While non-invasive prenatal testing (NIPT) has revolutionized prenatal diagnosis by allowing the detection of certain genetic problems in a fetus, it is currently limited and therefore not many genetic causes of abnormalities. However, a new technique, to be presented at the annual conference of the European Society of Human Genetics today (Saturday), introduces a technology called non-invasive fetal sequencing (NIFS) that will simultaneously screen almost 23,000 genes, as well as all the conditions currently recorded by NIPT, in pregnancies without prior fetal detection.
Presenting the research, Dr Christopher Whelan, a senior computer scientist working in Dr Michael Talkowski’s lab at the Broad Institute of Massachusetts Institute of Technology and Harvard, and the Center of Genomic Medicine at Massachusetts General Hospital, Boston, MA, USA, says the new technique was able to identify a very high proportion of detectable genomics in clinically relevant genomics (GCs). The finding suggests that NIFS can be used as a safer, equally accurate screening tool in all pregnancies, he says.
Most current NIPT methods are low-resolution and focus on only a small number of birth defects, and there is limited standardization among them. Comprehensive testing of all genes related to prenatal diagnosis is only accessible through invasive testing methods.
Currently, many women refuse invasive sequencing methods — amniocentesis and chorionic villus sampling (CVS) — because of the risk to the fetus, associated stress, access difficulties, and cost, even though its diagnostic capacity is high. We were trying to develop a test with similar diagnostic value, but without the risks and other disadvantages.”
Dr. Christopher Whelan, Senior Computer Scientist;
The researchers examined the NIFS in 565 pregnancies at an average of 17 weeks’ gestation. They applied fetal cell-free sequencing (cffDNA) to the analysis of maternal blood samples and used advanced computational methods to identify genetic variations in nearly 23,000 genes (the exome*) in each fetus. Checking their findings against those from direct fetal sequencing after amniocentesis or CVS allowed them to verify their accuracy. They found that NIFS detected approximately 95-99% of genetic variants found by invasive methods, depending on variant type and inheritance pattern, and importantly, 97.2% of genetic variants responsible for clinically significant conditions in the study. “The test performed very well in capturing all clinically relevant variants found by invasive GS that would have been missed by all current non-invasive tests, and in accurately genotyping over 97% of them. There were also some unexpected discoveries, such as twin pregnancies with abnormal tissue and evidence that some mothers had received results of bone marrow malignancy.” Whelan. “This provided further evidence of the power of the technique.”
NIFS is estimated to be much cheaper than the current gold standard of invasive GS, as it relies heavily on capabilities that already exist and are widely available in commercial diagnostic laboratories and does not require a medical procedure. The technique uses only a slightly larger number of sequence reads than is required for invasive GS and can be used earlier in pregnancy than that at which most fetal abnormalities are detectable by imaging. By providing timely access to genetic information and diagnoses, NIFS can reduce overall costs by enabling more informed management of a pregnancy. The test has already been shown to be accurate in samples from pregnancies as early as 10 weeks of gestation, with the proportion of cfDNA in maternal blood originating from the placenta (the fetal fraction) as low as 3%. “In these fractions, we still saw a very high agreement with the GS clinic performed on DNA from invasive tests,” says Dr. Whelan.
The researchers now plan to continue improving the capabilities of NIFS to be able to identify additional clinically relevant genetic variants not assessed by standard exome sequencing. They are also expanding and scaling up their studies to allow NIFS screening for all pregnancies in the future.
“While the diagnostic yields and overall performance of the test were not surprising, it was remarkable that we were able to access and sequence as much of the fetal genome as we did from a simple maternal blood draw during pregnancy. The NIFS stage also allows us to begin capturing, months before birth, the clinically relevant information currently assessed with newborn screening, allowing the early preparation for postnatal management,” says Dr. Whelan. “This is an exciting paradigm shift and turning point for prenatal diagnosis.”
Conference chair Professor Alexandre Reymond, who was not involved in the research, said: “Sequencing the entire genome of an embryo without even taking a sample from that embryo is a tour de force. It immediately opens up treatment and prevention opportunities and means that reproductive medicine will change forever.”
