A new blood test can detect thousands of foetal genetic conditions, offering a safer alternative to invasive procedures such as amniocentesis and chorionic villus sampling (CVS) for pregnancies where a genetic disorder is suspected. The technique, known as non-invasive foetal sequencing (NIFS), was presented at the European Society for Human Genetics conference in Gothenburg on Saturday by researchers from the Broad Institute of MIT and Harvard, Massachusetts General Hospital (MGH) and Brigham and Women’s Hospital.
What the test can detect
NIFS analyses cell-free foetal DNA fragments circulating in the mother’s bloodstream to screen for the majority of serious genetic conditions that appear on major newborn sequencing and foetal anomaly panels, including the over 2,500-gene Genomics England foetal anomalies panel. In validation studies it identified conditions such as Noonan syndrome, Charge syndrome, Stickler syndrome, achondroplasia and cystic fibrosis, along with dozens of other rare genetic disorders. According to Dr Christopher Whelan, a senior computational scientist at the Broad Institute and the Center for Genomic Medicine at MGH, “This test is capable of detecting thousands of serious genetic conditions … including many where early diagnosis may change pregnancy, delivery or newborn care.”
Existing non-invasive prenatal tests (NIPT) are limited to a small number of chromosomal abnormalities such as Down’s syndrome. NIFS, by contrast, expands the screening reach to include almost all genetic conditions on newborn screening panels. The researchers envision it becoming a frontline test for pregnancies where an ultrasound or other screening has flagged an anomaly — cases in which many women currently decline invasive sequencing because of the associated risks, stress, access difficulties or cost.
How the NIFS test works and its diagnostic accuracy
The test exploits the presence of cell-free foetal DNA (cffDNA) in the mother’s blood, most of which originates from the placenta. Using advanced sequencing techniques, the team analysed these tiny DNA fragments to identify genetic variants across nearly 23,000 genes — effectively covering the entire foetal exome, the protein-coding region of the genome. Sophisticated computational algorithms and bioinformatic pipelines are then used to distinguish foetal genetic signals from the background of maternal DNA, allowing accurate identification of single-base changes, small insertions and deletions that are present in the foetus but not the mother.
NIFS was tested on 565 pregnancies at an average of 17 weeks of gestation (with a separate proof-of-principle analysis involving 51 individuals). By sequencing the fragments and applying the computational methods, the researchers identified variants and then compared their findings with results from either amniocentesis or CVS. The test detected 95–99% of the genetic variants found by those invasive methods and more than 97% of clinically relevant variants — a concordance rate of 97.2% for variants linked to significant conditions. Importantly, NIFS has shown accuracy even at early gestational ages, with successful results from samples as early as 10 weeks when the foetal fraction (the proportion of cffDNA) can be as low as 3%.
The technology also proved capable of handling complex cases such as twin pregnancies and of revealing maternal confounders — for example, bone marrow transplants from male donors that can distort traditional NIPT results. Dr Whelan and his colleagues, including senior author Dr Michael Talkowski (director of MGH’s Center for Genomic Medicine and an associate professor at Harvard Medical School), estimate that NIFS would be considerably cheaper than invasive genome sequencing because it leverages existing commercial diagnostic laboratory capabilities and does not require a medical procedure.
Implications and expert opinions
Professor Alexandre Reymond of the University of Lausanne, who was not involved in the research, described the work as a “tour de force”. He said: “Sequencing the entire genome of a foetus without even getting a sample from that foetus … immediately opens up treatment and prevention opportunities and means that reproductive medicine will be changed for ever.” The test could allow for detection and intervention months before birth, potentially supplanting some newborn screening procedures and enabling early preparation for postnatal management.
Professor Angus Clarke, a clinical geneticist at Cardiff University, called the NIFS technique a “very impressive technical feat” that would be especially helpful where a genetic condition is suspected and prenatal treatment is possible. However, he also sounded a note of caution. Using the test for exploratory screening, rather than to answer a specific clinical question, could turn up variants of uncertain significance (VUS) — genetic changes whose impact is not yet understood. This, he warned, could cause significant anxiety for parents and lead to unnecessary surveillance and medicalisation of babies. “You’re putting parents in a really difficult position,” Clarke said. “When you don’t have a problem that you’re looking for an answer to, just coming out with potential answers can cause more problems.” The challenge of interpreting VUS, alongside the ethical considerations of incidental findings such as predisposition to unrelated conditions, remains a key issue as prenatal genomics advances.