What is PGS?

Preimplantation Genetic Screening (PGS) for Chromosomal Abnormalities

PGS screening

Have you ever envisioned that the tiny  sparkling embryo–ladies and the tiny handsome embryo–dudes can be  absolutely different after being “designed” in the laboratory? Have you  ever thought that experts rate them as “Normal one”, “abnormal one”, and  “mosaic one?” After that, the Respected Embryologist with extensive  experience will cast a suspicious glance at his notes and a furtive  glance at you through his smart glasses and say: “Normal embryos can be  transferred. Abnormal embryos cannot be transferred. You have the mosaic  embryos only.”

You will be confused  and will curl your lips into an amusing smile by the term “mosaic  embryo.” You will whisper: “And mosaic ones? ‘Who’ or ‘What’ Are They?  Is it Possible to Transfer Them? Should I Give This Little One the  Chance?’”

Here it should be also  noted that Mosaic Embryos are the most mysterious ones. They have both  normal and abnormal cells and can correct themselves! Wondering is it  possible to transfer them?

The  interpretation of mosaicism among tiny preimplantation embryo–babies is  complicated both for doctors and patients. The “Mosaic Embryo” is an  embryo with both types of cells: normal and abnormal ones. Therefore,  mosaic embryos represent a third category between normal (euploid) and  abnormal (aneuploid) embryos. Some of the mosaic embryos have perfect  chances to turn into the wonderful healthy fetuses. The others may cause  the early or late pregnancy loss or even more complexities. This  category of mosaic embryos may be characterized by decreased  implantation and pregnancy potential with an increased risk of genetic  abnormalities to the fetus and adverse pregnancy outcomes. But every  case of embryonic mosaicism is unique and should be investigated prior  to embryo implantation.

Many  preimplantation embryos designed during IVF treatment cycles contain two or more cytogenetically distinct cell lines. This phenomenon, known as  chromosomal mosaicism, can involve the presence of cells with different  types of abnormality [aneuploidy], the absence of any normal embryonic  cells or a mixture of normal [euploid] and abnormal [aneuploid]  embryonic cells. To Glance “Inside” the Tiny Sparkling Embryos and to  find out are they normal, abnormal, or mosaic, – the Preimplantation  PGS screening was designed.

Wondering  how to interpret “Preimplantation genetic screening (PGS)?” 


Preimplantation  genetic screening (PGS) for aneuploidy is a test to be performed on embryos during IVF treatment to screen for chromosomal abnormalities.


Recent  studies have represented that among tiny mosaic embryo–dudes and  embryo–ladies, or embryos with a mix of normal (euploid) and abnormal  (aneuploid) cells, many still have the potential to implant in the womb  and develop into chromosomally healthy fetuses, and, surely, turn in  healthy newborn–bundles!

The  interpretation of mosaicism among preimplantation embryos is complicated  thing both for doctors and couples. Doctors should identify those  mosaic embryos that won’t have the developmental abnormalities. Couples  should make the serious decision concerning the preimplantation genetic  screening (PGS) testing that reveals the abnormalities in the genetic  content. And this decision should be made only after the counselling.

Genetic  Counselling is exclusively designed for giving the couples the most  transparent and inclusive information about whether or not to pursue  PGS. The pre–test (pre–PGS) counseling should include a discussion about  the frequency of mosaic results, the challenges associated with the  interpretation of these results, the possibility of a false positive  diagnosis of embryonic mosaicism, and the limited predictive data  available. The Genetic Counsellor should also say that the priority for  embryo transfer should be given to mosaic embryos with low mosaicism  levels.


Part 1: Mosaic Embryos: ‘Who’ or ‘What’ Are They? Is it Possible to Transfer Them?

(1.1) What is an ‘EMBRYO’?

The  assembly of a new life first depends on the union between a  spermatozoon and an oocyte culminating in fertilization. If the  fertilization occurs, the EMBRYO APPEARS. Fertilization is a mysterious  phenomenon that turns two cells into a tiny embryo–dude or a tiny  embryo–lady, or if two oocytes are fertilized than…two tiny  embryo–dudes. Or two tiny embryo–ladies. Or if three oocytes are  fertilized than three tiny embryo–babies: two tiny embryo–dudes and one  tiny embryo–lady. Many versions can be inserted here.


