Gothenburg, Sweden: While non-invasive prenatal testing (NIPT) has revolutionised prenatal diagnostics by allowing the detection of a number of genetic problems in a foetus, it is currently limited and thus misses many genetic causes of abnormalities. But a new technique, to be presented to the annual conference of the European Society of Human Genetics today (Saturday), introduces a technology called non-invasive foetal sequencing (NIFS) that will simultaneously screen almost 23,000 genes, as well as all of the conditions currently captured by NIPT, in pregnancies both with and without a previously-detected foetal anomaly.
Presenting the research, Dr Christopher Whelan, a senior computational scientist working in the laboratory of Dr Michael Talkowski at the Broad Institute of Massachusetts Institute of Technology and Harvard, and at the Center of Genomic Medicine at Massachusetts General Hospital, Boston, MA, USA, says that the new technique was able to identify a very high proportion of the clinically relevant genetic variants that are currently only detectable by invasive genome sequencing (GS). The finding suggests that NIFS may be used as a safer, equally accurate screening tool in all pregnancies, he says.
Most current NIPT methods are low-resolution and focus only a small number of genetic abnormalities, and there is limited standardisation between them. Comprehensive testing of all genes relevant to prenatal diagnostics is only accessible through invasive testing methods. "Currently, many women refuse the invasive sequencing methods -- amniocentesis and chorionic villus sampling (CVS) -- because of the risk to the foetus, related stress, difficulties of access, and cost, even though its diagnostic capacity is high" says Dr Whelan. "We were trying to develop a test with similar diagnostic value, but without the risks and other downsides."
The researchers tested NIFS on 565 pregnancies at an average of 17 weeks of gestation. They applied deep cell free foetal DNA (cffDNA) sequencing to the analysis of maternal blood samples, and used advanced computing methods to identify genetic variants across nearly 23,000 genes (the exome*) in each foetus. Checking their findings against those from direct sequencing of the foetus following amniocentesis or CVS allowed them to verify their accuracy; they found that NIFS detected around 95-99% of the genetic variants found by the invasive methods, depending on variant type and inheritance pattern and, importantly, 97.2% of the genetic variants responsible for clinically important conditions in the study. "The test performed really well in capturing all of the clinically relevant variants found by invasive GS that would have been missed by all current non-invasive tests, and 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 a bone marrow transplant from a male donor that confounded NIPT results," says Dr Whelan. "This provided further evidence of the strength of the technique."
NIFS is estimated to be considerably cheaper than the current gold standard of invasive GS, since it is largely built on capabilities that already exist and are widely available in commercial diagnostic labs and does not require a medical procedure. The technique uses only a slightly greater number of sequencing reads than are needed for invasive GS, and it can be used at an earlier stage in pregnancy than that at which most foetal abnormalities are detectable by imaging. By providing earlier access to genetic information and diagnoses, NIFS can reduce overall costs by allowing more informed management of a pregnancy. The test has already been shown to be accurate in samples from pregnancies as early as 10 weeks gestation, with the proportion of cfDNA in maternal blood that comes from the placenta (the foetal fraction) as low as three percent. "At those fractions, we still saw a very high concordance with clinical GS performed on DNA from invasive testing," says Dr Whelan.
The researchers now intend to keep improving the capacities of NIFS to be able to identify additional clinically-relevant genetic variants that are not assessed by standard exome sequencing. They are also expanding and scaling their studies in order to enable NIFS screening for all pregnancies in the future.
"While the diagnostic yields and overall performance of the test was not a surprise, it was remarkable that we were able to access and sequence as much of the foetal genome as we did from a simple maternal blood draw during pregnancy. In the future, there is a lot of exciting work happening in the field of prenatal treatment for genetic disease. Together with NIFS, this could be transformative by allowing a treatment to be used at an earlier and more effective stage. NIFS also allows us to begin to capture, months before birth, the clinically relevant information that is currently assessed by newborn screening, allowing early preparation for postnatal management," says Dr Whelan. "This is an exciting paradigm shift and inflection point for prenatal diagnostics."
Chair of the conference Professor Alexandre Reymond, who was not involved in the research, said: "Sequencing the entire genome of a foetus without even getting a sample from that foetus is a tour de force. It immediately opens up treatment and prevention opportunities and means that reproductive medicine will be changed forever."
