HOW ARE GENOME SEQUENCING TECHNOLOGIES CHANGING PRENATAL TESTING?
One area where genomics is revolutionizing current practice is prenatal DNA testing. Prenatal DNA testing is a common practice used to monitor whether fetuses may have abnormal chromosome numbers (aneuploidy), which occurs about once in every 160 live births. It can also be used to identify mutations in genes. Prenatal DNA testing is commonly used when the chances of genetic abnormalities are high due to family history or advanced maternal age (e.g., greater than 35 years). Down, Edwards, and Patau syndromes are examples of having extra copies of chromosome 21, 18, and 13, respectively, and are the most common autosomal aneuploidies. Turner syndrome results from the lack of the second copy of X chromosome in women. The consequences of aneuploidies vary widely among the various syndromes and with the affected person but can include intellectual disability, congenital heart defects, and infertility, among others.
Until relatively recently, nearly all prenatal testing was performed by amniocentesis or chorionic villus sampling (CVS). During amniocentesis, a needle is used to collect fluid harboring fetal cells from the amniotic fluid surrounding the fetus whereas CVS samples the placenta. The cells are then analyzed for alterations in chromosome number or structure. Both of these tests are invasive, however, and carry a risk, albeit low, of miscarriage.
A more recent test involving genomics, noninvasive prenatal testing (NIPT), is now revolutionizing genetic testing of the fetus. It has been known for some time that fetal cells circulate in the mother’s blood; later it was discovered that fetal DNA also can be found in the mother’s blood. The amount is very low in early pregnancy—approximately 3%–4% of the cell- free DNA in the blood is derived from the fetus at five weeks, and the fraction rises to 10%–15% by the eighth month of pregnancy. With the advent of high-throughput sequencing, it is now possible to analyze the fetal DNA from the maternal blood—the paternal sequence in the fetal DNA has variants that are distinct from the maternal DNA. Originally, this approach was established to identify copy number variations (CNVs). Detection of CNVs is particularly important because births with aneuploidies are quite common, and duplication or deletion of genes can have developmental and/or health consequences. The aforementioned aneuploidies are relatively easy to detect using high throughput sequencing (Figure 1). In fact, a prenatal diagnostic test has recently been approved by the Food and Drug Administration (FDA) for detecting trisomies of chromosomes 21, 18, and 13 in a mother’s blood. The method is highly accurate and has a sensitivity of greater than 99% with few false positives. Smaller chromosome abnormalities also can be detected with this technology, although such tests are not yet approved by the FDA.
Figure 1. General strategy for genome analysis of circulating fetal DNA. Fetal DNA circulates in pregnant women throughout pregnancy. Total DNA is extracted from the blood fluid (i.e., plasma), sequenced, and the fetal DNA sequence deduced. Presently, this test is approved for detecting aneuploidies in the fetus, but the technology can be used to sequence entire genomes before birth.
The advantage of noninvasive fetal DNA testing is that it is very simple and can be performed using blood drawn during a routine prenatal checkup. It is only a matter of time before this test will be available for all pregnant women and may become routine. It is likely that some women may decline the noninvasive fetal DNA test, but it is easy to envision that a large number of parents will opt for the test to gain insight into their child’s likelihood of having a severe genetic disease.