(1.2) How does the embryo appear in a natural way?

Wondering  how does FERTILIZATION happen? Usually, a spermatozoon and an oocyte  ‘meet’ in one of the two Fallopian tubes that connect the ovaries to the  womb (uterus). Wondering how does the embryo–baby normally ‘appears’  and implants in the uterus? The tiny embryo–dude or the tiny embryo–lady  (fertilized oocyte) then moves down the Fallopian tube by being wafted  by fine hairs inside the tubes until it reaches the womb (uterus) two,  three or four days later. Once there, this tiny embryo–bundle wonders  where it should cuddle up itself in this new place. And it implants,  attaching itself to the womb lining and that is where it usually  continues to grow and develop.

The  ability of the Fallopian tube to transfer the early embryo into the  uterus is an excessive modality for a successful pregnancy. Apparently,  structural abnormalities and functional abnormalities of the Fallopian  tube will interfere with the embryo transfer process that can lead to  tubal pregnancy.


(1.3) How does the EMBRYO appear in case if it is IVF treatment cycle? 

In  Vitro Fertilization treatment cycle is designed to create the embryos  in the laboratory and after that to transfer them to the mother’s  uterus. In other words, FERTILIZATION [or EMBRYO ‘CREATION’] happens in  the laboratory.

Embryologists will  ‘design’ your tiny embryo–ladies and embryo–dudes in the laboratory.  They will take the retrieved oocytes and toss them in a Petri dish with  your husband’s sperm and let them do their thing. Another option is  called intracytoplasmic sperm injection (ICSI), where the Embryologists  manually fertilize the oocytes with the sperm individually, but it is  for extreme cases only.

The embryo  will appear inside your uterus via the catheter. Your tiny scared  embryo–lady or embryo–dude is taken out of the Petri–dish and waits for a  ‘BIG TRANSFER’. If it is the time to replace this small embryo–bundle  from the tube inside your uterus, it is placed inside a flexible  catheter. The procedure of Embryo Transfer takes only several minutes.  It takes all of three minutes to insert a weird kind of catheter, get it  to where it needs to be, accurately place your little embryo inside  your uterus, and that is all. YES, and it has to ‘LEARN’ so many things  inside. It wonders: ‘Where am I?’ ‘What has happened?’ ‘Everything is  pulsating around me…’ ‘Should I curl up here or there?’ ‘Oh, it is  better on the left side?’ ‘I am scared. I will just cuddle up to that  warm place and sleep there.’


(1.4) Embryo classification [Classifying mosaicism in embryos]

Most  fertility clinics and labs have the strong exclusion/inclusion criteria  for the embryo classification. They classify embryos as “normal”  (euploid) or “abnormal” (aneuploid). Normal embryos should implant  without complications. They (euploid embryos) should be preferentially  transferred over mosaic embryos. Abnormal embryos may implant, but even  in this case, the miscarriage will occur. And mosaic embryos are the  most mysterious ones. They not only have both normal and abnormal cells.  That means that they may correct themselves and become the viable  healthy fetuses or may cause the miscarriages and variable  abnormalities.

Embryonic  mosaicism occurs when the embryo has multiple genotype content. That  means that two or more cell populations with different genotypes are  present within the same embryo. New diagnostic techniques for  preimplantation genetic screening (PGS), such as next–generation sequencing, have led to increased revealing and reporting of mosaicism.  Most experts do not recommend transferring the mosaic embryos because of  the lower implantation rates, increased risks of miscarriages, and  increased risks of genetic abnormalities. But there is still one BUT.  The interpretation of mosaicism is complicated because the transfer of  some mosaic embryos has resulted in healthy fetuses and births of  healthy babies. Do you remember that sometimes the mosaic embryos can  correct themselves?


(1.5) What Are the Mosaic Embryos?

The  ‘Mosaic Embryo’ is the term that is assigned to that embryo that has  both normal and abnormal cells, that are revealed during preimplantation  genetic screening (PGS) testing. In the case of embryonic mosaicism,  the testing discloses the percentage of the cells with different genetic  complements and shows the potential embryonic viability.

