David has written previously about the different types of screening tests for Down syndrome (trisomy 21). Although these tests have certainly gotten better over time, even the best among them is subject to less than perfect sensitivity (90%) and a false positive rate of between 2 and 5%. Given the prevalence of Down syndrome, this means that out of 16 women that screen positive for Down syndrome, only one will carry an affected infant. Therefore, 15 women are unnecessarily subject to potentially dangerous amniocentesis procedure. Recently, there have been reports of some molecular testing that may change the way we screen women for Down syndrome forever.
In 1997, researchers discovered that DNA from a fetus actually circulates in the blood of the mother during pregnancy. It goes away very rapidly after the baby is delivered. This amazing observation meant that it might be possible to diagnose certain diseases in the fetus by simply taking a sample of mom's blood. Since then, many studies have been done to try to develop a method to screen for Down syndrome using maternal circulating fetal DNA.
In 2008, two papers were published, from different laboratories, which described the detection of trisomy 21 using "massively parallel genomic sequencing" (MPGS). In this method, DNA fragments are isolated from a sample of mom's blood. These include a mix of mom's DNA and infant DNA. The ends of the DNA fragments get a small piece of adapter DNA attached to it which allows the fragments to hybridize to a surface coated with the complimentary adapter DNA sequence. All the fragments bound to the surface are then simultaneously amplified. After amplification, the DNA is sequenced. With the help of bioinformatics, the researchers are able to determine what chromosome the DNA fragment came from. The number of sequences that originate from a particular chromosome is counted and tabulated for each chromosome. If a fetus has an extra chromosome, then the percentage of chromosome 21 fragments is higher than expected. Early studies suggested that this method might work with high sensitivity, but the studies were small.
Recently, a very large validation study was published that demonstrated that this method is not only sensitive, but also had a very low false positive rate.
The study involved women at high risk of delivering an infant with Down syndrome from 27 prenatal diagnostic centers worldwide. The authors compared fetal karyotyping (the gold standard for diagnosing Down syndrome) to MPGS in 212 Down syndrome and 1484 matched normal pregnancies. Their research demonstrated that MPGS was able to detect Down syndrome with 98.6% sensitivity and only a 0.20% false positive rate. This represents a huge improvement over currently available methods.
Currently, MPGS is only available at specialized centers and is quite expensive. However, with the advent of studies such as this, the availability and price of MPGS is bound to come within reach. Hopefully, within the next 10 years, we will see the end of maternal serum screening for Down syndrome as we currently know it.