DNA sequencing has created its way to the clinic in a dramatic new way: detecting chromosomal defects quite early in pregnancy. We’ve identified for 25 years that traces of fetal DNA can be detected in a pregnant women’s blood. But these traces are quite modest, and till now, we just didn’t have the technological innovation to detect an further copy of a chromosome, in which the DNA itself is otherwise typical.
Final week, in a research published in The New England Journal of Medication, Diana Bianchi and colleagues showed how DNA sequencing can detect an additional copy of a chromosome with outstanding accuracy. This report heralds a new era in prenatal DNA testing.
Very first, some background: 3 copies of chromosome 21 causes Down syndrome, a genetic condition that leads to intellectual disability and development delays. Down syndrome is also called trisomy 21, exactly where trisomy = three copies of a chromosome as an alternative of the regular two copies. Much much less widespread is Edwards syndrome, induced by 3 copies of chromosome 18. Edwards syndrome, or trisomy 18, has a lot more serious effects, with the huge majority of pregnancies not creating it full term. Possessing an added copy of any other chromosome virtually usually triggers an early miscarriage. For numerous reasons, prospective dad and mom want to know if a fetus carries any of these abnormalities.
The accuracy of the new test is outstanding. Out of 1914 young, healthful pregnant females, there have been just eight pregnancies in which the fetus had an additional chromosome, and the test detected all eight. What was most remarkable was its minimal false positive price: in complete, the new DNA-primarily based check had just 9 false positives (for either chromosome 21 or chromosome 18 trisomy). By contrast, the typical screening test, which also identified all eight correct situations, made 80 false positives, almost 9 times as numerous as DNA sequencing.
Why does this matter? In most circumstances, girls with a optimistic result on one of these tests will opt for amniocentesis (“amnio”), an invasive method exactly where a medical professional inserts a extended needle immediately into the womb and collects a sample of amniotic fluid. Amnio nearly always offers a definitive solution about Down syndrome. With the standard approach, its false optimistic fee is so higher that even with a positive test, in excess of 95% of amnios will be unfavorable, versus fifty five% with the new DNA sequencing test. Or to place it another way, as Bianci et al. wrote:
“if all women with constructive results had .. decided to undergo an invasive method, there would have been a relative reduction of 89% in the quantity of diagnostic invasive procedures.”
89% fewer invasive procedures is a enormous reduction, not only in fees but in stress for the mothers and fathers and danger to the baby (due to the fact amnio carries a little danger of miscarriage).
With DNA sequencing receiving faster and cheaper each and every yr, it may possibly be surprising that we are only now seeing it utilized to detect trisomy. The trouble with detecting an extra copy of a chromosome is that the DNA sequence itself is normal. If you sequence the genome, you will not discover any mutations that indicate that the fetus has an added chromosome copy. This is exactly where the outstanding efficiency of up coming-generation sequencing comes in.
In a matter of hrs, modern day sequencing machines can sample hundreds of thousands of small fragments of DNA. We can use computational evaluation to decide which fragments come from the fetus, and how numerous came from every single chromosome. If any chromosome has three copies, we’ll see a 50% increase in DNA from that chromosome. The power of sequencing lies in big numbers: since we can sequence a lot of fragments from every chromosome, a 50% increase is straightforward to detect.
The technique that Bianchi used to detect trisomy was published in 2011 by Amy Sehnert and colleagues from 2011, some of whom are contributors to the new NEJM examine. [Side note: they use a software program program known as Bowtie, produced by my former student Ben Langmead, to do the examination.] The technique is probably to get even much better in excess of time, more reducing the false positive price.
The American University of Obstetricians and Gynecologists has presently advisable DNA testing for pregnant females at higher chance of fetal aneuploidy (an extra chromosome). To be precise, they advocate that large-threat pregnant ladies be supplied fetal DNA testing as an selection, after they get genetic counseling. This new review, which was carried out in a low-threat population, exhibits that the positive aspects of prenatal DNA testing need to offered to all ladies.