Not  only IVF embryos’ may have mixed chromosomal contents, one embryo can  be normal, another embryo can be abnormal, and the third embryo can be  mosaic, but also those tiny embryo–dudes and embryo–ladies that appeared  naturally. Wondering what does that mean ‘mosaic embryo has mixed  chromosomal content’? The mosaic embryo contains some cells with a  normal number of chromosomes and others with an abnormal number of  chromosomes.

Mosaic embryos may  represent a third category of embryos being between normal and abnormal  ones. Wondering why do they represent the third category? They represent  the third category because of the mysterious self–correction  phenomenon. 


The experts say that mosaic cleavage stage embryos  left in extended culture have been shown to self–correct to euploid  blastocysts (normal embryos) in nearly 50% of cases. 


Therefore,  this pattern of mysterious embryonic mosaicism, which is characterized  by the presence of two or more genetically distinct cell lineages,  typically one with a chromosome abnormality and the other with a normal  chromosome composition, has become a controversial topic with the  spirited debate over their potential viability.


(1.6) What does the Mosaic Embryo look like inside?

Metaphorically  saying, have you ever seen the pearl rondelle beads accurately covered  ‘curled up’ in translucent package or envelope? If you have never even  envisioned that, Google the rondelle pearl beads ‘curled up’ in  translucent package or envelope. This is how your handsome embryo–dude  or gorgeous embryo–lady looks like inside. If we are talking about the  normal [healthy] embryo, this pearl content is accurately shaped,  ivory–colored and has no ‘dark–blue’ [abnormal] pearls.

The  mosaic embryo is a phenomenon. This tiny BUNDLE can be envisioned as  mixed pearls: ivory and dark–blue pears in the same line accurately  covered ‘curled up’ in translucent package or envelope. It doesn’t have  the pure chromosomal content. It has the affected [or even mixed]  chromosomal content. But this affected content has its own categories  as, in future, if the mosaic embryo corrects itself, the affected mosaic  cells can be ‘TRANSFERRED’ to the placenta and won’t affect the tiny  fetus, or, in the other case, they can turn the tiny embryo in ‘MOSAIC  FETUS’ with many abnormalities. And the hardest question is should you  give this little one the chance?


(1.7) Does the mosaicism affect all embryonic cells?

Mosaic  embryos can be categorized according to the percentage of abnormal  cells in the biopsy, the chromosomes involved, and the types of  abnormalities (full chromosome, the segment of a chromosome, single  chromosome involved or multiple).

The  mosaic embryo–dudes and embryo–ladies that have several chromosomes  affected by mosaic abnormality [mosaic aneuploidy] have significantly  lower implantation rates than any other category of mosaic embryos. In  contrast, embryos with a mosaic segmental abnormality have a capacity to  implant.


(1.8) How do they ‘REVEAL’ the mosaic embryos? 

Mosaic  preimplantation embryos contain two or more cell lines with different  chromosome content, the consequence of errors in chromosome segregation  occurring during mitotic divisions. In other words, their chromosome  content is mixed. The scientists have designed advanced techniques to  identify those tiny mosaic embryos. Wondering which ones?

In  the past, to identify the embryonic mosaicism, the experts used  fluorescence in situ hybridization (FISH), a method favored because it  represented the information on the chromosomal content of each cell.  Using this method, the experts usually examined only about one–third to  one–half of the chromosomes in each cell.

At present, the experts use the most advanced and accurate techniques for detecting the embryonic mosaicism.

Molecular  cytogenetic techniques (for example, array comparative genome  hybridization [aCGH], single–nucleotide polymorphism [SNP] array,  quantitative polymerase chain reaction [qPCR], next–generation  sequencing [NGS]) have the significant advantage over FISH technique.  Wondering which one? Molecular cytogenetic techniques represent the  information on the copy number of all 24 types of the chromosome.

Alternatively,  the experts may use comprehensive chromosome screening technologies.  These technologies involve the analysis of blastocyst biopsy samples,  typically composed of 5 embryonic cells, which are not separated but  instead are analyzed as a single entity. Although the presence of a  mixture of normal and aneuploid cells in the testing sample can  sometimes be detected with the use of methods such as aCGH, qPCR, and  SNP array, they are relatively insensitive for this purpose. If the  ideal results are obtained, mosaicism associated with proportions of  aneuploid cells ranging from 40% to 60% can be detected.

