Percentage of the total number of aneuploid samples.

+ Rate from the previous stage of development, PBs to blastomere.

++Rate from the previous stage of development blastomere to TE, PBs = polar bodies,TE = trophectoderm.

For the current study, infertile patients who underwent ART at the Ingenes Institute were included. The patients were clinically evaluated according to a standardized protocol that includes family and personal clinical history. The protocol was approved by the Ethics Committee of the Ingenes Institute, and a signed informed consent was obtained from all patients. IVF, embryo biopsy, and mCGH were performed according to the standard protocols of the Institute Ingenes as previously described [76, 77]. Only optimal morphological embryos were considered for this study. Selection and embryo transfer were done on Day 3 or Day 5 of development according to the embryo morphological assessment, using the criteria established by the Istanbul consensus Workshop on Embryo Assessment [78].

#### Table 2.

disabilities and mental retardation [5]. Table 2 describes data from different infer-

The relatively high aneuploidy rate observed in human embryos after an IVF/ ICSI cycle has been attributed to the technique itself since this prevalence seems to be lower in natural conceptions [61]. Many hypotheses have been proposed that may explain these findings: (1) controlled ovarian stimulation treatments, (2) factors related to the ICSI technique and (3) lab conditions as embryo culture.

To increase the number of oocytes that can be retrieved for IVF, gonadotrophins are commonly used for superovulation in humans. Exogenous administration of gonadotrophins results in higher concentrations of steroids that may affect oocyte and embryo quality. Ovarian stimulation effects have been well characterized mainly in the murine model and have shown that aggressive stimulation leads to a poorer embryo development potential that could increase the chromosomal abnormality rate [79]. In humans, studies are scarce and less conclusive. A recent study in a population of young normovulatory women showed that a high ovarian response after controlled ovarian stimulation with moderate gonadotropin doses did not increase the embryo aneuploidy rate. Indeed, the higher the ovarian response, the more the euploid embryos obtained [80]; the remaining question is whether this

tility centers predominantly showing that aneuploidy rates are similar.

3.1 Ovarian stimulation and the incidence of embryo aneuploidy

can also be extrapolated to infertile patients with good ovarian reserve.

embryo aneuploidy

Modern Medical Genetics and Genomics

40

3.2 Intracytoplasmic sperm injection (ICSI) technique and the incidence of

pal feature of ICSI is the direct injection of spermatozoa into an oocyte, which facilitates the production of fertilized embryos regardless of semen characteristics, such as sperm concentration and motility. However, the chromosomal integrity of ICSI zygotes is degraded compared to zygotes obtained from an in vitro fertilization [81, 82]. During the ICSI procedure, a sperm pretreatment is performed to mimic the conditions of natural fertilization and support the progression of fertilization effects. Studies on mouse models revealed that the chromosomal integrity of zygotes derived from ICSI without any pretreatment of spermatozoa was impaired in comparison with zygotes derived from conventional IVF [83]; even the culture sperm conditions may affect the chromosomal stability of the embryo [84]. Chromosomal damage may occur due to the injection of non-capacitated, acrosomeintact spermatozoa, so to reduce the risk of chromosomal aberrations during the ICSI procedure, it is crucial that sperm capacitation and the acrosome reaction be

appropriately artificially induced in the proper medium before use [85].

Fertilization and embryo development in vitro have the potential to introduce (often inadvertently) stress which cannot only impair embryo development in the

In vivo, the developing preimplantation embryo is exposed to gradients of nutrients, hormones, cytokines, and growth factors as it progresses through the fallopian tube to the uterus. Within the lumen of the female tract, the embryo resides in a few 100 nanoliters of a complex viscous fluid characterized by high levels of mucins, albumin, and glycosaminoglycans and by reduced levels of oxygen

3.3 Embryo culture and the incidence of embryo aneuploidy

laboratory but also have downstream effects after transfer.

ICSI has become critical for the treatment of severe male infertility. The princi-

Aneuploidy rates of different IVF clinics around the world; when mentioned, the most commonly affected chromosomes are listed.

(typically 2–8%). The embryo is in constant motion, moved by gentle ciliated and muscular action of the female tract [86]. This scenario is in stark contrast to the laboratory environment, where typical gametes and embryos are exposed to relatively large volumes of culture medium, remain static during culture while resting on a polystyrene substrate, and create unstirred layers where the end products of metabolism concentrate and nutrients become limited [87].

detects the relative color intensity, and a bioinformatics compares the intensity of each fluorophore in the sample versus the control to identify any bias and deter-

The mCGH analysis reports the ratio of sample DNA to a reference DNA, as a chromosomic profile where the molecular karyotype is represented. Usually, the sample DNA is labeled with a green fluorescent dye, while the reference DNA sample is tagged red [99]. Thus, diploid embryos will have a relatively equal ratio of green-to-red fluorescence in every pair of chromosomes, represented as a continuous horizontal plot line. Monosomy will be represented as a clear downward deviation in the plotted line, indicating a relative lack of green-to-red signal intensity; in contrary, a trisomy will be displayed as an upward deviation in the plotted line due

The specificity rate of mCGH-based PGT is about 99% [90]. The test results can be available within 12–15 h, considering that the entire analysis can be performed during this short time frame [90, 91]. Additionally, brand-specific features are offered by each manufacturer: Agilent's GenetiSure Pre-Screen Microarray offers a

detection rate of 100% for aberrations >10 Mb and 89% for >5.3 Mb [100];

NGS-based VeriSeq PGS is now offered as an alternative solution [102].

KaryoLite BoBs Kit from Perkin Elmer uses an alternative BACs-on-Beads technology and results are interpreted by the BoBsoft™ analysis software [99]; and RHS's EmbryoCellect Kit is the only mCGH-based PGT validated for mosaicism detection [101]. Recently, Illumina's 24sure PGS Microarray had been discontinued, and the

mCGH entails some disadvantages: first, the embryo sample requires a previous whole genome amplification (WGA) process to support single-cell diagnostics by mCGH [95], raising the possibility of introducing errors during the amplification [91]; second, mCGH is a semiquantitative technique that only reports the ratio of sample DNA to a reference DNA; it is to say that only imbalances in DNA content can be identified. Therefore, mCGH is unable to detect uniparental disomic or triploid embryos as it cannot discriminate between 46,XX from 69,XXX, and 46, XY from 69,XXY [90, 91, 95]. Last, the mCGH used for PGS cannot identify structural chromosome aberrations or diagnose mosaicism in a trophectoderm

NGS refers to the emerging technology of non-Sanger-based DNA sequencing that allows the sequence in parallel millions of DNA strands with high-throughput yield. In the field of ART, this powerful tool is being applied for PGT to replace

Different platforms are commercially available for NGS with different techno-

Despite the dissimilarities between platforms, the common basis of chromosome copy number analysis by NGS is the fragmentation of the amplified DNA sample into small segments of 100–200 base pairs that are further sequenced in parallel until the number of reads covering a determined position in the genome is attained, in general, a 30 coverage (sequencing each base pair 30 times) ensures sufficient accuracy. The sequence data obtained are then compared with a reference genome

logical approaches. Illumina's MiSeq NGS platform applies a sequencing-bysynthesis method, where DNA is attached and amplified in situ to be subsequently used as a template for synthetic sequencing with fluorescent-labeled reversibleterminator nucleotides [103]. Ion Torrent NGS technology, commercialized by ThermoFisher Scientific, is based on collecting data by sensing the hydrogen ions that are released as by-products when nucleotides are incorporated by a template-

directed DNA polymerase synthesis on an ion chip [104].

mine the ploidy status of the sample [90, 95, 98].

DOI: http://dx.doi.org/10.5772/intechopen.81884

Aneuploidy Rates Inversely Correlate with Implantation during In Vitro…

to a relative increase in the green-to-red signal intensity.

sample [90].

