Fetal chromosomal aneuploidy genomic sequence analysis is a non-invasive prenatal screening that evaluates the probability of specific genetic conditions in a developing fetus. This technique examines fetal DNA from the placenta found in the mother’s blood, offering an early look at genetic health. It is designed to identify the most common chromosomal aneuploidies, which are conditions caused by an abnormal number of chromosomes. The screening is an option for all pregnant women and can be performed as early as the ninth or tenth week of gestation, serving as a preliminary step that indicates likelihood, not a definitive diagnosis.
The Science of Cell-Free DNA Screening
Human cells contain 23 pairs of chromosomes, which house our genetic information. Fetal chromosomal aneuploidy occurs when a fetus has an incorrect number of chromosomes, such as an extra chromosome (a trisomy) or a missing chromosome (a monosomy). These numerical abnormalities can lead to various genetic disorders, some associated with significant health and developmental challenges.
The technology relies on cell-free DNA (cfDNA). During pregnancy, the placenta releases small fragments of its DNA into the maternal bloodstream. This placental DNA is typically genetically identical to the fetus’s DNA and mixes with the mother’s own cfDNA. The amount of this placental cfDNA, known as the fetal fraction, increases as the pregnancy progresses and must be at least 4% for the test to yield a reliable result.
The screening process requires only a standard blood draw from the pregnant person. In the laboratory, technicians use massively parallel sequencing, or next-generation sequencing, to analyze the millions of cfDNA fragments in the blood sample. This technique allows scientists to determine the chromosome of origin for each DNA fragment.
By counting the fragments from each chromosome, the analysis can detect proportional imbalances. For instance, if a fetus has Trisomy 21, there will be a slightly higher proportion of DNA fragments from chromosome 21 in the maternal blood sample than expected. This quantitative analysis enables the screening to identify pregnancies at a higher likelihood for specific aneuploidies.
Common Aneuploidies Detected
This genomic analysis is most frequently used to screen for the three most common autosomal trisomies. The most well-known is Trisomy 21, which causes Down syndrome. Trisomy 18 (Edwards syndrome) and Trisomy 13 (Patau syndrome) are also part of the standard screening panel. Edwards and Patau syndromes are much more severe and often life-limiting.
The analysis can also identify aneuploidies involving the sex chromosomes (X and Y). These conditions include Turner syndrome (Monosomy X), where a female is missing part or all of an X chromosome, and Klinefelter syndrome (XXY), where a male has an extra X. Other aneuploidies like Triple X syndrome (XXX) and Jacobs syndrome (XYY) may also be included in the screening panel.
The test’s predictive accuracy for sex chromosome aneuploidies can be lower than for common autosomal trisomies. This is partly due to factors like confined placental mosaicism, where the aneuploidy exists in the placenta but not the fetus. Some laboratories offer expanded panels that screen for rare aneuploidies or microdeletions, but this is not standard practice.
Understanding Screening Results
This analysis is a screening test, not a diagnostic one, meaning it assesses the probability of a condition rather than providing a definitive answer. Results are reported as either “low-risk” or “high-risk.” A low-risk result indicates the chance of the fetus having a screened aneuploidy is very small, though it does not eliminate the possibility.
A high-risk result signifies an increased likelihood that the fetus has a specific chromosomal condition, but it is not a confirmation. The reliability of a high-risk result is described by the Positive Predictive Value (PPV). The PPV is the probability that a fetus with a high-risk screen actually has the condition, and this value varies based on the specific aneuploidy and the pregnant person’s age.
For example, the PPV for Trisomy 21 is high, meaning a high-risk result is very likely to be a true positive. However, the PPV for other conditions like Trisomy 13 and certain sex chromosome aneuploidies is often lower. This means false positives can occur, where the test indicates high risk but the fetus is unaffected. While rare, false negatives are also possible.
Because of these limitations, no irreversible pregnancy decisions should be made based on screening results alone. A high-risk result is a signal that further, more conclusive testing should be considered to confirm the finding.
Confirmatory Diagnostic Procedures
Following a high-risk result from a genomic screen, the next step is genetic counseling. A genetic counselor helps expectant parents understand the specific results, the PPV for their situation, and the options available for definitive diagnostic testing.
To confirm a suspected aneuploidy, one of two primary invasive diagnostic procedures is offered: chorionic villus sampling (CVS) or amniocentesis. These tests provide a definitive diagnosis because they analyze cells taken directly from the pregnancy, either from the placenta or the amniotic fluid. The choice between them often depends on how far along the pregnancy is.
Chorionic villus sampling is performed earlier in pregnancy, typically between 10 and 13 weeks of gestation, and involves collecting a small sample of placental tissue. Amniocentesis is done later, after 15 weeks, and involves withdrawing a small amount of amniotic fluid, which contains fetal cells, from the uterus.
Both procedures are highly accurate for diagnosing chromosomal conditions but carry a small risk of complications, including miscarriage. The decision to proceed with diagnostic testing is a personal one, weighing the need for a definitive answer against the procedure’s risks.