The  most accurate method to detect embryonic mosaicism is the new advanced  technique of high–resolution next–generation sequencing (hr–NGS). hr–NGS  technique accurately detects embryonic mosaicism (aneuploid embryonic  cells) from 20% to 80%. This method is utterly sensitive for detecting  minor lines in mixed cell populations compared with aCGH (but several  experts suggest aCGH as it has 100% specificity and sensitivity).


(1.9) Why should they validate the ‘embryonic mosaicism’? 

Embryonic  mosaicism is closely associated with the pregnancy loss. It is proven  that the embryos with a mosaic biopsy miscarry more often and implant  less frequently, although it is also clear that some of the mosaic  embryos can correct themselves and turn into the viable fetuses.

Currently,  there is no technique that detects the embryonic mosaicism with 100%  specificity and sensitivity. To confirm that the embryo is ‘mosaic’ or  ‘normal’, sometimes more than one technique should be used. The embryos  categorized by hr–NGS as abnormal [aneuploid] or normal [euploid] are  recommended to be confirmed by the aCGH technique. Mosaic embryos  (20%–80% abnormal cells estimated by hr–NGS technique) may show the  different results. On the other hand, hr–NGS technique detects many more  mosaics than the aCGH technique.

Embryonic  mosaicism can be revalidated with the use of the aCGH and the mosaicism  may be not reliably detected. On the contrary, those embryos that are  categorized as ‘NORMAL’ with the use of hr–NGS technique, after the  revalidation with the use of the aCGH technique, may have the mosaic  chromosomal content.

The fact that  most of the mosaic embryos detected by hr–NGS are classified as ‘NORMAL’  when analyzed using the aCGH technique, indicates that validation of  the embryonic mosaicism should be done.

Some  of the experts may say that validation would result in fewer embryos  receiving a “normal” diagnosis after PGS–A, but, this strong criterion  may also result in transferring the most viable embryos with accurate  chromosomal content and decreasing the miscarriage rates.


(1.10) Embryo selection: which mosaic embryos are better to transfer?

Chromosomal  abnormalities that occur in mosaic embryos can be categorized as  ‘monosomies’ and ‘trisomies’ Normally, there are 46 chromosomes arranged  in 23 pairs. Twenty–two chromosomal pairs are called ‘autosomes’, and  one pair, number 23, is the sex chromosomes. Any variation from this  gold pattern causes chromosomal abnormalities.

A  chromosome from any of the pairs may be duplicated (trisomy) or absent  (monosomy); an entire set of 23 chromosome pairs can be duplicated three  (triploidy) or more (polyploidy) times; or one arm or part of one arm  of a single chromosome may be missing (deletion).

The  experts recommend that the percentage of mosaicism be considered in  embryo selection decisions. It must be also noted that the proportion of  aneuploidy should be less than 20 percent because the higher percentage  of aneuploidy is associated with the adverse outcomes. The higher  percentage of aneuploidy not only disturbs but also may disrupt the  delicate balance of genetic content.

They  also recommend the preferential transfer of embryos showing mosaic  monosomies over mosaic trisomies. The embryos showing mosaic  euploid/monosomy are preferable to euploid/trisomy, given that monosomic  embryos (excepting 45,X) are not viable. 

Another  recommendation given by the experts is to transfer some mosaic embryos  in preference to others, depending on the type of chromosome involved.  The most problematic mosaic embryos that shouldn’t be transferred are  those that have affected chromosomes 14 and 15; chromosomes 2, 7, and  16; and chromosomes 13, 18, and 21.

Mosaic  embryos involving chromosomes 14 and 15 will cause the genetic  disorder, called ‘disomy’. It is the condition of having a chromosome  represented twice in a chromosomal complement. Mosaic embryos that have  abnormalities in chromosomes 2, 7, and 16 are associated with  intrauterine growth retardation. And mosaic embryos with affected  chromosomes 13, 18, and 21 are considered to be problematic because in  trisomic form these abnormalities can potentially reach term and the  abnormalities they cause are beyond the imagination.


Part 2: Mosaic Embryo: Should You Give This Little One the Chance?

(2.1) Why does the mosaicism happen? 

You  won’t believe but the embryos are prone to mosaicism. Embryonic  mosaicism was found to result from mitotic errors occurring after  fertilization (after the embryo is created). As an early embryo (the  fertilized oocyte) develops into a fetus, cells that initially acquired  the extra chromosome give rise to new and larger populations of cells  with the extra chromosome. All cells produced from the initial abnormal  cell have the trisomy, but cells produced from the normal cells have the  usual 46 chromosomes.