43

4.2 Next-generation sequencing (NGS)

cytogenetic microarrays [98, 102].

Embryos are sensitive to both chemical and physical signals within their microenvironment. Factors within the laboratory as oxygen level, ammonium released from amino acids into the culture, poor laboratory air quality, temperature and pH, oil overlay, embryo culture volume/density, the static nature of culture, light, or even mechanical factors as pipetting, can negatively impact gametes and embryos and generate stress. When more than one stress factor is present in the laboratory, more negative synergies can result, and these factors play a significant role in influencing the development and events post transfer [88]. For example, recent studies have reported that a decrease in temperature has the potential to affect the stability of the oocyte's meiotic spindle, reducing fertilization rates, delaying embryo development, and decreasing clinical pregnancy rates [89]. However, more studies are needed to demonstrate the impact of embryo culture on aneuploidy rates.

### 4. Aneuploidy detection: techniques for PGT

PGT is the genetic diagnosis analysis performed to identify euploid embryos before uterine transfer [90]. PGT determines the numeric chromosomal constitution of a cellular biopsy sample obtained from a cultured embryo to determine its competence [91, 92].

PGT was first described in 1990 by Handyside et al. [93] when the sex of the sixto eight-cell stage embryos from two couples with a known risk of transmitting Xlinked diseases was assessed by DNA amplification of a Y chromosome-specific repeat sequence. The earliest PGT studies in the 2000s were based on the fluorescence in situ hybridization (FISH) technique where 3–12 chromosomes can be analyzed on the cleavage stage or polar body biopsies [90]. Those studies had disappointing results in clinical practice since it had no beneficial effect on live birth rate after IVF [94]. The major drawback of FISH-based PGT is the limited number of chromosomes that can be analyzed considering that aneuploidy can affect any of the 22 autosomes and both sex chromosomes [95]; consequently, there have been dramatic improvements in PGT technology to make it valuable for clinical practice.

Nowadays, several methodologies for 24-chromosome analysis are available for clinical use that aim to increase implantation rates and decrease miscarriage rates associated with IVF [90]: microarray comparative genomic hybridization (mCGH), single-nucleotide polymorphism (SNP) microarray, real-time polymerase chain reaction (qPCR), and next-generation sequencing (NGS) [96, 97]. This review will focus on the relevant aspects of the PGT techniques used in our laboratory.

#### 4.1 Microarray comparative genomic hybridization (mCGH)

mCGH is a ratio labeling protocol to compare the DNA product of a clinical sample to a healthy control. For PGT, biopsied embryonic cells must be lysed to extract the sample's DNA, which will be further amplified by a protocol that provides whole genome coverage [90, 95, 98]. The resulting DNA products are co-hybridized with a standard DNA control sample (46,XY and 46,XX) with a series of site-specific fluorophores on a microarray chip with approximately 4000 markers spaced throughout the genome [90]. Then, a confocal laser platform

Aneuploidy Rates Inversely Correlate with Implantation during In Vitro… DOI: http://dx.doi.org/10.5772/intechopen.81884

detects the relative color intensity, and a bioinformatics compares the intensity of each fluorophore in the sample versus the control to identify any bias and determine the ploidy status of the sample [90, 95, 98].

The mCGH analysis reports the ratio of sample DNA to a reference DNA, as a chromosomic profile where the molecular karyotype is represented. Usually, the sample DNA is labeled with a green fluorescent dye, while the reference DNA sample is tagged red [99]. Thus, diploid embryos will have a relatively equal ratio of green-to-red fluorescence in every pair of chromosomes, represented as a continuous horizontal plot line. Monosomy will be represented as a clear downward deviation in the plotted line, indicating a relative lack of green-to-red signal intensity; in contrary, a trisomy will be displayed as an upward deviation in the plotted line due to a relative increase in the green-to-red signal intensity.

The specificity rate of mCGH-based PGT is about 99% [90]. The test results can be available within 12–15 h, considering that the entire analysis can be performed during this short time frame [90, 91]. Additionally, brand-specific features are offered by each manufacturer: Agilent's GenetiSure Pre-Screen Microarray offers a detection rate of 100% for aberrations >10 Mb and 89% for >5.3 Mb [100]; KaryoLite BoBs Kit from Perkin Elmer uses an alternative BACs-on-Beads technology and results are interpreted by the BoBsoft™ analysis software [99]; and RHS's EmbryoCellect Kit is the only mCGH-based PGT validated for mosaicism detection [101]. Recently, Illumina's 24sure PGS Microarray had been discontinued, and the NGS-based VeriSeq PGS is now offered as an alternative solution [102].

mCGH entails some disadvantages: first, the embryo sample requires a previous whole genome amplification (WGA) process to support single-cell diagnostics by mCGH [95], raising the possibility of introducing errors during the amplification [91]; second, mCGH is a semiquantitative technique that only reports the ratio of sample DNA to a reference DNA; it is to say that only imbalances in DNA content can be identified. Therefore, mCGH is unable to detect uniparental disomic or triploid embryos as it cannot discriminate between 46,XX from 69,XXX, and 46, XY from 69,XXY [90, 91, 95]. Last, the mCGH used for PGS cannot identify structural chromosome aberrations or diagnose mosaicism in a trophectoderm sample [90].

#### 4.2 Next-generation sequencing (NGS)

NGS refers to the emerging technology of non-Sanger-based DNA sequencing that allows the sequence in parallel millions of DNA strands with high-throughput yield. In the field of ART, this powerful tool is being applied for PGT to replace cytogenetic microarrays [98, 102].

Different platforms are commercially available for NGS with different technological approaches. Illumina's MiSeq NGS platform applies a sequencing-bysynthesis method, where DNA is attached and amplified in situ to be subsequently used as a template for synthetic sequencing with fluorescent-labeled reversibleterminator nucleotides [103]. Ion Torrent NGS technology, commercialized by ThermoFisher Scientific, is based on collecting data by sensing the hydrogen ions that are released as by-products when nucleotides are incorporated by a templatedirected DNA polymerase synthesis on an ion chip [104].

Despite the dissimilarities between platforms, the common basis of chromosome copy number analysis by NGS is the fragmentation of the amplified DNA sample into small segments of 100–200 base pairs that are further sequenced in parallel until the number of reads covering a determined position in the genome is attained, in general, a 30 coverage (sequencing each base pair 30 times) ensures sufficient accuracy. The sequence data obtained are then compared with a reference genome

(typically 2–8%). The embryo is in constant motion, moved by gentle ciliated and muscular action of the female tract [86]. This scenario is in stark contrast to the laboratory environment, where typical gametes and embryos are exposed to relatively large volumes of culture medium, remain static during culture while resting on a polystyrene substrate, and create unstirred layers where the end products of

Embryos are sensitive to both chemical and physical signals within their microenvironment. Factors within the laboratory as oxygen level, ammonium released from amino acids into the culture, poor laboratory air quality, temperature and pH, oil overlay, embryo culture volume/density, the static nature of culture, light, or even mechanical factors as pipetting, can negatively impact gametes and embryos and generate stress. When more than one stress factor is present in the laboratory, more negative synergies can result, and these factors play a significant role in influencing the development and events post transfer [88]. For example, recent studies have reported that a decrease in temperature has the potential to affect the stability of the oocyte's meiotic spindle, reducing fertilization rates, delaying embryo development, and decreasing clinical pregnancy rates [89]. However, more studies are needed to

PGT is the genetic diagnosis analysis performed to identify euploid embryos before uterine transfer [90]. PGT determines the numeric chromosomal constitution of a cellular biopsy sample obtained from a cultured embryo to determine its

