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For decades, the only application of genetic screening that most individuals would ever encounter was testing for aneuploidies in pregnant women, particularly those over age 35. The risk of a fetus being affected by Trisomy 21 (discussed as a clinical entity in Chapter 3) increases gradually as a woman ages, and 35 was somewhat arbitrarily selected as the age at which the risk of Trisomy 21 was sufficiently high to justify testing by amniocentesis or chorionic villus sampling (CVS), each of which carries with it a very small risk of miscarriage or other fetal complications. However, the majority of children with Trisomy 21 are born to women younger than 35, simply because younger women have disproportionately more children than their reduced risk for Trisomy 21.


Less invasive testing has become common practice for women of any age that relies on ultrasound imaging of the fetus (looking for specific characteristics of Trisomy 21 and nuchal translucency, which can be increased in many conditions), and by measuring some combination of alpha-fetoprotein (AFP), estriol, PAPP-A, inhibin, and/or beta-human chorionic gonadotropin (beta-hCG) in the mother's blood. For sequential integrated screening, a first blood draw occurs between 10 and 14 weeks of gestation, the second blood draw between 15 and 20 weeks, with a measurement of nuchal translucency between approximately 11 and 14 weeks. Variations include a single blood draw between 15 and 20 weeks (quad screening), or serum integrated screening (both blood samples without measuring nuchal translucency). Based on the mother's age, these values are used to calculate a modified risk of Trisomy 21, neural tube defects, and a small number of additional conditions in the fetus, and to determine if amniocentesis or further ultrasound imaging might be indicated to rule in or out a diagnosis.

A major advantage of integrated screening is that it relies on physical and serum-based markers that can be disturbed by a range of fetal abnormalities. Mosaic aneuploidies, subchromosomal insertions and deletions, translocations, neural tube defects, and Smith–Lemli–Opitz syndrome are examples of conditions that are still only detectable by integrated screening with follow-up invasive diagnostic testing. Integrated screening is also relatively inexpensive compared to sequencing-based technologies.

These tests should be familiar to any obstetric practitioner and have been available for many years. This type of integrated screening will not be discussed in detail in this text. Also familiar to any who regularly employ this type of screening is the limited specificity of these tests. Sensing a commercial opportunity in prenatal screening, research was directed at improving the sensitivity and specificity of prenatal testing for aneuploidies.


Several high-profile publications have recently highlighted the utility of noninvasive prenatal screening (NIPS) based on cell-free DNA (cfDNA) as a means to detect trisomies[1,2]. After approximately ...

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