Prenatal testing has been in practice for decades, helping doctors prepare women for the births of their babies. But until non-invasive prenatal testing (NIPT) came on the market recently, some prenatal tests can be quite invasive and risky, especially for women who carry high-risk fetuses. To push NIPT technology further, a group of researchers at the University of California, San Diego School of Medicine have devised a way to expand the use of NIPT
to detect smaller, subtler chromosomal abnormalities.
NIPT came about with the discovery of cell-free fetal DNA that’s present in the blood of the expectant mothers. By taking a blood sample from the mother, researchers could isolate DNA belonging to the baby and run a gamut of genetic tests to inform the health condition of the baby. This new platform offers many advantages over conventional methods like amniocentesis
or chorionic villus sampling
(CVS), which are invasive, painful, and carry a risk for miscarriage and infection. Thus far, however, NIPT has been limited to detecting large chromosomal aberrations, like whole duplication of chromosome 21 in Down Syndrome.
The research team, led by Dr. Kang Zhang, attempted to “zoom in and examine a small segment of a chromosome” by combining NIPT with semiconductor sequencing
. They collected blood from 1,476 pregnant women whose ultrasounds had revealed abnormal fetal structures. The average gestational age for the pregnant women was 24 weeks. The researchers then sequenced the maternal blood using semiconductor sequencing, a form of “sequencing by synthesis” based on the release and detection of hydrogen ions. The sequencing results were validated with array comparative genomic hybridization and then compared to the conventional invasive diagnoses made for each of the women. Dr. Zhang published
that this method could detect subchromosomal duplications and deletions with 94.5% sensitivity compared to the conventional methods.
While remarkable, there are several caveats to the study. First, the high sensitivity was achieved by increasing sequencing depths from 3.5 million read to 10 million reads and restricting the size of chromosomal abnormalities to greater than 1 Mb. This means that the reliability of the method is dependent on sequencing depth, which is not surprising but should be taken into consideration. Second, the researchers reported 55 false positives, of which 35 were due to maternal chromosomal abnormalities. To increase the specificity for their method, the team has to conduct additional validation tests to screen out maternal DNA contamination.
Dr. Zhang and his research team aim to improve their method to detect chromosomal abnormalities less than 1 Mb, and also at an earlier gestational age of 12 to 16 weeks. He also expressed hope that the new platform can be extended to diagnosing other conditions.
"While this study focused on cell-free DNA sequencing in pregnant women, this method could be applied more broadly to other genetic diagnoses, such as analyzing circulating tumor DNA for detection of cancer." – Dr. Kang Zhang.
As a word of caution, Dr. Zhang noted that with increased detection potential comes the increased likelihood of uncovering chromosomal aberrations of unknown clinical significance
. "If our NIPT extension is put into clinical practice, great care must be taken in presenting results and providing appropriate counseling to patients," cautions Dr. Zhang.
Watch the video to learn more about fetal DNA and NIPT!