PGT was first described in 1990 by Handyside et al. [93] when the sex of the sixto eight-cell stage embryos from two couples with a known risk of transmitting Xlinked diseases was assessed by DNA amplification of a Y chromosome-specific repeat sequence. The earliest PGT studies in the 2000s were based on the fluorescence in situ hybridization (FISH) technique where 3–12 chromosomes can be analyzed on the cleavage stage or polar body biopsies [90]. Those studies had disappointing results in clinical practice since it had no beneficial effect on live birth rate after IVF [94]. The major drawback of FISH-based PGT is the limited number of chromosomes that can be analyzed considering that aneuploidy can affect any of the 22 autosomes and both sex chromosomes [95]; consequently, there have been dramatic improvements in PGT technology to make it valuable for clinical practice. Nowadays, several methodologies for 24-chromosome analysis are available for clinical use that aim to increase implantation rates and decrease miscarriage rates associated with IVF [90]: microarray comparative genomic hybridization (mCGH), single-nucleotide polymorphism (SNP) microarray, real-time polymerase chain reaction (qPCR), and next-generation sequencing (NGS) [96, 97]. This review will

focus on the relevant aspects of the PGT techniques used in our laboratory.

mCGH is a ratio labeling protocol to compare the DNA product of a clinical sample to a healthy control. For PGT, biopsied embryonic cells must be lysed to extract the sample's DNA, which will be further amplified by a protocol that provides whole genome coverage [90, 95, 98]. The resulting DNA products are co-hybridized with a standard DNA control sample (46,XY and 46,XX) with a series of site-specific fluorophores on a microarray chip with approximately 4000 markers spaced throughout the genome [90]. Then, a confocal laser platform

4.1 Microarray comparative genomic hybridization (mCGH)

metabolism concentrate and nutrients become limited [87].

Modern Medical Genetics and Genomics

demonstrate the impact of embryo culture on aneuploidy rates.

4. Aneuploidy detection: techniques for PGT

competence [91, 92].

42

and counted by bioinformatics software. The copy number of a specific chromosome should be proportional to the number of counted sequences; therefore, an increase or reduction in the number of reads will, respectively, represent a trisomy or monosomy [97, 99].

NGS allows to simultaneously perform both qualitative and quantitative analyses of multiple embryos with high-resolution data for chromosomal analysis [96, 97]. The higher sensitivity and precision offered by NGS [96, 105, 106] makes possible to exclude embryos with mosaicism [105, 106] and partial aneuploidies or triploidies [106], improving pregnancy outcomes due to its enhanced capability for detecting those challenging abnormalities.

PGT by NGS can predict not only chromosome copy number for the diagnosis of whole chromosome aneuploidy with 99.98% assignment consistency [97] but also single-gene disorders [107], abnormalities of the mitochondrial genome [108], and segmental chromosome imbalances [97, 99]. Balanced chromosomal rearrangements cannot be detected by NGS [97].

The increasing demand and accelerated development are continuously reducing the cost of NGS technology [109]. Also, potential cost-benefit ratios can be achieved when the full sequencing capacity of the apparatus is exploited [96, 97, 99]. Furthermore, molecular tools, like barcoding, are being implemented to allow multiplex high-throughput sequencing [110]; this promising strategy will reduce the diagnosis' cost per patient by performing simultaneous analysis of multiple embryos from different patients [97].

### 5. Aneuploidy and women age

In our study, by analyzing the mCGH data, the total number of aneuploidies was found to be 734, and from these, 641 (87.3%) were derived from patients and 93 (12.7%) from donors. Overall, this study displayed similar rates of monosomies, trisomies, double aneuploidies, and multiple aneuploidies. The total number of monosomies (191) was similar to the number of trisomies (194), accounting for 26 and 26.4% of the total aneuploidies, correspondingly. Furthermore, the total number of double (165) and multiple (184) aneuploidies was also very similar, accounting for 22.5 and 25.1% of the total aneuploidies, correspondingly. Nevertheless, it is worth noticing that when considering only the donor group, monosomies seem to be more prevalent: 38.7% of the total donors' aneuploidies were monosomies vs. 24.7% of trisomies, 16.1% of double aneuploidies, and 20.4% of multiple aneuploidies; what is more, the percentage of monosomies in the donor group is higher than that of the monosomies of the patient group (38.7 vs. 24.3%). The most common monosomies affected chromosomes 15, 16, and 22, whereas the most common trisomy affected chromosomes 16, 19, and 21 (Table 3).

displayed high aneuploid rates, 28.5 and 27.4%, respectively (Table 4). Given the high rates of aneuploidy in younger women, attention should be paid in detecting aneuploidy in embryos from women of young maternal age, especially since this group of patients is not routinely encouraged to perform a PGT. Still, whether there is a difference between the distribution of aneuploidies between donors and

furthermore, the number of the most common aneuploidies of the mCGH data is listed.

Most frequent types of aneuploidies in the mCGH data of the current study.

Nine embryos had completely abnormal mCGH profiles.

Even embryos had completely abnormal mCGH profiles.

Two embryos had completely abnormal mCGH profiles.

All Patients Donors

Total 734 641 93 Monosomy 191 (26.0%) 155 (24.3%) 36 (38.7%) Chr 15 13 13 0 Chr 16 21 18 3 Chr 22 22 22 0 Chr X 10 8 2 Chr Y 40 26 14 Trisomy 194 (26.4%) 171 (26.7%) 23 (24.7%) +Chr 16 26 24 2 +Chr 18 9 7 2 +Chr 19 23 21 2 +Chr 20 17 13 4 +Chr 21 20 20 0 +Chr 22 19 19 0 +Chr X 10 8 2 +Chr Y 1 1 0 Dual 165 (22.5%) 150 (23.4%) 15 (16.1%) Multiple 184 (25.1%)a 165 (25.7%)<sup>b</sup> 19 (20.4%)<sup>c</sup> The current study included 441 patients, resulting in 474 cycles. A total of 1629 embryos were analyzed; from those, 54 were excluded due to failed WGA, leaving 1575 embryos for analysis, 1258 from patients, and 317 from donors. Biopsies were performed at the blastomere (Day 3, patients = 238 and donors = 50) and blastocyst stages (Day 5, patients = 1020 and donors = 267). Finally, 734 embryos (46.6%) were found to be aneuploid (patients = 641 and donors = 93). The total number of monosomies and trisomies is provided along with their respective percentages;

Aneuploidy Rates Inversely Correlate with Implantation during In Vitro…

DOI: http://dx.doi.org/10.5772/intechopen.81884

When stratifying our analysis in age groups (a, ≤29; b, 30–34; c, 35–37; d, 38–40; e, 41–43; and f, ≥44 years of age), a visible continuous increase in aneuploidy rate can be observed as maternal age increases (Table 4); furthermore, this increase in aneuploidy goes hand in hand with a continuous decrease in implantation, as it can be observed in the decrease of positive beta-human chorionic gonadotropin (β-hCG) values as age increases (β-hCG values ≥10 mUI/ml from Day 14 after

patients remains uncertain.

a

b

c

45

Table 3.

transference were considered positive).

It has been shown that the lowest risk for embryonic aneuploidy is between ages 26 and 30, with aneuploidy rates steadily increasing with maternal age after 26 years of age [111] and leaping significantly from the age of 39 [112]. For this reason, women of advanced maternal age are encouraged to favor oocyte donation to yield high-quality viable embryos.

