Non-invasive prenatal testing (NIPT) has revolutionized prenatal diagnosis by allowing the detection of many genetic problems in the fetus, but it currently has limitations and therefore misses many genetic causes of abnormalities. But new technology being presented today (Saturday) at the annual meeting of the European Society of Human Genetics, called non-invasive fetal sequencing (NIFS), will simultaneously screen for almost 23,000 genes and all the conditions currently captured by NIPT, regardless of the presence or absence of previously detected fetal abnormalities.
Christopher Whelan, a senior computational scientist working in the lab of Dr. Michael Tarkowski at the Massachusetts Institute of Technology and Harvard’s Broad Institute and the Center for Genomic Medicine at Massachusetts General Hospital in Boston, Massachusetts, who published the study, said this new technology allowed them to identify a very high proportion of clinically relevant genetic variants that are currently only detectable through invasive genome sequencing. (GS). The findings suggest that NIFS could be used as a safer and equally accurate screening tool in all pregnancies, he says.
Most current NIPT methods have low resolution, focus only on a small number of genetic abnormalities, and their standardization is limited. Comprehensive testing of all genes relevant for prenatal diagnosis is only possible through invasive testing methods.
Currently, many women refuse invasive sequencing methods such as amniocentesis and chorionic villus sampling (CVS) due to risks to the fetus, associated stress, difficulty of access, and cost, despite diagnostic capabilities. We were trying to develop a test with similar diagnostic value but without the risks and other drawbacks. ”
Dr. Christopher Whelan, Senior Computational Scientist
Researchers tested NIFS on 565 pregnancies with an average gestational age of 17 weeks. They applied deep cell-free fetal DNA (cffDNA) sequencing to the analysis of maternal blood samples and used advanced computing techniques to identify genetic variations across approximately 23,000 genes (exome*) in each fetus. We were able to confirm that our results were accurate by comparing them with results obtained from direct sequencing of fetuses after amniocentesis or CVS. They found that NIFS detected approximately 95-99% of the genetic mutations found with invasive methods, depending on the variant type and inheritance pattern, and, importantly, detected 97.2% of the genetic mutations that caused clinically significant symptoms in this study. “The test performed very well in capturing all clinically relevant mutations found in invasive GS that would have been missed by all current non-invasive tests, and accurately genotyped more than 97% of them. There were also some unexpected findings, including twin pregnancies with abnormal tissue and evidence that some mothers had received bone marrow transplants from male donors, which confounded NIPT results,” says Dr. Whelan. “This was further evidence of the strength of this technology.”
NIFS is estimated to be significantly cheaper than the current gold standard for invasive GS because it is built primarily on existing capabilities widely available in commercial diagnostic laboratories and does not require medical intervention. This technique uses only a slightly higher number of sequencing reads than that required for invasive GS and can be used in the early stages of pregnancy when most fetal abnormalities can be detected by imaging. By providing early access to genetic information and diagnosis, NIFS can enable more informed pregnancy management and reduce overall costs. The test has already been shown to be accurate in pregnancy samples as early as 10 weeks of gestation, with only 3% of cfDNA from the placenta in maternal blood (fetal fraction). “Even at these rates, we found very high concordance with clinical GS performed on invasive testing DNA,” says Dr. Whelan.
The researchers now intend to continue to improve the ability of NIFS to identify more clinically relevant genetic variants that cannot be assessed by standard exome sequencing. They are also expanding and scaling the study to enable NIFS screening for all pregnancies in the future.
“While the diagnostic yield and overall performance of the test was not surprising, it is noteworthy that we were able to access and sequence as much fetal genome as was obtained from a simple maternal blood draw during pregnancy. There is a lot of exciting research being done in the area of prenatal treatment of genetic diseases in the future. It could be transformative, allowing treatments to be used at a more effective stage. NIFS also allows us to begin collecting clinically relevant information months before birth, which is now being assessed through newborn screening, allowing for early preparation for postnatal management,” says Dr. Whelan. “This is an exciting paradigm shift and turning point for prenatal diagnostics.”
Professor Alexandre Raymond, chair of the conference, who was not involved in the study, said: “Sequencing the entire genome of a fetus without even taking a sample from the fetus is an absolute masterpiece. This opens up immediate opportunities for treatment and prevention and means a permanent change in reproductive medicine.”
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European Society of Human Genetics
