Preimplantation Genetic Testing (PGT)
What is PGT?
Preimplantation Genetic Testing (PGT) is a genetic test for embryos created with in-vitro fertilization (IVF). The goal of preimplantation genetic testing is to tell you about the genetic health of the embryo. There is not preimplantation genetic testing that can tell you about all health conditions of an embryo or characteristic traits such as eye color, but there are three main types that can tell you about the number of chromosomes and if a particular condition is present or not. This informational page will go into more detail of the different types of preimplantation genetic testing, how it is performed, who is it for, and the limitations of testing.
What is IVF?
Before being able to test the embryos, they will need to be created through the process of in vitro fertilization (IVF). IVF is the process in which multiple egg cells are retrieved by a person with ovaries. In order to retrieve as many egg cells as possible, the person is given hormone injections to mature more egg cells than in a typical month.
The egg cells are fertilized by the intended sperm which creates an embryo as shown in the above picture. Once the embryo is about 5 or 6 days old, an embryologist will take about 5-10 cells from the embryo. The embryo is referred to as a blastocyst at this stage of embryo development. There are about 200 cells, and they are organized into an outside layer and inside layer as shown on the left. The outside layer is called the trophectoderm. These cells will become the placenta and supporting structures of the pregnancy. The cells inside the blastocyst are called the inner cell mass. They will become the future baby. The trophectoderm cells are the ones that are biopsied and sent to a genetic testing lab to perform one or two of the available PGT tests. The embryo (or blastocyst) is never sent to the lab directly and will stay with the clinic.
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This is the most common test performed on the embryo. PGT-A assesses the embryo sample for aneuploidy. Aneuploidy means there are too many or too few chromosomes. PGT-A can be considered for anyone undergoing IVF because anyone can have an embryo or embryos with aneuploidy. However, as a woman or person with ovaries ages, the chance for aneuploidy increases, so this screen may be offered if a someone is over 35 years of age. If an embryo has too many or too few chromosomes, then this can lead to implantation failure, miscarriage, or a child with a chromosomal condition.
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PGT-SR is designed for when a person has a structural rearrangement (also known as a balanced rearrangement or translocation) within their chromosomes. This means they have all the chromosomes they need, but those chromosomes are arranged in a way that when go on to have a pregnancy, they may give too many or too few chromosomes which can lead to chromosomal abnormalities in the embryo. If an embryo is transferred that is suspected to have chromosomal abnormalities, then this can lead to implantation failure, miscarriage, or a child with a chromosomal condition. PGT-SR assesses the number of chromosomes for the embryo sample, with particular focus on the potential chromosome imbalances that can result from the person’s structural rearrangement.
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PGT-M assesses the embryo sample for monogenic (also known as single gene conditions) conditions. A monogenic condition is caused by one gene that is nonfunctional. Cystic fibrosis is one example of a monogenic condition. If a person or reproductive pair are known carriers of a condition or if someone has a genetic condition themselves, then they could have PGT-M to detect which embryos may have the condition and which do not. They can then choose which embryos to transfer based on that information.
There are three main PGT tests available. A short description of each is below.
How does someone decide which PGT test is right for them, if any?
The decision to pursue this testing can depend on a multitude of factors such as the person’s previous reproductive history and current situation. Just because someone is undergoing IVF, it does not mean they have to do PGT. Some of the considerations that will be made include maternal age and a previous history of miscarriage as well as if there have been any identified genetic risks. A person’s provider can be a helpful resource to determine, if any, preimplantation genetic testing is going to be helpful.
For PGT-A, there is some discussion as to which patient population would benefit most from this analysis. Per the STAR trial paper, women/people with ovaries that are over 35 have benefited the most from the PGT-A analysis given this population has an increasing chance to have embryos with chromosomal abnormalities. For those under 35 years of age, there is still the chance to have embryos with chromosomal abnormalities, but it is more likely the embryos have the typical number of chromosomes.
Embryos with chromosomal abnormalities are much more common in human reproduction than is generally discussed. One way to think about why that might be is because the embryos created are ones that have not experience any pressures of the natural selection process. Had the embryos with chromosomal abnormalities been spontaneously conceived, they likely would have resulted as implantation failure or early miscarriage. The existence of that embryo may have never even been known. But with IVF, it is very much known and counted.