Interestingly, some studies have identified that women of younger ages possess an increased prevalence of aneuploidy, with >40% of aneuploidy in women of 23 years and under [111] and 58% of aneuploidy in women of <31 years of age. In the current study, both the donor (≤29 years) and the patient group of ≤29 years


Aneuploidy Rates Inversely Correlate with Implantation during In Vitro… DOI: http://dx.doi.org/10.5772/intechopen.81884

The current study included 441 patients, resulting in 474 cycles. A total of 1629 embryos were analyzed; from those, 54 were excluded due to failed WGA, leaving 1575 embryos for analysis, 1258 from patients, and 317 from donors. Biopsies were performed at the blastomere (Day 3, patients = 238 and donors = 50) and blastocyst stages (Day 5, patients = 1020 and donors = 267). Finally, 734 embryos (46.6%) were found to be aneuploid (patients = 641 and donors = 93). The total number of monosomies and trisomies is provided along with their respective percentages; furthermore, the number of the most common aneuploidies of the mCGH data is listed.

a Nine embryos had completely abnormal mCGH profiles. b

Even embryos had completely abnormal mCGH profiles. c Two embryos had completely abnormal mCGH profiles.

#### Table 3.

and counted by bioinformatics software. The copy number of a specific chromosome should be proportional to the number of counted sequences; therefore, an increase or reduction in the number of reads will, respectively, represent a trisomy

NGS allows to simultaneously perform both qualitative and quantitative analyses of multiple embryos with high-resolution data for chromosomal analysis [96, 97]. The higher sensitivity and precision offered by NGS [96, 105, 106] makes possible to exclude embryos with mosaicism [105, 106] and partial aneuploidies or triploidies [106], improving pregnancy outcomes due to its enhanced capability for

PGT by NGS can predict not only chromosome copy number for the diagnosis of whole chromosome aneuploidy with 99.98% assignment consistency [97] but also single-gene disorders [107], abnormalities of the mitochondrial genome [108], and

The increasing demand and accelerated development are continuously reducing the cost of NGS technology [109]. Also, potential cost-benefit ratios can be achieved

In our study, by analyzing the mCGH data, the total number of aneuploidies was found to be 734, and from these, 641 (87.3%) were derived from patients and 93 (12.7%) from donors. Overall, this study displayed similar rates of monosomies, trisomies, double aneuploidies, and multiple aneuploidies. The total number of monosomies (191) was similar to the number of trisomies (194),

accounting for 26 and 26.4% of the total aneuploidies, correspondingly.

Furthermore, the total number of double (165) and multiple (184) aneuploidies was also very similar, accounting for 22.5 and 25.1% of the total aneuploidies, correspondingly. Nevertheless, it is worth noticing that when considering only the donor group, monosomies seem to be more prevalent: 38.7% of the total donors' aneuploidies were monosomies vs. 24.7% of trisomies, 16.1% of double aneuploidies, and 20.4% of multiple aneuploidies; what is more, the percentage of monosomies in the donor group is higher than that of the monosomies of the patient group (38.7 vs. 24.3%). The most common monosomies affected chromosomes 15, 16, and 22, whereas the most common trisomy affected chromosomes 16, 19, and 21

It has been shown that the lowest risk for embryonic aneuploidy is between ages

Interestingly, some studies have identified that women of younger ages possess

26 and 30, with aneuploidy rates steadily increasing with maternal age after 26 years of age [111] and leaping significantly from the age of 39 [112]. For this reason, women of advanced maternal age are encouraged to favor oocyte donation

an increased prevalence of aneuploidy, with >40% of aneuploidy in women of 23 years and under [111] and 58% of aneuploidy in women of <31 years of age. In the current study, both the donor (≤29 years) and the patient group of ≤29 years

segmental chromosome imbalances [97, 99]. Balanced chromosomal

when the full sequencing capacity of the apparatus is exploited [96, 97, 99]. Furthermore, molecular tools, like barcoding, are being implemented to allow multiplex high-throughput sequencing [110]; this promising strategy will reduce the diagnosis' cost per patient by performing simultaneous analysis of multiple

or monosomy [97, 99].

Modern Medical Genetics and Genomics

detecting those challenging abnormalities.

embryos from different patients [97].

5. Aneuploidy and women age

to yield high-quality viable embryos.

(Table 3).

44

rearrangements cannot be detected by NGS [97].

Most frequent types of aneuploidies in the mCGH data of the current study.

displayed high aneuploid rates, 28.5 and 27.4%, respectively (Table 4). Given the high rates of aneuploidy in younger women, attention should be paid in detecting aneuploidy in embryos from women of young maternal age, especially since this group of patients is not routinely encouraged to perform a PGT. Still, whether there is a difference between the distribution of aneuploidies between donors and patients remains uncertain.

When stratifying our analysis in age groups (a, ≤29; b, 30–34; c, 35–37; d, 38–40; e, 41–43; and f, ≥44 years of age), a visible continuous increase in aneuploidy rate can be observed as maternal age increases (Table 4); furthermore, this increase in aneuploidy goes hand in hand with a continuous decrease in implantation, as it can be observed in the decrease of positive beta-human chorionic gonadotropin (β-hCG) values as age increases (β-hCG values ≥10 mUI/ml from Day 14 after transference were considered positive).


Values are shown as mean standard error. Significance was determined by one-way ANOVA followed by a Bonferroni or Dunnett's T3 post hoc test. Superscripts indicate a significant difference(<sup>p</sup><0.05, two-tailed):

aVersus 29 years old group.

bVersus 30–34 years old group.

 cVersus 35–37 years old group.

dVersus 38-40 years old group.

eVersus 41–43 years old group.

fVersus 44 years old group.gVersusdonors.

Table

 4. Comparative of aneuploidy and pregnancy rates between age

 groups. 6. Remarks

analysis.

Acknowledgements

Abbreviations

ANOVA analysis of variance

IVF in vitro fertilization

Chr chromosome

MI meiosis I MII meiosis II

OR odds ratio

47

ART assisted reproductive techniques

FISH fluorescence in situ hybridization ICSI intracytoplasmic sperm injection

NGS next-generation sequencing

PGS preimplantation genetic screening PGT preimplantation genetic testing qPCR real-time polymerase chain reaction SNP single-nucleotide polymorphism WGA whole genome amplification

β-hCG beta-human chorionic gonadotropin

One of the most critical reasons for unsuccessful IVF procedures is implantation failure due to aneuploid embryos. Aneuploidies are the primary cause of perinatal death and genetic abnormalities; consequently, the detection of chromosomal disorders constitutes the most frequent indication for PGT. Here, we report on the aneuploidy rates found in IVF procedures in Mexico. Even though there are studies that assert that PGT does not improve pregnancy rates, we show that aneuploidy rates inversely correlate with implantation and that levels of aneuploidy among high morphological quality embryos are still an important issue to be faced in everyday ART practice, and this evidence works in favor of continuing to use PGT

This work was supported by the Consejo Nacional de Ciencia y Tecnología

(Conacyt-Programa de Estímulos a la Innovación 2018-253224).

Aneuploidy Rates Inversely Correlate with Implantation during In Vitro…

DOI: http://dx.doi.org/10.5772/intechopen.81884

mCGH microarray comparative genomic hybridization

Aneuploidy Rates Inversely Correlate with Implantation during In Vitro… DOI: http://dx.doi.org/10.5772/intechopen.81884

## 6. Remarks

One of the most critical reasons for unsuccessful IVF procedures is implantation failure due to aneuploid embryos. Aneuploidies are the primary cause of perinatal death and genetic abnormalities; consequently, the detection of chromosomal disorders constitutes the most frequent indication for PGT. Here, we report on the aneuploidy rates found in IVF procedures in Mexico. Even though there are studies that assert that PGT does not improve pregnancy rates, we show that aneuploidy rates inversely correlate with implantation and that levels of aneuploidy among high morphological quality embryos are still an important issue to be faced in everyday ART practice, and this evidence works in favor of continuing to use PGT analysis.

## Acknowledgements

This work was supported by the Consejo Nacional de Ciencia y Tecnología (Conacyt-Programa de Estímulos a la Innovación 2018-253224).

