**2. Chromosomal anomalies**

Chromosomal anomalies are produced by genomic or chromosomal mutations. Chromosomal anomalies could be numerical and structural. Numerical chromosomal anomalies produce an important genomic imbalance and the phenotype of carriers is severely affected. Numerical chromosomal anomalies are represented by aneuploidies (trisomies, monosomies, etc.) and polyploidies (triploidy and tetraploidy). These are generated by errors during meiosis, fertilization or first mitosis of embryo. The most common error is chromosomal non-disjunction during the first meiosis that generates an aneuploidy (trisomy or monosomy) and is associated with advanced maternal age. Structural chromosomal anomalies are generated by changes of structure of one or multiple chromosomes and could be divided into unbalanced and balanced anomalies. Unbalanced structural chromosomal anomalies are characterized by absence (partial monosomy) or supplementary (partial trisomy) chromosomal segment(s) and produce a genomic imbalance that induces an abnormal phenotype. Balanced chromosomal anomalies are characterized by changes in the position of some chromosomal segments, but the quantity of genetic material remains unchanged. The phenotype of carriers is usually normal, but they could present a malsegregation of derivative chromosomes during meiosis that generates formation of gametes with genomic imbalances. Fertilizing such gametes results in embryos with unbalanced chromosomal anomalies [1].

Unbalanced chromosomal anomalies produce a severe modification of phenotype and generate chromosomal diseases. The majority of such anomalies do not permit survival of the embryo and the pregnancy ends in miscarriage. Other anomalies—gonosomal trisomies (XXX, XXY, XYY), some autosomal trisomies (21, 18, 13), some cases with X monosomy, some partial monosomies or partial trisomies—are compatible with life, but children have a chromosomal disease [1].

**1. Introduction**

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that allow a prenatal diagnosis [1].

**2. Chromosomal anomalies**

chromosomal anomalies [1].

Chromosomal anomalies represent large genomic modifications that could be identified using light microscope. Apart from these characteristics, many chromosomal anomalies produce severe changes in the phenotypes of carriers that induce a high rate of miscarriage (>50% of spontaneous abortions are produced by a chromosomal anomaly) and chromosomal disorders in neonates and infants (global incidence in newborns is 1%). Early identification of chromosomal anomalies during the prenatal period has become the purpose of prenatal screening and diagnosis. Prenatal screening allows discovery of pregnancies at risk using non-invasive methods that do not harm the pregnant woman and fetus. An abnormal prenatal screening imposes the confirmation by using a prenatal diagnosis method. Prenatal screening methods could be biochemical, ultra-sonographic and genomic. Biochemical methods imply detection of some serum constituents in maternal blood like hCG, β-hCG, aFP, μE3, PAPP-A, and so on. Ultra-sonographic methods imply the use of ultrasound for the assessment of morphologic features of the fetus. Genomic prenatal screening allows the detection of free fetal DNA in maternal blood. Prenatal diagnosis imposes the use of the invasive methods that allow the harvesting of these fetal cells (trophoblastic cells, amniotic cells or blood cells). The major inconvenience of invasive methods is the risk of miscarriage or fetal damage. Fetal cells could be used for cytogenetic or molecular genetics investigations

