Find out more about genetic diagnostic methods
PGT-A (Preimplantation Genetic Testing for Aneuploidy)
(earlier known as PGS: Preimplantation Genetic Screening)
Preimplantation screening is a genetic examination of embryos before their reintroduction into the woman’s uterus. The examination allows us to choose the euploid embryo or embryos, or those with a standard number of chromosomes and without any identified genetic abnormality, and therefore increase the chance of pregnancy or limit the risk of miscarriage or the birth of a child with a chromosome defect. Biopsy is performed on day 5 or 6 of their development, which means on the blastocysts, when a group of cells from each good quality blastocyst is sampled. Only the part from which placenta is made is sampled, which means minimum risk for the further development of the embryo. The sampled material is sent to a genetic laboratory for examination. The embryos themselves stay in our centre, but because they would not survive until the expected result of the examination it is necessary to freeze them after the biopsy. The result is produced in approx. 3-6 weeks. The results of chromosome screening are always known before the transfer of the embryo to the mother’s womb.
Can we recommend PGT-A to you as well?
Many IVF cycles may end in disappointment because the embryo may fail to nest successfully within the mother’s body. It is the incorrect number of chromosomes in an embryo that has been transferred to the mother’s womb that constitutes potentially the most common cause of artificial fertilisation. When the embryo exhibits excess chromosomes or lacks others it is called aneuploidy. After introducing the aneuploid embryo the implant mostly never occurs – approx. 50% of all gravidities (negative pregnancy test) or pregnancies end with a miscarriage during the first trimester – approx. 10-15%.
Preimplantation screening is suitable for couples who exhibit the following indications:
- higher female partner age – as the female partner’s age increases so does the risk of aneuploidy in embryos due to the diminishing quality of her eggs. It was proven that this is the main cause of the rapid decrease of fertility in women older than 33-35 years of age. It is therefore not only the number of eggs that is diminishing but also their quality.
- repeated miscarriage after excluding all other causes
- repeated failures of previous assisted reproduction cycles
- miscarriage or birth of a foetus with a development defect (chromosome abnormity)
- numerical gonosomal aberrations (e.g. 47XXX, 47XYY) and small gonosomal mosaics detected in peripheral blood (above 10%)
- male (andrological) factor (e.g. serious oligoastenoteratozoospermia) using sperm obtained through the MESA/TESE/PESA/TESA method
- cases after oncological disease treatment using chemotherapy or radiotherapy in one or both partners
Purpose of PGT-A
The purpose of PGT-A is to increase the chance of the birth of a healthy child and boost the success rate of the IVF cycle. In a common IVF cycle without preimplantation examination the embryos are chosen for transfer based on morphological criteria or the dynamics of their development. However, these criteria probably do not suffice to reliably exclude an embryo with a genetic abnormity.
In some cases the couples with a fertility defect oppose chromosome screening because they fear the freezing procedure, the biopsy itself, or in connection with the postponing of the transfer plan and so postponing their desired goal – a healthy baby. However, there is not nearly enough solid ground for such worries. Biopsy and freezing is a procedure for which only embryos of superior quality are selected, and so it presents only minimum stress to these embryos. The success rate of “fresh” blastocyst transfers of optimum quality is comparable with the transfer of embryos after freezing. The postponement of the transfer by a few months (1-3) therefore in this case provides a greater chance of success – birth of a healthy baby.
It is mainly caused by the fact that the negative pregnancy test, spontaneous miscarriage or silent miscarriage within the first trimester. If a manual revision of the uterine cavity is needed after the miscarriage of the foetus, the minimum recommended time period before the next embryotransfer is 6-12 weeks.
Other potential benefits of PGT-A:
- Lower risk of complications during pregnancy, lower number of multiple pregnancies – after preimplantation screening we typically recommend the transfer of only one embryo.
- The shortening of the treatment and reduction of financial costs connected with the birth of a healthy child thanks to a lower number of repeated cycles.