## Abbreviations


Category

46

Number of samples (n, cycles)

Age (years)

Body mass index (kg/m2

Ova collected (n) Ova fertilized (n)

Embryos (n)

Fertilization

Aneuploidy

Pregnancy rate (%) Values are shown as mean

(<sup>p</sup> < 0.05, two-tailed): aVersus 29 years old group.

bVersus 30–34 years old group.

cVersus 35–37 years old group.

dVersus 38-40 years old group. eVersus 41–43 years old group.

fVersus 44 years old group.

gVersus donors.

Table 4. Comparative

 of aneuploidy

 and pregnancy

 rates between age groups.

standard error. Significance

 was determined by one-way ANOVA followed by a Bonferroni or Dunnett's T3 post hoc test. Superscripts

 rate (%)

 rate (%)

)

23.6

16.8

14.3

11.2

77.9

27.4

 60.87b,c,d,e,f,g

50.99a,c,d,e,f,g

49.09a,b,d,e,f,g

44.00a,b,c,e,f,g

55.17a,b,c,d,f,g

42.86a,b,c,d,e,g

 indicate a significant difference

50.79a,b,c,d,e,f

33.3d,e,f

36.0

29.2d,e,f

35.7

30.3d,e,f

57.7

34.9a,b,c,f,g

66.6

37.7a,b,c,g

87.4

19.5a,b,c,d,g

28.5

28.7d,e,f

 17.0

 76.3

 15.1

 79.7

 14.2

 76.6

 16.6

 77.0

 18.9

 83.6

 15.2

 76.1

 16.0

 6.3e,f

11.7

 7.9d,e,f

10.6

 6.0d,e,f

7.7

 4.2b,c,g

7.5

4.6a,b,c,g

6.2

3.9a,b,c,g

10.4

 4.6d,e,f

 6.9e,f

15.2

 8.6d,e,f

13.6

 7.5d,e,f

10.3

 5.2b,c,g

9.8

5.5a,b,c,g

7.6

4.8a,b,c,g

13.9

 6.2d,e,f

 7.9e,f

17.3

 9.8d,e,f

16.1

 9.0d,e,f

12.0

 6.3b,c,g

11.0

5.9a,b,c,g

8.9

6.0a,b,c,g

15.8

 8.1d,e,f

Modern Medical Genetics and Genomics

 3.8g

24.6

 3.8g

24.3

 3.9g

24.4

 3.7g

24.8

 3.8g

24.6

 2.8g

21.8

2.5a,b,c,d,e,f

≤29

30–34

35–37

38–40

41–43

≥44

Donors

g

83

f

e

d

c

b

a

27

27.0

2.4b,c,d,e,f,g

32.5

1.3a,c,d,e,f,g

36.1

0.7a,b,d,e,f,g

39.0

0.8a,b,c,e,f,g

41.8

0.8a,b,c,d,f,g

45.0

1.6a,b,c,d,e,g

22.8

3.0a,b,c,d,e,f

66

72

105

90

31 Modern Medical Genetics and Genomics

## Author details

Elizabeth Schaeffer<sup>1</sup> , Leonardo Porchia1,3, Almena López-Luna1,2, Dinorah Hernández-Melchor1,2 and Esther López-Bayghen1,2\*

1 Laboratorio de Investigación y Diagnóstico Molecular, Instituto de Infertilidad y Genética SC, INGENES, CDMX, México

References

25(13):R538-R542

2012. pp. 3-22

R208. Spec no. 2

[5] Hassold T, Hunt P. To err

Genetics. 2001;2(4):280-291

1996;11(10):2217-2222

[6] Battaglia DE et al. Influence of maternal age on meiotic spindle assembly in oocytes from naturally cycling women. Human Reproduction.

[7] Kim JW et al. Chromosomal abnormalities in spontaneous abortion after assisted reproductive treatment. BMC Medical Genetics. 2010;11:153

Incidence, origin, and etiology. Environmental and Molecular Mutagenesis. 1996;28(3):167-175

1q41-qter: Further delineation of trisomy 1q syndromes. American Journal of Medical Genetics. Part A.

2008;146A(20):2663-2667

49

[8] Hassold T et al. Human aneuploidy:

[9] Kulikowski LD et al. Pure duplication

[10] Campos TCaF, Puntero B. Trisomía parcial 1q por translocación materna.

[1] Torres EM, Williams BR, Amon A. Aneuploidy: Cells losing their balance.

DOI: http://dx.doi.org/10.5772/intechopen.81884

Aneuploidy Rates Inversely Correlate with Implantation during In Vitro…

Anales Españoles de Pediatría. 2000;52:

[11] Rasmussen SA et al. Partial duplication 1q: Report of four patients and review of the literature. American Journal of Medical Genetics. 1990;36(2):

[12] Acosta Sabatés MM, Hernández García I, García Martínez DA, Lavaut Sánchez K. Duplication 2 q 2.1- q 3.1: A

[13] Sebold CD et al. Partial trisomy 2q: Report of a patient with dup (2)

(q33.1q35). American Journal of Medical Genetics. Part A. 2005;134A(1):80-83

duplication 3q syndrome and report of a patient with Currarino syndrome and de novo duplication 3q26.32-q27.2. Clinical

[16] Natera-de Benito D et al. A patient with a duplication of chromosome 3p (p24.1p26.2): A comparison with other partial 3p trisomies. American Journal of Medical Genetics. Part A. 2014;164A(2):

[17] Charrow J, Cohen MM, Meeker D. Duplication 3p syndrome: Report of a new case and review of the literature. American Journal of Medical Genetics.

[18] Varley J, Wehner T, Sisodiya S. Diaphragm myoclonus followed by generalised atonia in a patient with trisomy 4p: Unusual semiology in an unusual condition. Epileptic Disorders.

[14] Schumacher RE, Rocchini AP, Wilson GN. Partial trisomy 2q. Clinical

Genetics. 1983;23(3):191-194

Genetics. 2017;91(5):661-671

548-550

1981;8(4):431-436

2015;17(4):473-477

[15] Dworschak GC et al. Comprehensive review of the

case report. Revista Cubana de

Pediatría. 2008;80:1

178-184

137-143

Genetics. 2008;179(2):737-746

[2] Orr B, Godek KM, Compton D. Aneuploidy. Current Biology. 2015;

[3] Storchova Z. The causes and consequences of aneuploidy in eukaryotic cells. In: Aneuploidy in Health and Disease. Croatia: InTech;

[4] Hassold T, Hall H, Hunt P. The origin of human aneuploidy: Where we have been, where we are going. Human Molecular Genetics. 2007;16:R203-

(meiotically) is human: The genesis of human aneuploidy. Nature Reviews.

2 Departamento de Toxicología, Cinvestav-IPN, CDMX, México

3 Tecnologías DAAT SA de CV, Xalapa, Veracruz, México

\*Address all correspondence to: ebayghen@cinvestav.mx

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Aneuploidy Rates Inversely Correlate with Implantation during In Vitro… DOI: http://dx.doi.org/10.5772/intechopen.81884

## References

[1] Torres EM, Williams BR, Amon A. Aneuploidy: Cells losing their balance. Genetics. 2008;179(2):737-746

[2] Orr B, Godek KM, Compton D. Aneuploidy. Current Biology. 2015; 25(13):R538-R542

[3] Storchova Z. The causes and consequences of aneuploidy in eukaryotic cells. In: Aneuploidy in Health and Disease. Croatia: InTech; 2012. pp. 3-22

[4] Hassold T, Hall H, Hunt P. The origin of human aneuploidy: Where we have been, where we are going. Human Molecular Genetics. 2007;16:R203- R208. Spec no. 2

[5] Hassold T, Hunt P. To err (meiotically) is human: The genesis of human aneuploidy. Nature Reviews. Genetics. 2001;2(4):280-291

[6] Battaglia DE et al. Influence of maternal age on meiotic spindle assembly in oocytes from naturally cycling women. Human Reproduction. 1996;11(10):2217-2222

[7] Kim JW et al. Chromosomal abnormalities in spontaneous abortion after assisted reproductive treatment. BMC Medical Genetics. 2010;11:153

[8] Hassold T et al. Human aneuploidy: Incidence, origin, and etiology. Environmental and Molecular Mutagenesis. 1996;28(3):167-175

[9] Kulikowski LD et al. Pure duplication 1q41-qter: Further delineation of trisomy 1q syndromes. American Journal of Medical Genetics. Part A. 2008;146A(20):2663-2667

[10] Campos TCaF, Puntero B. Trisomía parcial 1q por translocación materna.

