Is cell-free fetal DNA (cffDNA) testing conclusive for all fetal conditions?

From the Guidelines

No, cell-free fetal DNA (cffDNA) testing is not conclusive for all fetal conditions. This non-invasive prenatal test primarily screens for common chromosomal abnormalities like Down syndrome (trisomy 21), Edwards syndrome (trisomy 18), Patau syndrome (trisomy 13), and certain sex chromosome disorders with high accuracy (over 99% for Down syndrome) 1. However, cffDNA has significant limitations. It cannot detect most genetic disorders, structural abnormalities, neural tube defects, or microdeletions with high reliability. The test analyzes fragments of placental DNA in maternal blood, not direct fetal cells, which can sometimes lead to false results, particularly in cases of confined placental mosaicism where abnormal cells exist in the placenta but not the fetus. For definitive diagnosis of genetic conditions, invasive procedures like amniocentesis or chorionic villus sampling remain necessary. Additionally, cffDNA testing may not be reliable in multiple gestations, with maternal obesity, or when performed too early in pregnancy (before 10 weeks). Patients should understand that cffDNA is a screening tool that indicates risk, not a diagnostic test that provides certainty about fetal conditions.

Some key points to consider:

• cffDNA testing is not a diagnostic test, but rather a screening tool that indicates risk 1
• The test has high accuracy for detecting certain chromosomal abnormalities, but has limitations in detecting other genetic disorders or structural abnormalities 1
• Invasive procedures like amniocentesis or chorionic villus sampling are necessary for definitive diagnosis of genetic conditions 1
• cffDNA testing may not be reliable in certain situations, such as multiple gestations or maternal obesity 1
• Patients should be counseled about the benefits and limitations of cffDNA testing, as well as the options for diagnostic testing or no testing 1

It's also important to note that the test's limitations and potential for false results should be taken into account when interpreting the results. As stated in the study by 1, "cell-free fetal DNA screening only detects trisomy 21,18, and 13 and sex chromosome aneuploidies, so failure to undergo invasive diagnostic testing will miss certain genetic causes of increased nuchal translucency such as Noonan syndrome and 22q11.2 deletion syndrome". Therefore, patients should be advised to undergo diagnostic testing if they receive an abnormal cffDNA result or if they are at high risk for genetic disorders.

From the Research

Cell-Free Fetal DNA Testing Conclusiveness

• Cell-free fetal DNA (cffDNA) testing is not conclusive for all fetal conditions, as it has limitations in detecting certain chromosomal abnormalities 2.
• The test can detect common autosomal and sex chromosome aneuploidies, but it may not detect other clinically significant chromosomal abnormalities, such as mosaic karyotypes, unbalanced chromosomal rearrangements, and rare autosomal trisomies 2.
• Studies have shown that cffDNA testing can detect trisomy 21,18, and 13 with high sensitivity and specificity, but it is not diagnostic for these conditions due to the presence of confined placental mosaicism 3.
• The test performance is affected by the condition under investigation, and it is essential to consider the biological influence of confined placental mosaicism when interpreting the results 3.

Limitations of Cell-Free Fetal DNA Testing

• cffDNA testing has a "no-results" rate, which can be due to various factors, including low fetal fraction or poor sample quality 4.
• The test may not detect all cases of chromosomal abnormalities, and false-negative results can occur 2, 5.
• The positive predictive value of cffDNA testing varies depending on the condition being tested, and it is essential to confirm the results with invasive prenatal testing 6.

Clinical Relevance of Cell-Free Fetal DNA Testing

• cffDNA testing is a valuable tool for prenatal screening, and it can provide high-quality care for pregnant women 6.
• The test can detect a range of chromosomal abnormalities, including trisomy 21,18, and 13, as well as sex chromosome abnormalities and other autosomal aneuploidies 3, 5.
• The clinical relevance of cffDNA testing is highlighted by its ability to detect maternally inherited deletion and duplication copy-number variations (CNVs) and recurrent genomic disorders 5.