Chromosomal anomalies are produced by genomic or chromosomal mutations. Chromosomal anomalies could be numerical and structural. Numerical chromosomal anomalies produce an important genomic imbalance and the phenotype of carriers is severely affected. Numerical chromosomal anomalies are represented by aneuploidies (trisomies, monosomies, etc.) and polyploidies (triploidy and tetraploidy). These are generated by errors during meiosis, fertilization or first mitosis of embryo. The most common error is chromosomal non-disjunction during the first meiosis that generates an aneuploidy (trisomy or monosomy) and is associated with advanced maternal age. Structural chromosomal anomalies are generated by changes of structure of one or multiple chromosomes and could be divided into unbalanced and balanced anomalies. Unbalanced structural chromosomal anomalies are characterized by absence (partial monosomy) or supplementary (partial trisomy) chromosomal segment(s) and produce a genomic imbalance that induces an abnormal phenotype. Balanced chromosomal anomalies are characterized by changes in the position of some chromosomal segments, but the quantity of genetic material remains unchanged. The phenotype of carriers is usually normal, but they could present a malsegregation of derivative chromosomes during meiosis that generates formation of gametes with genomic imbalances. Fertilizing such gametes results in embryos with unbalanced The epidemiological studies showed that the frequency of chromosomal anomalies will be reduced during pregnancy, from 1/4 at conception to 1/100 at birth (**Table 1**). The aneuploidies are the most frequent of these anomalies. The most common chromosomal disorders are Down syndrome (trisomy 21—**Figure 1**, birth prevalence 1/700–1/800) [2, 3], Klinefelter syndrome (trisomy XXY—**Figure 2**, birth prevalence 1/1000), triplo X syndrome (trisomy X—**Figure 3**, birth prevalence 1/1000), Turner syndrome (monosomy X—**Figure 4**, birth prevalence 1/2000 girls), Edwards syndrome (trisomy 18—**Figure 5**, birth prevalence 1/6500) and Patau syndrome (trisomy 13—**Figure 6**, birth prevalence 1/12,500). The risk of a couple having an affected child with a major trisomy (13, 18 and 21) is associated with advancing maternal age. In the last decade, the age of women at first pregnancy increases such that the birth prevalence for trisomy 21 in the USA has increased from 1 in 740 in 1974 to 1 in 504 by 1997 [4, 5].

The majority of chromosomal disorders has a high lethality rate during pregnancy and thus in the first trimester there are a significant number of fetuses affected than at full term. For example, in the case of trisomy 21, there is a 40% fetal loss between 12 weeks and full term and a 30% fetal loss between 16 weeks and full term. For trisomies 13 or 18, the loss is more important with an 80% fetal loss between 12 weeks and full term and a 40% fetal loss between 16 weeks and full term [6].

The incidence of the main chromosomal disorders in neonates is present in **Table 2**.

For trisomy 21, the risk at 12 weeks of gestation is 1/1000 for a woman aged 20 years and 1/250 for a woman aged 35 years. The risk of delivering an affected baby with Down syndrome is 1/1500 for a woman aged 20 years and 1/350 for a woman aged 35 years. For trisomy 18, the risk at 12 weeks of gestation is 1/2500 (for a woman aged 20 years) and 1/600 (for a woman aged 35 years) [7].


**Table 1.** Incidence of chromosomal anomalies in prenatal and perinatal period (adapted from Gorduza [1]).

**Figure 1.** Trisomy 21 (collection of cytogenetic laboratory, "Grigore T. Popa" University of Medicine and Pharmacy Iaşi, Romania).

**Figure 2.** Trisomy XXY (collection of cytogenetic laboratory, "Grigore T. Popa" University of Medicine and Pharmacy Iaşi, Romania).

In the case of gonosomal aneuploidies the risks are not correlated with advanced maternal age, and with the exception of monosomy X, the chromosomal anomaly does not modify the viability of the fetus. In monosomy X, the prevalence of anomaly is about 1/1500 at 12 weeks of gestation and 1/4000 at 40 weeks. For the gonosomal trisomies (47,XXX, 47,XXY and 47,XYY), the overall prevalence of 1/500 does not decrease with

**Figure 4.** Monosomy X (collection of cytogenetic laboratory, "Grigore T. Popa" University of Medicine and Pharmacy

**Figure 3.** Trisomy X (collection of cytogenetic laboratory, "Grigore T. Popa" University of Medicine and Pharmacy Iaşi,

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gestation [7].

Iaşi, Romania).

Romania).

The risk of delivering an affected baby with Edwards syndrome is 1/18,000 for a woman aged 20 years and 1/4000 for a woman aged 35 years. For trisomy 13, the risk at 12 weeks of gestation is 1/8000 (for a woman aged 20 years) and 1/1800 (for a woman aged 35 years). The risk of delivering an affected baby with Patau syndrome is 1/42,000 for a woman aged 20 years and 1/10,000 for a woman aged 35 years [7].