Anales Españoles de Pediatría. 2000;52: 178-184

[11] Rasmussen SA et al. Partial duplication 1q: Report of four patients and review of the literature. American Journal of Medical Genetics. 1990;36(2): 137-143

[12] Acosta Sabatés MM, Hernández García I, García Martínez DA, Lavaut Sánchez K. Duplication 2 q 2.1- q 3.1: A case report. Revista Cubana de Pediatría. 2008;80:1

[13] Sebold CD et al. Partial trisomy 2q: Report of a patient with dup (2) (q33.1q35). American Journal of Medical Genetics. Part A. 2005;134A(1):80-83

[14] Schumacher RE, Rocchini AP, Wilson GN. Partial trisomy 2q. Clinical Genetics. 1983;23(3):191-194

[15] Dworschak GC et al. Comprehensive review of the duplication 3q syndrome and report of a patient with Currarino syndrome and de novo duplication 3q26.32-q27.2. Clinical Genetics. 2017;91(5):661-671

[16] Natera-de Benito D et al. A patient with a duplication of chromosome 3p (p24.1p26.2): A comparison with other partial 3p trisomies. American Journal of Medical Genetics. Part A. 2014;164A(2): 548-550

[17] Charrow J, Cohen MM, Meeker D. Duplication 3p syndrome: Report of a new case and review of the literature. American Journal of Medical Genetics. 1981;8(4):431-436

[18] Varley J, Wehner T, Sisodiya S. Diaphragm myoclonus followed by generalised atonia in a patient with trisomy 4p: Unusual semiology in an unusual condition. Epileptic Disorders. 2015;17(4):473-477

Author details

48

Elizabeth Schaeffer<sup>1</sup>

, Leonardo Porchia1,3, Almena López-Luna1,2,

1 Laboratorio de Investigación y Diagnóstico Molecular, Instituto de Infertilidad y

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Dinorah Hernández-Melchor1,2 and Esther López-Bayghen1,2\*

2 Departamento de Toxicología, Cinvestav-IPN, CDMX, México

3 Tecnologías DAAT SA de CV, Xalapa, Veracruz, México

\*Address all correspondence to: ebayghen@cinvestav.mx

Genética SC, INGENES, CDMX, México

Modern Medical Genetics and Genomics

provided the original work is properly cited.

[19] Collia A et al. Partial duplication of chromosome 4 in a patient with bilateral ocular coloboma. Archivos Argentinos de Pediatría. 2012;110(4):e59-e62

[20] Celle L et al. Duplication of chromosome region 4q28.3-qter in monozygotic twins with discordant phenotypes. American Journal of Medical Genetics. 2000;94(2):125-140

[21] Velagaleti GV, Morgan DL, Tonk VS. Trisomy 5p. A case report and review. Annales de Génétique. 2000;43 (3–4):143-145

[22] Fujita M et al. A new case of "complete" trisomy 5p with isochromosome 5p associated with a de novo translocation t(5;8)(q11;p23). Clinical Genetics. 1994;45(6):305-307

[23] Orye E, Benoit Y, van Mele B. Complete trisomy 5p owing to de novo translocation t(5;22)(q11;p11) with isochromosome 5p associated with a familial pericentric inversion of chromosome 2, inv 2(p21q11). Journal of Medical Genetics. 1983;20(5):394-396

[24] Sivasankaran A et al. De-novo 'pure' partial trisomy (6)(p22.3!pter): A case report and review of the literature. Clinical Dysmorphology. 2017;26(1): 26-32

[25] Savarese M et al. Familial trisomy 6p in mother and daughter. American Journal of Medical Genetics. Part A. 2013;161A(7):1675-1681

[26] Zelante L et al. Interstitial "de novo" tandem duplication of 7(q31.1-q35): First reported case. Annales de Génétique. 2003;46(1):49-52

[27] Alfonsi M et al. A new case of pure partial 7q duplication. Cytogenetic and Genome Research. 2012;136(1):1-5

[28] Mellado C, Moreno R, López F, Sanz P, Castillo S, Villaseca C, et al. Trisomia

8: Reporte de cuatro casos. Revista Chilena de Pediatría. 1997;53(2):93-98

Clinical Dysmorphology. 2001;10(2):

DOI: http://dx.doi.org/10.5772/intechopen.81884

Aneuploidy Rates Inversely Correlate with Implantation during In Vitro…

European Journal of Medical Genetics.

[46] Saldarriaga W, Rengifo-Miranda H,

Chilena de Pediatría. 2016;87(2):129-136

[47] Zellweger H, Beck K, Hawtrey CE. Trisomy 18. Report of a case and discussion of the syndrome. Archives of Internal Medicine. 1964;113:598-605

[48] Bharucha BA et al. Trisomy 18: Edward's syndrome (a case report of 3

[49] Jung SI et al. Two cases of trisomy 19 as a sole chromosomal abnormality in myeloid disorders. The Korean Journal of Laboratory Medicine. 2008;28(3):

[50] Humphries JE, Wheby MS. Trisomy 19 in a patient with myelodysplastic syndrome and thrombocytosis. Cancer Genetics and Cytogenetics. 1990;44(2):

[51] Avila M et al. Delineation of a new chromosome 20q11.2 duplication syndrome including the ASXL1 gene. American Journal of Medical Genetics. Part A. 2013;161A(7):1594-1598

[52] Sidwell RU et al. Pure trisomy 20p

formation and whole arm translocation. Journal of Medical Genetics. 2000;

[53] Hayes SA et al. Cardiovascular and general health status of adults with trisomy 21. International Journal of Cardiology. 2017;241:173-176

[54] He X, Yao D, Zhao ZY. Trisomy 22

Zhongguo Dang Dai Er Ke Za Zhi. 2015;

syndreom: A report of 2 cases.

resulting from isochromosome

37(6):454-458

17(5):524-525

cases). Journal of Postgraduate Medicine. 1983;29(2):129-132

174-178

187-191

Ramirez-Cheyne J. Trisomy 18 syndrome: A case report. Revista

2012;55(3):222-224

[38] Lu HT, Han XH. One case report of Patau syndrome. Zhonghua Er Ke Za

[39] Dutta UR, Pidugu VK, Dalal A. Partial proximal trisomy 14: Identification and molecular

characterization in a girl with global developmental delay. Genetic Counseling. 2013;24(2):207-216

[40] Lacro RV et al. Duplication of distal 15q: Report of five new cases from two different translocation kindreds. American Journal of Medical Genetics.

[42] Laus AC et al. Karyotype/phenotype correlation in partial trisomies of the long arm of chromosome 16: Case report and review of literature. American Journal of Medical Genetics. Part A.

