All individuals have fragmented DNA in their blood that is not contained in the nucleus of cells but free floating and can be assayed from plasma or serum. The discovery that during pregnancy maternal plasma contains fetal cell- free DNA derived from trophoblast cells of the placenta, which have the same genome as the fetus, has drastically changed the approach to prenatal screening for fetal chromosomal anomalies. After 10 weeks of gestation, the proportion of cell- free DNA in maternal blood that is derived from trophoblast, referred to as fetal fraction, is ~5% to 20%. The circulating cell- free DNA can be analyzed using high- throughput DNA sequencing technologies to noninvasively evaluate whether the fetus has aneuploidy. This led to the introduction and rapid expansion of cell- free DNA- based noninvasive prenatal screening (NIPS) (also known as noninvasive prenatal testing [NIPT]) for trisomies 21, 13, and 18, with sensitivities and specificities approaching 99% for trisomy 21 (Table 1). A growing number of commercial NIPS tests on the market assess variable combinations of testing for these common aneuploidies, combined with sex chromosome abnormalities (see Table 1), other rare autosomal aneuploidies, and selected microdeletions. A few providers also offer genome- wide analysis of copy number gains and losses. Cell- free DNA can also be used to detect Y chromosome sequences for the purposes of determining fetal sex.

Table1. Sensitivity, Specificity, Positive and Negative Predictive Values of Cell- Free DNA Screening for Chromosomal Abnormalities

Analyzing cell- free DNA for aneuploidy detection is done in different ways, but the common principle is to detect the small increased amount of total cell- free DNA from a particular chromosome if the fetus has trisomy. In one approach, referred to as the counting approach, total cell- free DNA is subjected to next generation sequencing, and millions of molecules of DNA are each mapped to its particular chromosome of origin (Fig. 1). The number of molecules that map to each chromosome is counted, without knowing which of the fragments are fetal and which are maternal. Because chromosome 21 constitutes ~1.5% of total DNA in the genome, ~1.5% of total fragments should be assigned to chromosome 21 if the fetus and mother have two normal copies of chromosome 21. If, however, the fetus has trisomy 21, more sequences than expected will map to chromosome 21, and this can be measured relative to the number of sequences that map to an appropriate reference chromosome or to the full set of chromosomes not including chromosome 21. Similar calculations can be used for the other autosomal trisomies and for sex chromosome aneuploidies. Other commonly used approaches evaluate not only the amount of cell- free DNA coming from each chromosome but also take into account differences in the nucleotide sequence between the maternal and fetal DNA (polymorphisms) to assign whether the sequenced DNA comes from the maternal or the fetal DNA.

Fig1. Schematic diagram of noninvasive prenatal screening for trisomies by analysis of cell- free DNA in maternal blood. Fetal component of maternal plasma cell- free DNA is shown in red; maternal contribution is in blue. Millions of molecules of DNA are sequenced and assigned to each chromosome by computerized alignment against the human genome. Highly accurate measurements of small but significant increases in the fraction of molecules assigned to chromosome 13, 18, 21, or X compared to a reference indicate increased risk for trisomy of each of these chromosomes.

Although cell- free DNA provides a substantial improvement in sensitivity and specificity of screening for fetal trisomies (particularly trisomy 21), it remains a screening test, not a diagnostic test. A result that indicates the fetus is at increased risk for a chromosomal abnormality should be confirmed by diagnostic testing, either via CVS or amniocentesis (presented later in this chapter). If prenatal diagnostic testing is declined, it should be confirmed on a blood sample obtained from the infant after birth. Furthermore, the accuracy by which NIPS can predict that the fetus is affected by a chromosomal abnormality, calculated as the positive predictive value (PPV) varies. The PPV depends on the prevalence of the condition tested for, and PPV for common trisomies is lower for younger women but is not affected by age for monosomy X (see Table 1). The accuracy by which NIPS correctly predicts that a fetus is unaffected, the negative predictive value (NPV), is greater than 99% for all aneuploidies, as there are far more unaffected fetuses in the population in all age groups. PPVs are typically lower for rarer conditions, such as rare autosomal trisomies and microdeletions and duplications. Therefore the current recommendation in the United States and many other countries is that NIPS is not recommended for screening for conditions other than the common aneuploidies (trisomies 21, 13, 18). As the technology continues to improve and more data are accumulated, this guidance may change in the future. For example, newer data on screening performance for 22q11.2 deletions are promising.

Other Current and Future Applications of Cell- Free Fetal DNA Analysis

Cell- free fetal DNA in maternal plasma is also used to genotype the fetus at the RH locus and to determine fetal sex. In some countries, noninvasive tests for a growing number of single- gene disorders in high- risk pregnancies are already available (Table 2), and noninvasive cell- free DNA sequencing tests for small panels of genes have been introduced already but with still limited validation, and cell- free DNA- based sequencing of the entire fetal genome has been explored on a research basis. Refinements in the analysis of cell- free DNA will likely make noninvasive testing for many other genetic disorders available in the future.

Table2. Cell- Free DNA Assays Developed for Single- Gene Disorders

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مواضيع ذات صلة

The Origin and Frequency of Different Types of Mutation

Screening for Down Syndrome and Other Aneuploidies

Screening for Neural Tube Defects

Genetic Alterations Associated with Acromegaly

The Profession of Genetic Counseling

Applying Genomics to Individualize Cancer Therapy

The Role of Epigenetics in Cancer

Screening for Genetic Susceptibility to Disease

Pharmacogenomics

Monogenic Diseases Show One of Three Patterns of Inheritance

Tumor Suppressor Genes in Autosomal Dominant Cancer Syndromes

Activated Oncogenes in Hereditary Cancer Syndromes