**Figure 3.** Trisomy X (collection of cytogenetic laboratory, "Grigore T. Popa" University of Medicine and Pharmacy Iaşi, Romania).

**Figure 4.** Monosomy X (collection of cytogenetic laboratory, "Grigore T. Popa" University of Medicine and Pharmacy Iaşi, Romania).

In the case of gonosomal aneuploidies the risks are not correlated with advanced maternal age, and with the exception of monosomy X, the chromosomal anomaly does not modify the viability of the fetus. In monosomy X, the prevalence of anomaly is about 1/1500 at 12 weeks of gestation and 1/4000 at 40 weeks. For the gonosomal trisomies (47,XXX, 47,XXY and 47,XYY), the overall prevalence of 1/500 does not decrease with gestation [7].

The risk of delivering an affected baby with Edwards syndrome is 1/18,000 for a woman aged 20 years and 1/4000 for a woman aged 35 years. For trisomy 13, the risk at 12 weeks of gestation is 1/8000 (for a woman aged 20 years) and 1/1800 (for a woman aged 35 years). The risk of delivering an affected baby with Patau syndrome is 1/42,000 for a woman aged 20 years and

**Figure 2.** Trisomy XXY (collection of cytogenetic laboratory, "Grigore T. Popa" University of Medicine and Pharmacy

**Figure 1.** Trisomy 21 (collection of cytogenetic laboratory, "Grigore T. Popa" University of Medicine and Pharmacy Iaşi,

1/10,000 for a woman aged 35 years [7].

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Romania).

Iaşi, Romania).

**Figure 5.** Trisomy 18 (collection of cytogenetic laboratory, "Grigore T. Popa" University of Medicine and Pharmacy Iaşi, Romania).

screening and diagnosis. Different such methods were developed during the last decades and now it is possible to discover the chromosomal pathology of the embryo in a couple at risk.

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The main procedures of prenatal screening are biochemical screening and ultrasound that allow the identification of pregnancies with increased genetic risk. The prenatal screening methods were introduced in medical practice in the1980s, based on the association between incidence of trisomy 21 (Down syndrome) and advanced maternal age. A decade later both the maternal serum biochemistry and detailed ultra-sonographic examination in the second trimester were developed and allowed the identification of high-risk pregnancies. In the 1990s, the prenatal screening shifted to first trimester by a combination of maternal age, fetal nuchal translucency (NT) thickness and maternal serum-free β-hCG and PAPP-A. In the last 10 years, the prenatal screening methods changed again by the introduction of genomic screening that

The prenatal diagnosis imposes the obtaining of embryonic or fetal cells by using invasive methods like chorionic villus sampling (CVS), amniocentesis or cordocentesis. All these methods present risks for spontaneous miscarriages, obstetrical hemorrhages and fetal damages.

Biochemical screening is based on the determination of maternal serum markers that are associated with an increased risk of chromosomal diseases. Biochemical screening could be

The embrionar or fetal cells are used for cytogenetic or molecular diagnosis.

**3. Methods of prenatal screening and diagnosis**

**Table 2.** Incidence of chromosomal anomalies in neonates (adapted from Gorduza [1]).

searches free fetal DNA in maternal blood [8].

**3.1. Biochemical screening**

**Figure 6.** Trisomy 13 (collection of cytogenetic laboratory, "Grigore T. Popa" University of Medicine and Pharmacy Iaşi, Romania).

Triploidy is unrelated to maternal age and the prevalence is about 1/2000 at 12 weeks, but the majority of affected fetuses die by 20 weeks and the born babies are mosaics 46/69 [7].

The birth of a child is an important event in the life of every family and represents the end of a long period of uncertainty generated by fear that the future child will be abnormal. The high incidence of chromosomal anomalies during prenatal life and the severity of phenotype of chromosomal anomalies that allow survival, imposed the development of methods of prenatal


**Table 2.** Incidence of chromosomal anomalies in neonates (adapted from Gorduza [1]).

screening and diagnosis. Different such methods were developed during the last decades and now it is possible to discover the chromosomal pathology of the embryo in a couple at risk.
