A new technology called non-invasive fetal sequencing (NIFS) was introduced at the annual conference of the European Society of Human Genetics on June 12. The technique allows simultaneous screening of almost 23,000 genes and all conditions currently detected by non-invasive prenatal testing (NIPT), in pregnancies both with and without previously identified fetal anomalies.
Dr. Christopher Whelan, a senior computational scientist at the Broad Institute of Massachusetts Institute of Technology and Harvard, as well as at the Center of Genomic Medicine at Massachusetts General Hospital in Boston, said that NIFS identified a high proportion of clinically relevant genetic variants currently only detectable through invasive genome sequencing. "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," Whelan said. "This provided further evidence of the strength of the technique."
Current NIPT methods are limited to detecting only a small number of genetic abnormalities with low resolution and lack standardization between tests. Comprehensive testing for all genes related to prenatal diagnostics is typically available only through invasive procedures.
Researchers tested NIFS on 565 pregnancies averaging 17 weeks gestation using deep cell-free fetal DNA sequencing from maternal blood samples. Advanced computing methods allowed identification of genetic variants across nearly 23,000 genes in each fetus. When compared to direct sequencing following amniocentesis or chorionic villus sampling (CVS), NIFS detected about 95-99% of genetic variants found by invasive methods depending on variant type and inheritance pattern, including detection rates as high as 97.2% for clinically important conditions.
NIFS is estimated to be considerably less expensive than current gold-standard invasive genome sequencing because it uses existing capabilities available in commercial diagnostic labs and does not require medical procedures. The test can be used earlier in pregnancy than most imaging-based detection methods; it has shown accuracy even when administered as early as ten weeks gestation with low levels (three percent) fetal fraction in maternal blood samples.
Whelan said researchers plan to improve NIFS so it can identify additional clinically relevant variants not assessed by standard exome sequencing and are working toward expanding studies for future use in universal pregnancy screening. "While the diagnostic yields and overall performance...was not a surprise, it was remarkable that we were able to access and sequence as much...from a simple maternal blood draw during pregnancy," Whelan said.
Professor Alexandre Reymond, chairing the conference but not involved with this research, said, "Sequencing the entire genome of a fetus without even getting a sample from that fetus is a tour de force. It immediately opens up treatment and prevention opportunities and means that reproductive medicine will be changed forever."