[43] Aviña Fierro JA, Blum ER, Aviña DAH. Trisomía 16 completa. Reporte de un caso clínico. Revista Mexicana de Pediatría. 2005;72(5):237-239

[44] Ho AC et al. A newborn with a 790

microduplication presenting with aortic stenosis, microcephaly and dysmorphic facial features—Is cardiac assessment necessary for all patients with 17p13.3 microduplication? European Journal of Medical Genetics. 2012;55(12):758-762

microduplication in chromosome band 17p13.1 associated with intellectual disability, afebrile seizures, dysmorphic features, diabetes, and hypothyroidism.

[41] Schnatterly P et al. Distal 15q trisomy: Phenotypic comparison of nine cases in an extended family. American Journal of Human Genetics. 1984;36(2):

Zhi. 2011;49(7):555-556

1987;26(3):719-728

2012;158A(4):821-827

kb chromosome 17p13.3

[45] Belligni EF et al. 790 kb

51

444-451

149-150

[29] Brambila-Tapia AJ et al. Pure 9p trisomy derived from a terminal balanced unreciprocal translocation. Genetic Counseling. 2014;25(3):289-297

[30] Arnold GL et al. Trisomy 9: Review and report of two new cases. American Journal of Medical Genetics. 1995;56(3): 252-257

[31] Wong SL et al. Distal 10q trisomy with copy number gain in chromosome region 10q23.1-10q25.1: The Wnt signaling pathway is the most pertinent to the gene content in the region of copy number gain: A case report. BMC Research Notes. 2015;8:250

[32] Manolakos E et al. Proximal 10q duplication in a child with severe central hypotonia characterized by arraycomparative genomic hybridization: A case report and review of the literature. Experimental and Therapeutic Medicine. 2014;7(4):953-957

[33] Utine GE et al. Partial trisomy 11q syndrome (11q23.1!11qter) due to de novo t (11q; 13q) detected by multicolor fluorescence in situ hybridisation. Genetic Counseling. 2005;16(3):291-295

[34] Pihko H, Therman E, Uchida IA. Partial 11q trisomy syndrome. Human Genetics. 1981;58(2):129-134

[35] Geckinli BB et al. Clinical report of a patient with de novo trisomy 12q23.1q24.33. Genetic Counseling. 2015;26(4):393-400

[36] Oka N et al. Norwood procedure performed on a patient with trisomy 13. International Heart Journal. 2016;57(1): 121-122

[37] Tunca Y, Kadandale JS, Pivnick EK. Long-term survival in Patau syndrome.

Aneuploidy Rates Inversely Correlate with Implantation during In Vitro… DOI: http://dx.doi.org/10.5772/intechopen.81884

Clinical Dysmorphology. 2001;10(2): 149-150

[19] Collia A et al. Partial duplication of chromosome 4 in a patient with bilateral ocular coloboma. Archivos Argentinos de Pediatría. 2012;110(4):e59-e62

Modern Medical Genetics and Genomics

8: Reporte de cuatro casos. Revista Chilena de Pediatría. 1997;53(2):93-98

[29] Brambila-Tapia AJ et al. Pure 9p trisomy derived from a terminal balanced unreciprocal translocation. Genetic Counseling. 2014;25(3):289-297

[30] Arnold GL et al. Trisomy 9: Review and report of two new cases. American Journal of Medical Genetics. 1995;56(3):

[31] Wong SL et al. Distal 10q trisomy with copy number gain in chromosome region 10q23.1-10q25.1: The Wnt signaling pathway is the most pertinent to the gene content in the region of copy number gain: A case report. BMC Research Notes. 2015;8:250

[32] Manolakos E et al. Proximal 10q duplication in a child with severe central hypotonia characterized by arraycomparative genomic hybridization: A case report and review of the literature.

[33] Utine GE et al. Partial trisomy 11q syndrome (11q23.1!11qter) due to de

[34] Pihko H, Therman E, Uchida IA. Partial 11q trisomy syndrome. Human

[35] Geckinli BB et al. Clinical report of a

[36] Oka N et al. Norwood procedure performed on a patient with trisomy 13. International Heart Journal. 2016;57(1):

[37] Tunca Y, Kadandale JS, Pivnick EK. Long-term survival in Patau syndrome.

Experimental and Therapeutic Medicine. 2014;7(4):953-957

novo t (11q; 13q) detected by multicolor fluorescence in situ hybridisation. Genetic Counseling.

Genetics. 1981;58(2):129-134

patient with de novo trisomy 12q23.1q24.33. Genetic Counseling.

2005;16(3):291-295

2015;26(4):393-400

121-122

252-257

[20] Celle L et al. Duplication of chromosome region 4q28.3-qter in monozygotic twins with discordant phenotypes. American Journal of Medical Genetics. 2000;94(2):125-140

[21] Velagaleti GV, Morgan DL, Tonk VS. Trisomy 5p. A case report and review. Annales de Génétique. 2000;43

[22] Fujita M et al. A new case of "complete" trisomy 5p with

[23] Orye E, Benoit Y, van Mele B. Complete trisomy 5p owing to de novo translocation t(5;22)(q11;p11) with isochromosome 5p associated with a familial pericentric inversion of chromosome 2, inv 2(p21q11). Journal of Medical Genetics. 1983;20(5):394-396

isochromosome 5p associated with a de novo translocation t(5;8)(q11;p23). Clinical Genetics. 1994;45(6):305-307

[24] Sivasankaran A et al. De-novo 'pure' partial trisomy (6)(p22.3!pter): A case report and review of the literature. Clinical Dysmorphology. 2017;26(1):

[25] Savarese M et al. Familial trisomy 6p in mother and daughter. American Journal of Medical Genetics. Part A.

[26] Zelante L et al. Interstitial "de novo" tandem duplication of 7(q31.1-q35): First reported case. Annales de Génétique. 2003;46(1):49-52

[27] Alfonsi M et al. A new case of pure partial 7q duplication. Cytogenetic and Genome Research. 2012;136(1):1-5

[28] Mellado C, Moreno R, López F, Sanz P, Castillo S, Villaseca C, et al. Trisomia

2013;161A(7):1675-1681

(3–4):143-145

26-32

50

[38] Lu HT, Han XH. One case report of Patau syndrome. Zhonghua Er Ke Za Zhi. 2011;49(7):555-556

[39] Dutta UR, Pidugu VK, Dalal A. Partial proximal trisomy 14: Identification and molecular characterization in a girl with global developmental delay. Genetic Counseling. 2013;24(2):207-216

[40] Lacro RV et al. Duplication of distal 15q: Report of five new cases from two different translocation kindreds. American Journal of Medical Genetics. 1987;26(3):719-728

[41] Schnatterly P et al. Distal 15q trisomy: Phenotypic comparison of nine cases in an extended family. American Journal of Human Genetics. 1984;36(2): 444-451

[42] Laus AC et al. Karyotype/phenotype correlation in partial trisomies of the long arm of chromosome 16: Case report and review of literature. American Journal of Medical Genetics. Part A. 2012;158A(4):821-827

[43] Aviña Fierro JA, Blum ER, Aviña DAH. Trisomía 16 completa. Reporte de un caso clínico. Revista Mexicana de Pediatría. 2005;72(5):237-239

[44] Ho AC et al. A newborn with a 790 kb chromosome 17p13.3 microduplication presenting with aortic stenosis, microcephaly and dysmorphic facial features—Is cardiac assessment necessary for all patients with 17p13.3 microduplication? European Journal of Medical Genetics. 2012;55(12):758-762

[45] Belligni EF et al. 790 kb microduplication in chromosome band 17p13.1 associated with intellectual disability, afebrile seizures, dysmorphic features, diabetes, and hypothyroidism.

