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At ACMG, Presenters Discuss False-Positive, False-Negative NIPT Results

PHOENIX (GenomeWeb News) – While non-invasive prenatal tests allow patients and their healthcare providers to assess the risk of fetal aneuploidy in a pregnancy, presenters at the American College of Medical Genetics and Genomics annual meeting Friday cautioned that sometimes the screens return false-positive or false-negative results.

Currently, four US companies —Ariosa Diagnostics, Natera, Sequenom, and Verinata Health, which is now owned by Illumina — offer such non-invasive prenatal screening. The tests typically screen fetal DNA circulating in maternal blood for aneuploidies, namely of chromosomes 13, 18, and 21, and are beginning to screen for sex chromosome aneuploidies. The tests are usually offered to pregnant women with an increased risk of aneuploidy due to advanced maternal age, family history, or abnormal ultrasound results.

"[It's] not just a simple blood test," Holli Drendel, a cytogenetics fellow at Indiana University School of Medicine, said during her presentation. She emphasized that NIPT is a screening tool, not a diagnostic one.

As non-invasive prenatal screening tests pick up cell free DNA in maternal blood, the screen can detect circulating DNA from other sources, said Christopher Osborne, a genetic counselor at the University of North Carolina at Chapel Hill.

He presented the case of a 37-year-old woman who, due to advanced maternal age, underwent screening using Verinata's test. Her results were indicative of aneuploidies at chromosomes 13 and 18. Follow-up amniocentesis and SNP microarray assessment, however, showed a normal, male fetus.

Thinking there might have been a lab error, Osborne had the test run again, but it gave the same results. Further, a third specimen was later sent to Sequenom for analysis with its test, but it was unable to report any results.

He and his team suspected that the problem might be confined placental mosaicism, in which there is a discrepancy between the number of chromosomes seen in the placenta versus in the fetus. To determine whether that was the case, they received consent from the patient to receive a sample of the placenta for biopsy, but postpartum examination of that tissue ruled mosaicism out as a cause.

Two weeks after delivering a normal, male infant, the patient complained of worsening pelvic pain and she was diagnosed with metastatic small cell carcinoma of vaginal origin.

"We do think the abnormal [screen result] was driven by circulating cell-free tumor DNA," Osborne said. He later added that they also "advocate that abnormal [results] prompt consideration of maternal malignancy."

Other times, a positive test may actually indicate confined placental mosaicism. Indiana's Drendel presented the case of a 36-year-old woman whose non-invasive prenatal test from Sequenom indicated a risk for trisomy 13. Additionally, chorionic villus sampling showed a mosaic karyotype while G-banded analysis of amniotic fluid was normal.

The infant was examined one day and 83 days after birth and showed no signed of trisomy 13.

Cord blood, obtained postpartum, was normal. However, karyotyping of four quadrants of the placenta, also postnatal, showed mosaicism for trisomy 13, indicating confined placental mosaicism, Drendel said.

By contrast, Rachel Allen, a genetic counselor at Lescale Maternal Fetal Medicine in New York State, presented two cases in which non-invasive prenatal screens returned false negative results. In the first case, a 35-year-old woman who had conceived through intrauterine insemination received non-invasive prenatal screening results indicating that no aneuploidy had been detected. However, ultrasounds increasingly show evidence of a chromosomal defect — screens conducted during the first trimester estimated a one in six risk for Down syndrome and a one in 36 risk for either trisomy 13 or trisomy 18. Finally, an amniocentesis confirmed that the fetus had trisomy 21.

Similarly, in the second case, this time involving a 37-year-old woman, the non-invasive prenatal screen conducted during the first trimester indicated that everything was within the normal range, while ultrasounds indicated increased risk of Down syndrome. Pathological testing following termination confirmed trisomy 21.

After contacting the test provider, Allen said that for the first case the test did not pick up a sufficient fraction of fetal DNA, and thus the returned results were based mainly on maternal DNA. She said she has requested the same information regarding the second case, but she has not yet heard back.