Читать книгу Protocols for High-Risk Pregnancies - Группа авторов - Страница 45

In 2011, cell‐free DNA screening (also known as noninvasive prenatal testing or noninvasive prenatal screening) became clinically available as a screening test for aneuploidy. This screening test relies on the analysis of cell‐free DNA (cfDNA) fragments in the maternal circulation. After 10 weeks of gestation, approximately 10–15% of the cfDNA in the maternal serum is of placental origin and therefore reflects the fetal DNA. Clinical testing measures the chromosomal contribution of the cfDNA in the maternal circulation to determine whether there is over‐ or underrepresentation of targeted chromosomes. Different laboratories use different approaches, including massively parallel shotgun sequencing (MPSS), a targeted microarray approach, or targeted sequencing using single nucleotide polymorphisms (SNPs); performance for aneuploidy screening is generally comparable between platforms. Standard cfDNA screening tests for trisomies 13, 18, and 21, and can also assess the sex chromosomes to determine fetal sex and, in some cases, screen for sex chromosomal aneuploidy.

The accurate performance of cfDNA screening depends on the presence of adequate fetal (placental) cfDNA, referred to as the “fetal fraction.” In some laboratories, a result is not provided when the fetal fraction falls below a prespecified level; this cut‐off is typically about 4%. Early gestational age, increasing maternal body mass index, and fetal aneuploidy are associated with a lower fetal fraction and increase the chances of a failed test.

Studies of test performance for cfDNA screening report a >99% detection rate for fetal trisomy 21 and 98% detection for trisomy 18 with a combined false‐positive rate (FPR) of 0.13–0.25%. Because trisomy 13 is a rare disorder, data are far more limited but reported detection rates vary from 40% to 100% in individual studies. The detection rate of sex chromosome aneuploidy is also difficult to determine due to limited data.

Importantly, these data were calculated for patients with a reported result, and as many as 3–4% of samples result in test failure. Test failure, particularly in the setting of low fetal fraction, is associated with an increased risk of aneuploidy and patients should be counseled accordingly and offered follow‐up testing.

While cfDNA screening has excellent performance in detection of trisomy 21, both false‐positive and false‐negative results can occur, particularly with low fetal fraction. The presence of mosaicism or a vanishing twin may result in false‐positive cfDNA results. Standard cfDNA screening tests do not provide risk assessment for other chromosomal, genetic, or structural disorders. Some laboratories offer expanded cfDNA panels to test for chromosomal microdeletions, rare autosomal trisomies, or genome‐wide copy number variants. Such tests have not been clinically validated, performance characteristics are unknown, and these are generally not recommended at the present time.