Or, there is  another version of the mosaicism. The embryonic mosaicism happens  because the sperm or oocyte itself had an extra copy of the chromosome.  Normally, an early embryo (fertilized oocyte) contains 46 chromosomes.  Mosaicism occurs in case if an early embryo (fertilized oocyte) contains  47 chromosomes. This occurs as a result of trisomy, in which there is  an extra copy of a chromosome appears in an embryonic cell. In some  cases, only some of the embryonic cells have the extra chromosome. Why  does an extra copy of a chromosome appear in some embryonic cells? This  happens in case if the sperm or oocyte itself had an extra copy of the  chromosome, and the extra copy was not passed on to all cells after  fertilization.

And the most wonderful thing is that the mosaic embryos may correct themselves. Isn’t it amusing?


(2.2) Is it possible to reveal the mosaicism in an early embryo? 

Yes,  it is possible to reveal the mosaicism in an embryo. Preimplantation  genetic screening (PGS) was exclusively designed for the detection of  the embryonic mosaicism in a single biopsy. The testing, usually  performed on day 5 of embryo development, is completed by taking a tiny  biopsy of the embryonic cells and examining the genetic makeup of the  cell. During the examination, embryologists can detect, and often  diagnose, potential chromosomal abnormalities.


(2.3) Embryo selection: which mosaic embryos are better to transfer?

Chromosomal  abnormalities that occur in mosaic embryos can be categorized as  ‘monosomies’ and ‘trisomies’ Normally, there are 46 chromosomes arranged  in 23 pairs. Twenty–two chromosomal pairs are called ‘autosomes’, and  one pair, number 23, is the sex chromosomes. Any variation from this  gold pattern causes chromosomal abnormalities.

A  chromosome from any of the pairs may be duplicated (trisomy) or absent  (monosomy); an entire set of 23 chromosome pairs can be duplicated three  (triploidy) or more (polyploidy) times, or one arm or part of one arm  of a single chromosome may be missing (deletion).

The  experts recommend that the percentage of mosaicism be considered in  embryo selection decisions. It must be also noted that the proportion of  aneuploidy should be less than 20 percent because the higher percentage  of aneuploidy is associated with the adverse outcomes. The higher  percentage of aneuploidy not only disturbs but also may disrupt the  delicate balance of genetic content.

They  also recommend the preferential transfer of embryos showing mosaic  monosomies over mosaic trisomies. It should be also noted that if the  mosaic embryo doesn’t correct itself, the consequences can be fatal,  including the early or late pregnancy loss, physical and cognitive  defects, morbidity and mortality.


(2.4) Genetic Counseling is highly recommended

Because  mosaic embryos are less likely to produce a viable pregnancy your  doctor may recommend you not to transfer them. Normal embryos should be  preferentially transferred over mosaic embryos. In case if you would  decide to transfer the tiny mosaic embryo–dude or gorgeous mosaic  embryo–lady, you should know that this small bundle of nerves has the  chances as it may correct itself. If the transfer of the mosaic embryo  is being considered, you should have also the genetic counseling about  potential benefits and risks that are closely associated with this  issue.


CONCLUSION: 

The mosaic embryo is a phenomenon as it contains both normal and abnormal  embryonic cells. And it is difficult to say, which embryonic cells will  prevail. This mystery hides either miracle or frustration. Therefore,  prior to transfer the tiny mosaic embryo, it should be accurately  validated.

The use of only one  advanced technique for the detection of mosaicism and/or the application  of diagnostic criteria that categorize most mosaic embryos as either  normal or abnormal has negative clinical consequences. Mosaic embryos  may be categorized as abnormal [aneuploidy], leading to potentially  viable embryos being discarded, or as entirely normal, carrying an  elevated risk of aneuploid pregnancy.

Every  chromosome can be associated with an abnormal phenotype when in mosaic  form, the spectrum extending from apparently normal to severely  affected/lethal. However, as mentioned above, the types of mosaicism  observed during preimplantation embryonic development, and those that  affect the fetus or the newborn might represent different phenomena.  This is probably one of the most important questions remaining to be  answered by the experts.

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