pregnancy and resulted in live-born infants.

It's unclear whether there is any clinical utility in informing apparently healthy women about their mosaicism, Bianchi explained. On the other hand, she said, it's possible that an increased awareness of fetal RATs could offer opportunities to treat some conditions at birth rather than waiting for neonatal screening or diagnostic test results to be returned. Such information may also have implications for reproductive health and pre-implantation genetic testing.