Expert Commentary
When is cell-free DNA best used as a primary screen?
At age 38 years, cell-free DNA screening as the first-line test becomes the optimal strategy; at age 40 years, cell-free DNA as a primary screen...
CASE: Low-risk patient requests cell-free DNA screening
Ms. Smith is a 25-year-old woman (G1P0) presenting at 10 weeks’ gestation for her first prenatal visit. She requests cell-free DNA (cfDNA) screening to test for fetal aneuploidy. You explain that the current recommendations are for traditional screening, and inform her that her insurance may not cover the cost of cfDNA screening. She is anxious to learn the sex of her fetus as early as possible, and indicates that she would like to pursue cfDNA. After further discussion of the pros and cons, you order the test.
Prenatal screening is currently recommended in pregnancy for a number of genetic disorders, chromosomal aneuploidy, and structural birth defects in the fetus, regardless of maternal age or family history. There is a broad range of sonographic and maternal serum-based options available for carrying out aneuploidy risk assessment in the first and/or second trimester.
In addition, cfDNA screening for fetal aneuploidy has been clinically available since 2011 and has seen tremendous uptake, particularly in the high-risk population. Recent data indicate that cfDNA screening likewise has very high sensitivity and specificity for trisomy 21 in the low-risk population. 1,2
Many low-risk patients are asking providers about the pros and cons of cfDNA screening, and the appropriateness of this test as a primary screen, including in low-risk patients, is the focus of this article.
What is cfDNA?
cfDNA consists of small (<200 base pairs) fragments of DNA that are present in the maternal serum. After 10 weeks of gestation, about 10% of the total circulating cfDNA in the maternal serum is derived from the placenta and can therefore be used to test for fetal disorders ( FIGURE).3
Although cfDNA screening has been reported to be possible for many different types of genetic conditions, such as RhD type and single-gene disorders such as achondroplasia, 4 most clinical testing is done for fetal chromosomal disorders, including trisomies 13, 18, and 21 and the sex chromosomes. In addition, some laboratories provide testing for other trisomies (16 and 22), as well as some of the microdeletion syndromes (22q11.2, 1p36, Prader Willi syndrome, and others). 5
Analysis of cfDNA to assess the risk for aneuploidy is done using a number of different approaches; these generally all include next-generation sequencing with advanced bioinformatics analyses. 3,6–9 Although the laboratories use somewhat different techniques, all of them share very high sensitivity and specificity for detection of trisomy 21 ( TABLE 1 ).10
Sensitivities for trisomy 13 and sex chromosomal abnormalities are somewhat lower, but the specificity is greater than 99% for each condition, meaning that false-positive rates are very low.
The accuracy of cfDNA in identifying chromosomal aneuploidy depends on several factors, including the relative amount of fetal to maternal DNA, the chance that a chromosome abnormality is present (that is, the risk based on maternal age or results of other screening), and other factors such as the presence of twins or a nonviable second fetus, or the presence of placental mosaicism.
Because of these variables, both false-positive and false-negative results can occur, and the test is not diagnostic but rather is considered a screening test. A positive result does not mean that the fetus is definitely affected with aneuploidy.
