What's Next in Prenatal Genetic Testing?

Jay A. Shendure, MD, PhD


March 25, 2014

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Editor's Note:
At the Future of Genomic Medicine VII conference in March 2014, leading experts in genomic research and clinical application discussed the expanding influence of genomics on the practice of medicine. Medscape asked Jay A. Shendure, MD, PhD, Associate Professor of Genome Sciences at the University of Washington in Seattle, to offer insight on how the advent of noninvasive genetic testing has influenced prenatal assessments and what might be next on the horizon in the field of reproductive medicine.

Medscape: How have advances in genetics and technology influenced prenatal assessment?

Dr. Shendure: Over the past decades, the technologies for testing fetuses for conditions including but not limited to trisomies have advanced. You can see this in nongenetic testing, with such methods as ultrasonography and then serum screening for protein level markers, that these tests have gotten better and better through the years.

Nonetheless, it is also clear that particularly for trisomies, the current tests are quite limited in sensitivity and specificity. That is where we are at.

In parallel to that, various methods have been developed for testing of specific genetic abnormalities prenatally. Generally, these have been done using invasive methods -- relying on amniocentesis or chorionic villus sampling (CVS) to get the material -- rather than noninvasive methods.

In my field in genetics and DNA sequencing, there has been a sea change in the technologies in the past 10 years. In the wake of the Human Genome Project, the cost of sequencing an individual human genome was on the order of $10 million to $100 million. That has dropped by a factor of 100,000 or so in this past decade, and we are now very close to the $1000 genome.

Many people in our field thought that the first applications of these technologies in the clinic would be in the context of trying to assess risk factors for disease in adults. What surprised our field is that the place where these technologies have had the most impact in the immediate term has been in reproductive medicine. Almost overnight, we were seeing such tests as ultrasonography and serum screening getting replaced by sequencing of cell-free DNA in plasma.

All of us are walking around with DNA free-floating as small fragments in our plasma (the plasma being the cell-free component of blood). In us, of course, that material is derived from dead cells. During pregnancy, about 10% of that material derives from the placenta or fetus. By deep-sequencing that material, one can look for a very slight uptick in the number of reads corresponding to certain chromosomes in which trisomies occur.

It turns out that this is a much more sensitive and specific way of screening for trisomies than the current, conventional methodologies.

It is important to emphasize that these are not diagnostic tests. Rather, they are screening tests and still require follow-up with an invasive method to have a confirmatory diagnosis. But they are far superior to the existing or conventional methods in terms of performance.

A couple of years ago, my group set out to try to develop and apply methods for inferring not just the status of trisomies, but also the entire inherited fetal genome, using samples obtained noninvasively from the parents.[1]

In particular, we had samples from an 18-week pregnancy (second trimester); we had blood from the mother and saliva from the father. Using a method called "haplotype-resolved genome sequencing," we were able to obtain a very high-quality sense of what the genomes of the parents were. Using that in conjunction with very deep sequencing of the mixture of the mother's and the child's DNA in the plasma, we were able to accurately infer the genome of the child.

This has only been done a few times at a very high expense. This contrasts with the situation with looking for trisomies, where literally hundreds of thousands of tests have been done in the past few years.

Whether these new approaches will now extend from looking just at trisomies all the way to looking at entire genomes is an open question, but it is something that will play out over the next few years.

Medscape: How might these new research methodologies be implemented in current practice?

Dr. Shendure: There are already efforts to use the same methods to look not just at trisomies, but at other sorts of large changes, such as deletions of megabase scale regions of the genomes, which in some cases are associated with very specific syndromes.

That comes with the risk for a higher false-positive rate -- as you are testing for more things and are looking for things that are smaller, you are invariably going to have this risk of slipping into higher false-positive rates. But that is where some of the companies are already going.

In terms of the methods we use, there is a big leap that one has to take in order to go to the whole genome. So I think you can imagine transitioning to the whole genome at some point, but the cost of sequencing has to drop a bit further before that is practical.

The other question here is: If we are sequencing genomes, what do we report? What do we look at? It is probably not going to be everything. Trying to figure that out is going to be another big challenge, putting aside the technical challenges.

Medscape: Where is research in the field of reproductive medicine headed?

Dr. Shendure: At this stage, it is quite difficult to make a concrete guess about which way things are going to go. Are we going to do lots of carrier screening for recessive disorders preconception, or will a lot of this be done post-conception?

My general sense is that you are going to see more on both ends. There will be more couples that elect to have preconception carrier screening, potentially pursuing preimplantation diagnosis in instances where they identify themselves as carriers for risk alleles of the same recessive gene. But you are also going to see these post-conception tests creeping toward increasing amounts of resolution and, eventually, whole-genome sequencing.

I am very interested in the question, but it is difficult to say at this point.


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