- Based on the results of the embryo genetic testing the couple may decide to repeat the IVF cycle with their own eggs, or in case of a bad result, ask for a cycle with donated eggs/sperm.
- Couples with a worse estimated success rate of the IVF cycle can significantly increase their estimate using PGT-A and achieve the same level of success as couples who have a good lookout from the start, which means a success rate of over 40% per transfer even in case of the transfer of a single embryo.
Course and method of examination:
Currently the trend is to examine the higher phases of the embryotic development (which provides us with a more complex set of information about the embryo under examination). Biopsy samples a group of 10-20 cells on day 5 or 6 of the embryotic development – the so-called blastocysts are the target of the biopsy. This procedure allows us to assess the complete genome of the future foetus (maternal as well as paternal share). However, the embryotransfer of the “fresh” embryo is not possible due to technical reasons. The biopsy has no negative impact on the embryo’s ability to nest in the womb. Because only such cells are sampled which are as yet undifferentiated, their sampling does not create any consequences in the form of foetus damage. Biopsy has no impact on the genetic information of the foetus as well.
Your embryos (blastocysts) will be examined by the NGS (Next Generation Sequencing) method which enables us to examine the whole chromosome spectrum, or 23 couples. NGS is more sensitive compared to the older method, aCGH (Array-CGH) and it is able to discover even embryos with a mosaic.
Possibility of embryo cumulating before genetic testing
Generally, it is necessary to obtain a sufficient number of quality embryos. We have to take into account the fact that a certain part of the embryos will not be suitable on day 5 or 6 to be subjected to biopsy and a part of those embryos who underwent biopsy will probably be ruled out due to a positive presence of a defect in the number of quality of chromosomes. If in one cycle we are unable to obtain a sufficient number of eggs/embryos after fertilisation so that the chance for finding a healthy embryo is good, it is possible to freeze all embryos and after some time perform another stimulation, egg collection and their fertilisation. Embryos from both or multiple cycles are then used jointly. This procedure is called accumulation. In this manner it is possible to achieve a higher chance of finding a healthy embryo and prevent unfruitful investments of the couple in question.
PGT-M (Preimplantation Genetic Testing for Monogenic/Single Gene Diseases)
Preimplantation genetic diagnostic is therefore a method which enables us to choose a so-called “healthy embryo” without specific genetic impairment. The main advantage of such procedure is the elimination of risk of the foetus carrying monitored genetic impairment. The couple therefore do not have to deal with any potential issues connected with an artificial abortion of the pregnancy. The principle and procedure as seen by the couple is similar to that of the PGT-A method.
The scientific databases contain reference to more than 5000 rare hereditary diseases, which are potentially possible to detect using preimplantation diagnostic. Monogenic hereditary diseases are caused by the lack of function or change of function of one of our genes.
If we are to describe the rare diseases in layman’s terms according to heredity types, it is possible to divide them into three basic groups:
- recessive heredity
- dominant heredity
- gonosomal heredity
The risk of transfer of the disease varies for the individual groups onto the offspring, as do the various requirements for the selection of the embryo suitable for transfer.
Among the most common rare diseases in our rank there is:
- cystic fibrosis
- spinal muscular atrophy
- metabolic defects
- Marphan syndrome
- Huntington chorea
- familiar hypercholesterolmia
- fragile X syndrome
- muscular dystrophy syndrome
- Other hereditary predispositions to tumorous diseases, e.g. BRCA1 and BRCA2.
The most common way the partners learn about the genetic predispositions in the family is, unfortunately, when they conceive a child in which a serious disease of hereditary nature is found. In the better case it is possible that one or both partners learn of their predisposition in advance – in case that the genetic examination is performed preventively due the condition of another family member, or from the so-called predictive panel etc. For families with genetic predispositions PGT-M is the only reliable method to exclude the possibility of transfer of serious defects and hereditary disease onto the offspring. If it is determined that the partners are suitable candidates for an IVF cycle with preimplantation examination of the embryos they consult a clinical geneticist who specialises in the area of preimplantation diagnostics.
