NEW YORK (GenomeWeb) – Researchers at the Centre for Human Genetics of the University of Leuven in Belgium have found that noninvasive prenatal testing for fetal chromosomal aneuploidies can uncover maternal incidental findings other than cancer that are important for the health of the mother or her fetus.
As a result of their study, which was published online in Genetics in Medicine last week, as well as findings from previous projects, medical genetics centers in Belgium earlier this year adopted guidelines for managing fetal and maternal incidental findings from NIPT and have been reporting these routinely to women undergoing testing.
"NIPT can be seen as broader than just [a test reporting on] fetal trisomies 13, 18, and 21; it becomes a whole pregnancy management tool," Joris Vermeesch, chair of the department of human genetics at Leuven and the senior author of the study, told GenomeWeb.
His team at the University Hospitals Leuven is one of eight academic medical genetics centers in Belgium conducting NIPT and runs on the order of 9,000 tests per year. NIPT is currently not reimbursed by Belgium's public health insurance system and is offered to patients by the center for €390 ($440). In addition, private NIPT providers cover a small segment of the Belgian market, Vermeesch said.
Like the other genetics centers in Belgium, Leuven uses genome-wide low-coverage sequencing for its NIPT, analyzing cell-free DNA extracted from the mother's blood on Illumina HiSeq 2500 or NextSeq 500 sequencers. Similar genome-wide methodologies are employed by Sequenom, Illumina, and BGI, while others, such as Roche's Ariosa and Natera, use targeted approaches. The issue of maternal and fetal incidental findings does not apply to those targeted tests because they only look at specific sections of the genome.
To analyze the sequence reads, the Leuven group uses an analysis pipeline that plots z-scores for small intervals across the genome, thus identifying regions of increased or decreased sequence coverage, which indicates chromosomal or segmental aneuploidies. The analysis method, published in 2015, has since been licensed to Agilent's Cartagenia, which commercialized it earlier this year as part of a software called OneSight.
Analyzing the data using this approach, Vermeesch said, allows testing labs to detect fetal abnormalities in chromosomes other than 13, 18, and 21, which are less common than the three trisomies that most NIPTs are designed to detect and are therefore often classified as fetal incidental findings.
In addition, labs can detect copy number changes in DNA that originates from the mother, which makes up about 90 percent of the cell-free plasma DNA. One type of such maternal incidental findings is cancer, based on aberrations in DNA shed by the tumor. Last year, the Leuven team published a study in which they found cancer — one ovarian carcinoma and two lymphomas — in three of 4,000 women undergoing NIPT who had no symptoms of the disease.
The other type of maternal incidental finding, which was the focus of the most recent study, is constitutional copy number changes that cause or predispose to genetic disease.
For their latest study, the researchers analyzed NIPT results from almost 10,000 women. In about 0.4 percent of them, they found recurrent CNVs that also occur in the normal population and are known as risk factors for developmental disorders, such as autism spectrum and psychiatric disorders. The team decided not to report these findings because either the mother already has the disorder and knows about it, or she does not have it and thus appears to be at a low risk for it. Also, it is not clear from the NIPT whether the fetus has inherited the CNV, which would require an invasive follow-up test.
"If the fetus is positive, then the mother would be faced with the dilemma of whether to continue her pregnancy for a variant she is carrying herself," the researchers wrote.
In about 10 percent of women, the team found non-recurrent CNVs, most of which have no known disease association. However, in five cases, after confirming the results with a microarray test on DNA from the mother's white blood cells, they reported the findings because they seemed clinically relevant for either the mother or her fetus.
Three of those cases involved deletions in one of the X chromosomes, which could affect a male fetus if he inherited that chromosome, or future pregnancies with male fetuses. "Even if the fetus is a girl and we find a serious X chromosome imbalance, we will report it back to the woman because she might be interested in more pregnancies," Vermeesch explained. "We feel it's beneficial for her to know that she is a carrier of a potentially severe disorder."
In another case, they found a mosaic large segmental deletion of chromosome 13 that another test showed was present in about 20 percent of the mother's blood cells. Invasive testing revealed that the fetus did not carry this deletion, but the researchers decided to report it to the woman because she is at risk of passing it on to future children.
The fifth case revealed a deletion in chromosome 21 that includes the RUNX1 gene. Loss of one copy of this gene is known to cause a platelet disorder and to increase the risk of myeloid cancer. The researchers decided to report this result mainly because of the platelet disorder, which posed a risk of severe bleeding during delivery. This allowed the woman's doctor to take precautions for the birth. It turned out that the woman already knew about her platelet dysfunction but did not know the cause.
Following the results of the study, which the center already had in hand earlier this year, as well as in response to previous studies, the Belgian Society for Human Genetics in March published a set of guidelines on how to manage incidental findings detected by NIPT, both fetal and maternal ones.
Genetic centers in Belgium now report incidental NIPT findings routinely, Vermeesch said. Women are informed about the possibility of such findings when they sign up for the test but cannot opt out of receiving them.
Overall, their incidence is low, he noted — about 1 in 2,000 for maternal cancers, 1 in 2,000 for constitutional maternal CNVs of clinical significance, and a little more for fetal incidental findings, "but in terms of health and healthcare, I think it's a major benefit."
Reporting these results adds to the overall cost of the test, though. While the majority of cases don't require additional analysis and "just float through" the largely automated pipeline, Vermeesch said, he estimated that for every 200 tests, one extra day of analysis by an expert is needed. Also, follow-up tests on the mother or invasive tests on the fetus are required to confirm the results.
While Vermeesch advocates for reporting incidental NIPT findings when available, the primary aim of NIPT remains the detection of common fetal trisomies, he said, and targeted tests that cannot reveal incidental findings might have a cost advantage. "So a test which manages that but cannot detect any maternal findings, I don't think that's a bad test," he said.