New technique could expand number of diseases detected by non=invasive prenatal testing

Researchers at the University of California, San Diego School of Medicine developed a method to expand the types of chromosomal abnormalities that non-invasive prenatal testing (NIPT) can detect. The study uses a semiconductor sequencing platform to identify small chromosomal deletions or duplications, such as occur in Cri du Chat Syndrome and DiGeorge Syndrome, with a simple blood test from the expectant mother.
Detecting these types of small chromosomal abnormalities with conventional techniques usually requires an invasive procedure to obtain foetal DNA, such as amniocentesis or chorionic villus sampling. These procedures carry a small but concerning risk for miscarriage and infection. Since the recent discovery that foetal DNA can be found in the blood of pregnant women, NIPT has been increasingly used to detect certain chromosomal abnormalities through a maternal blood test. So far, though, NIPT is typically used only to detect abnormalities that result from larger chromosomal abnormalities — too many or too few of a particular chromosome, for example, such as occurs in Down syndrome.

“We have found that NIPT can be extended in a way that allows us to zoom in and examine a small segment of a chromosome,” said Kang Zhang, MD, PhD, professor of ophthalmology and chief of Ophthalmic Genetics at UC San Diego School of Medicine, who led the study with collaborators in China. “And 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 analysing circulating tumour DNA for detection of cancer.”
Zhang and his team analysed blood plasma from 1,476 pregnant women with foetal structural abnormalities detected by ultrasound. These women also underwent an invasive diagnostic procedure and conventional foetal DNA analysis. The researchers compared that information to semiconductor sequencing results on circulating foetal DNA obtained from a blood test on the pregnant women at an average gestational age of 24 weeks. The new semiconductor sequencing method detected 69 of 73 (94.5 percent) of abnormalities of a certain size (greater than one million base pairs) detected by the conventional method.

According to the researchers, the cost of NIPT with semiconductor sequencing has the potential to be less expensive than the conventional, invasive prenatal testing method, especially as genetic sequencing technologies continue to decrease in cost.

While promising, there is still need for improvement before this NIPT application can be used clinically. In the study, semiconductor sequencing detected 55 false positives, of which 35 (63.6 percent) were due to maternal, rather than foetal, chromosomal abnormalities. That means the new method will require a validation test to screen out maternal abnormalities.

NIPT with semiconductor sequencing also needs to be tested at early time points in the pregnancy — at 12 to 16 weeks — and the researchers hope to further improve the technique to be able to detect even smaller genetic abnormalities.
The problem is that the more variations they are able to detect, the more they are likely to pick up chromosomal deletions or duplications of unknown clinical significance or with mild clinical consequences. Many of the abnormalities detected could be normal inherited variations. UC San Diego Health