The sampled DNA cells are then used to determine the genetic set of the embryo. We are therefore able to say, with an almost 100% accuracy, whether the tested embryo is healthy or is a carrier of a disease, or bears genetic predisposition connected to the future development of the disease.
The embryo which passes this testing and is classified as genetically suitable is then transferred to the mother’s uterus. If the couple has multiple embryos suitable for transfer, these may be used in case of repeated transfer or in the future should the couple want another child.
Preimplantation genetic diagnostics by the means of translocation (or other structural chromosome defects) is suitable for couples in which one or both partners is a confirmed carrier of balanced translocation or a different chromosome structural rearrangement. Translocations constitute the most common chromosome structural abnormities, which appear with a frequency of approx. 1:625. Those who are carriers of balanced translocation may not exhibit any development defects or any afflictions or diseases. The problem arises in case of reproduction, when sperm or eggs may be created which do not contain the right amount of genetic material, i.e. a certain part is missing or is in excess
If such sperm and eggs become part of fertilisation, a genetically abnormal person with multiform development defects and serious organ afflictions. In the overwhelming majority of cases, however, the foetus experiences spontaneous abortion or the development defect is discovered during the prenatal diagnostics. In rare cases such an afflicted child is also born. The risk of creation of a so-called imbalanced embryo is 5% if the male partner is the carrier of balanced translocation, or 12% if it is the female partner.
Translocation may be a common case of miscarriages. Couples which experience repeated miscarriages should have their karyotype examined. This examination allows for the number of chromosomes to be determined and also discover whether chromosome translocation is present or not.
Karyomapping is a new technology of genetic analysis of the embryo which may prevent the transfer of genetic predisposition onto the next generation. That is true for both couples in which both partners are carriers of the given disease and the persons who themselves suffer from a hereditary disease.
First, it is necessary to obtain a blood sample from the future father, mother and one other close relative who is known to either suffer from the disease or is healthy (in relation to the given disease). In most cases the afflicted child of the given couple is the relative in question. The relative’s blood sample is referred to as the “reference sample“.
Using karyomapping it is possible to examine chromosomes, elements made by our DNA and proteins which contain genes and are located in human cells. The karyomapping method is used to examine the mother’s, father’s and the reference sample’s chromosomes at about 300 000 different places. This creates a reliable “DNA profile” of the chromosome with the mutated gene. Then all embryos are examined in such manner that it is possible to reliably eliminate those containing a mutated gene.
If the DNA profile connected with the mutated gene is not present, it can be said that the embryos inherited a normal copy of the gene without mutation and should be healthy with respect to the given disease. Such embryos are suitable for transfer into the mother’s womb.
How is karyomapping different from other methods used in case of PGD hereditary diseases?:
- Simplification and speed
Apart from the DNA of the partners it is not necessary to request DNA from other family members. All that is needed is a DNA sample from one of the afflicted family member (a child, or any other relative), and in certain cases only the DNA samples of both partners are needed.
- A solution even for tumorous diseases
This method is suitable not only for all monogenic diseases but also for all hereditary tumorous diseases such as mutations in BRCA1 and BRCA2 genes.
- Two in one
As part of the karyomapping examination aneuploidy screening of all chromosomes (PGS) is automatically performed, which delivers all the advantages connected with this examination. Only such embryos are selected for transfer that are healthy and contain the right number of chromosomes, which increases the chance to get pregnant and also excludes the conception of a child with other development defects caused by the incorrect number of chromosome (Down syndrome, Edwards syndrome…).
Preimplantation genetic diagnostics cannot ensure the birth of an absolutely heathy child but it can reliably exclude transfer of a specific genetic predisposition onto the next generation. However, transfer of the “healthy” embryo does not mean that you shall not be recommended prenatal screening in the first and second trimester of the pregnancy.