European Journal of Medical Genetics. 2012;55(3):222-224

[46] Saldarriaga W, Rengifo-Miranda H, Ramirez-Cheyne J. Trisomy 18 syndrome: A case report. Revista Chilena de Pediatría. 2016;87(2):129-136

[47] Zellweger H, Beck K, Hawtrey CE. Trisomy 18. Report of a case and discussion of the syndrome. Archives of Internal Medicine. 1964;113:598-605

[48] Bharucha BA et al. Trisomy 18: Edward's syndrome (a case report of 3 cases). Journal of Postgraduate Medicine. 1983;29(2):129-132

[49] Jung SI et al. Two cases of trisomy 19 as a sole chromosomal abnormality in myeloid disorders. The Korean Journal of Laboratory Medicine. 2008;28(3): 174-178

[50] Humphries JE, Wheby MS. Trisomy 19 in a patient with myelodysplastic syndrome and thrombocytosis. Cancer Genetics and Cytogenetics. 1990;44(2): 187-191

[51] Avila M et al. Delineation of a new chromosome 20q11.2 duplication syndrome including the ASXL1 gene. American Journal of Medical Genetics. Part A. 2013;161A(7):1594-1598

[52] Sidwell RU et al. Pure trisomy 20p resulting from isochromosome formation and whole arm translocation. Journal of Medical Genetics. 2000; 37(6):454-458

[53] Hayes SA et al. Cardiovascular and general health status of adults with trisomy 21. International Journal of Cardiology. 2017;241:173-176

[54] He X, Yao D, Zhao ZY. Trisomy 22 syndreom: A report of 2 cases. Zhongguo Dang Dai Er Ke Za Zhi. 2015; 17(5):524-525

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of chromosomal risk following

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2008;456(7218):53-59

2011;475(7356):348-352

606-607

109(4):627-632

2015;11(6):e1005241

840:155-170

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The Journal of Reproduction and Development. 2018 Oct 12;64(5):371- 376. DOI: 10.1262/jrd.2018-040. Epub

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amplification. Nature. 1990;344(6268):

Preimplantation genetic screening: A systematic review and meta-analysis of RCTs. Human Reproduction Update.

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[97] Fiorentino F et al. Development and

[98] Kurahashi H et al. Preimplantation

validation of a next-generation sequencing-based protocol for 24 chromosome aneuploidy screening of embryos. Fertility and Sterility. 2014;

genetic diagnosis/screening by comprehensive molecular testing. Reproductive Medicine and Biology.

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rticle.jsp?pageId=8100002

products/embryocellect/

com/array/array\_kits/24surepgs-microarray-kit.html

101(5):1375-1382

2016;15(1):13-19

[94] Mastenbroek S et al.

2011;17(4):454-466

768-770

100-106

[86] Gardner DK et al. Environment of the preimplantation human embryo in vivo: Metabolite analysis of oviduct and uterine fluids and metabolism of cumulus cells. Fertility and Sterility.

[87] Gardner DK, Lane M. Culture of viable mammalian embryos. In: Cibelli J, Wilmut I, Jaenisch R, Gurdon J, Lanza R, West M, Campbell K, editors. Principles of Cloning. 2nd ed. Elsevier; 2014. pp. 63-84. DOI: https://doi.org/

[88] Wale PL, Gardner DK. The effects of chemical and physical factors on mammalian embryo culture and their importance for the practice of assisted

Reproduction Update. 2016;22(1):2-22

[89] Wang WH et al. Limited recovery of

[90] Brezina PR, Anchan R, Kearns WG. Preimplantation genetic testing for aneuploidy: What technology should you use and what are the differences? Journal of Assisted Reproduction and

2018 Jul 7

1996;65(2):349-353

10.1016/C2010-0-66663-6

human reproduction. Human

meiotic spindles in living human oocytes after cooling-rewarming observed using polarized light microscopy. Human Reproduction.

2001;16(11):2374-2378

Genetics. 2016;33(7):823-832

testing. BMJ. 2015;350:g7611

BMJ. 2012;345:e5908

54

[91] Brezina PR, Kutteh WH. Clinical applications of preimplantation genetic

[92] Brezina PR, Brezina DS, Kearns WG. Preimplantation genetic testing.

[93] Handyside AH et al. Pregnancies from biopsied human preimplantation embryos sexed by Y-specific DNA

[104] Rothberg JM et al. An integrated semiconductor device enabling nonoptical genome sequencing. Nature. 2011;475(7356):348-352

[105] Fragouli E. Next generation sequencing for preimplantation genetic testing for aneuploidy: Friend or foe? Fertility and Sterility. 2018;109(4): 606-607

[106] Friedenthal J et al. Next generation sequencing for preimplantation genetic screening improves pregnancy outcomes compared with array comparative genomic hybridization in single thawed euploid embryo transfer cycles. Fertility and Sterility. 2018; 109(4):627-632

[107] Treff NR et al. Evaluation of targeted next-generation sequencingbased preimplantation genetic diagnosis of monogenic disease. Fertility and Sterility. 2013;99(5):1377-1384 e6

[108] Fragouli E et al. Altered levels of mitochondrial DNA are associated with female age, aneuploidy, and provide an independent measure of embryonic implantation potential. PLoS Genetics. 2015;11(6):e1005241

[109] Yin X et al. Massively parallel sequencing for chromosomal abnormality testing in trophectoderm cells of human blastocysts. Biology of Reproduction. 2013;88(3):69

[110] Knapp M, Stiller M, Meyer M. Generating barcoded libraries for multiplex high-throughput sequencing. Methods in Molecular Biology. 2012; 840:155-170

[111] Franasiak JM et al. The nature of aneuploidy with increasing age of the female partner: A review of 15,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening. Fertility and Sterility. 2014;101(3):656-663 e1

[112] Lukaszuk K et al. Next generation sequencing for preimplantation genetic testing of blastocysts aneuploidies in women of different ages. Annals of Agricultural and Environmental Medicine. 2016;23(1):163-166

Chapter 4

Abstract

Malformations

invasive medical procedures.

detection of fetal malformations

1. Introduction

57

Gladys Cristina Al Jashi and Isam Al Jashi

Screening (Bi Test, Triple Test,

Panorama Test) and Amniocentesis

for Early Diagnosis of Congenital

The genetic consult is very important in the diagnosis of early fetal

malformations and its complications at birth and after it. Our research is based on a 3-year research on 6097 pregnant women who underwent screening Bi-Test or Triple Test. We discovered 408 pregnant women who were found positive and needed amniocentesis for a diagnostic of certitude. Out of them, 14 had a positive result from which 10 were found with Down syndrome and 4 with Edwards syndrome. In Romania, amniocentesis has become the most used method of prenatal diagnosis for pregnant women at 35 or above with a family history of hereditary congenital anomalies. However, the latest screening test from maternal blood, the Panorama test, can discover many malformations (for chromosomes 21, 18, and 13 and the abnormality of the sex chromosome). The accuracy for false positive is 2% and false negative 98%. In that light, the purpose of our study is to decrease the use of amniocentesis and to introduce the latest tests (Panoramic) for the early diagnosis of fetal malformation, the use of maternal blood, and the avoidance of using

Keywords: screening Bi-Test,Triple Test, Panorama Test, amniocentesis for early

Talking with the patient about his or her family medical history, such as if the couple had a person with Down syndrome in their family or any other malformation, is important. That can be considered as a 'genetic consultation' in order to find out about any possible genetic problems before screening or any other tests. The specialist tries, in the first place, to make the patient understand the nature of his disease he is confronting, what's the most possible evolution of it, and last but not least what are the possibilities of treating it. A major objective of the genetic consult is to make the patient understand what are the factors that lead to the development of the disease, what are the mechanisms that transmit the disease, and how high is the risk of appearance to other family members. The doctor establishes, after running different tests, the correct diagnosis of the disease, its evolution, its prognosis,

as well as the possibilities of treatment for a higher quality of life.

## Chapter 4
