Goodbye Amniocentesis, Hello Fetal Whole Genome Sequencing...Now What?

Eric Topol, MD, Genomic Medicine, 12:36AM Jan 9, 2013

Eric Topol, MD: Director, Scripps Translational Science Inst.

In this segment, I review the remarkable progress in the past 2 years for fetal DNA analysis through 4 major publications:
1. Lo YM, et al. Sci Transl Med. 2010 Dec 8;2(61):61ra91.
2. Kitzman JO, et al. Sci Transl Med. 2012 Jun 6;4(137):137ra76.
3. Fan HC, et al. Nature.2012 Jul 19;487(7407):320-324.
4. Wapner RJ, et al. N Engl J Med. 2012 Dec 6;367(23):2175-2184.
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Below is a transcript of Dr. Topol's post " Goodbye Amniocentesis, Hello Fetal Whole Genome Sequencing...Now What?." We look forward to your feedback.

Let me review with you a really hot area in medicine – the whole pursuit of fetal whole genome sequencing or chromosomal analysis. This field has gotten legs in the last couple years at a pace that is truly extraordinary.

We've known for a long period of time that there's some fetal DNA in maternal plasma sample, but it was in 2010 that a group from Hong Kong, in collaboration with Sequenom investigators, not only found that more than 12% of maternal plasma DNA content was from the fetus, but was also able to show that this could be sequenced. By bringing together the father's DNA sequence and mother's, you could come up with the sequence of the fetus at an early point in the pregnancy – in the first trimester.

This was followed very quickly in June and July of 2012. In June, Dr Jay Shendure and his team at University of Washington took this to another level of ability to do sequencing, but still involving the paternal sample of DNA. And then, Dr Stephen Quake, in Nature, published in July, just weeks later, showed an ability to get the DNA sequence of the fetus with the maternal sample only. Most recently, in the December 6th issue of the New England Journal of Medicine, there were two papers using arrays, that is, going kind of backwards in technology and not using sequencing, but showing superiority over amniocentesis in terms of accuracy.

This is, of course, what we want to be able to put aside – amniocentesis. About 250,000 of these are done in the US per year, and it carries a small but important risk of miscarriage as well as risk to the mother. Chorionic villus sampling is even more invasive and has more attended risk.

Karyotyping is on the way out, and, at the very least, microarray to pick up the big chromosomal aberrations – Trisomy 15, 18, and 21, or Down syndrome – is now coming into play. There are four companies, one of which was just sold, Verinata to Illumina, the leader in this space in terms of the number of fetal DNA assays being done; Sequenom has done 60,000 of these in the past year and that's expected to at least double in 2013. There are two other companies, Ariosa and Natera, that are also working in the space, so four different companies are competing (and are suing each other).

But we're missing the big picture here. It's not just about being able to diagnose Down syndrome or other major chromosomal aberrations.

Now we're talking about whole genome sequencing and the ability in the first 8-12 weeks of pregnancy, well before the time where termination of pregnancy would be deemed potentially acceptable. This is obviously a big issue from an ethical standpoint, but where do we draw the line? Furthermore, if a child is sequenced and certain things are known at the time of birth, later, when that child grows up and says to the parent, "Why did you do this to me? Why did you get my DNA sequence?," are we prepared for these things?

This is something that's going to be debated hotly, well beyond the question of preempting amniocentesis.

I'm really interested in your thoughts. It's certainly a hot issue with a very intense area of knowledge base that is rapidly growing, which is really good to see. I look forward to your comments and thanks very much for watching or reading this segmen