The rate of chromosomal abnormality in pregnancy is much lower than for embryos given those initial spontaneously conceived embryos have already gone through the process of implanting and developing in the uterus for many weeks, so they are more likely to not have a chromosomal abnormality given they made it that far. However, there is still the possibility of select chromosomal abnormalities to result as an ongoing pregnancy.
For PGT-M and PGT-SR, these tests are specific to individuals who have known specific risks for genetic conditions or chromosomal abnormalities. Depending on the condition the person or couple are carriers of will help determine if PGT is helpful. Some people may feel the condition they could pass on is one that is manageable, and they would otherwise welcome a baby with the condition; therefore, they may not want to select against the condition. For others, the opposite is true. Further discussion with a provider is important to better understand the genetic chances and available options.
Are there limitations to the testing?
Absolutely, yes
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Each genetic testing lab will have their own accuracy rate. It is important to know what the accuracy rate is referring to. Often this will the lab’s ability to detect what is present in the cells that were sent for analysis. No lab has a 100% accuracy rate given the methodology used for testing. False positives and false negatives are possible with PGT but are usually rare occurrences. Additional testing during or after pregnancy can always be considered to confirm the PGT results.
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The few cells that are sent for analysis are those that are going to become the future placenta/ supporting structures of pregnancy. Usually, the genetic makeup of those cells should be the same as the rest of the embryo given they all originated from the same conception cell. However, for chromosomes specifically, there is the possibility of a phenomenon called mosaicism. Mosaicism is when there are some cells with one genetic makeup and other cells with another genetic makeup. In the context of PGT, it may be that the trophectoderm cells are a mixture of chromosomal results - some chromosomes may be normal whereas other chromosomes are abnormal. Given only a few cells are tested for, it is difficult to predict if the rest of the embryo has only normal chromosomes, abnormal chromosomes, or is mosaic throughout.
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While preimplantation genetic testing is a genetic test, it is by no means a comprehensive genetic test. There are many genetic conditions that are not being assessed. With both the PGT-A and PGT-SR tests, these are only evaluating for chromosomal abnormalities and will not assess for single gene conditions like Cystic Fibrosis. PGT-A and PGT-SR also do not evaluate for all chromosomal conditions, specifically very small pieces of the chromosome that might be missing or extra. These are referred to as microdeletions or microduplications.
For PGT-M, only the specified genetic condition will be assessed. So if there is a known risk for Sickle Cell disease, only Sickle Cell disease will be evaluated for, not all single gene conditions. There is no PGT test that can assess for all single gene conditions. Science is not yet there.
One more piece of information before you go -
This page highlighted the three main types of preimplantation genetic testing, but there is another assessment available through a few labs. It is not quite recommended by the professional organizations, and it’s utility and accuracy are still unclear. Nevertheless, we wanted to provide the details here.
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PGT-P is assessing the embryo sample’s chance of developing conditions that are considered polygenic such as diabetes type 1 and 2, schizophrenia, coronary artery disease, heart attack, hypercholesterolemia, hypertension, breast cancer, testicular cancer, prostate cancer, and some skin cancer.
Polygenic means multiple genes. The conditions listed above are believed to be caused by multiple genes.
The approach of assessing polygenic conditions is by looking at genetic changes called single nucleotide polymorphisms (SNPs) located in multiple genes. The SNPs do not actually cause disease but certain changes may be seen more frequently in people with the disease. Therefore, if the chance is present, it may be that the embryo has a higher than average chance to develop the disease. It is important to know that the genetic change is not causative and does not mean the embryo will develop the condition.
PGT-P is another way to prioritize embryo transfer.
Along the same lines, there is another approach to performing preimplantation genetic testing that is not yet recommended by professional organizations either. Instead of the trophectoderm biopsy described above, the scientists are trying to use the DNA found in the culture media of a growing embryo. The accuracy of this is also debated, but below is a summary on noninvasive PGT.
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An embryo is placed in a lab dish with culture media. Culture media is a gel or liquid with nutrients in it to help the embryo grow and develop. Scientists have discovered there is DNA in the culture media. Studies are taking place to determine the feasibility of using this DNA to predict if the embryo has aneuploidy or has the typical number of chromosomes.
It is important to keep in mind the efficacy of niPGT is being compared to another screen, PGT-A. It is known that the PGT-A results of a trophectoderm biopsy does not always match the would be PGT-A results of the inner cell mass.
Another concern is the origin of the DNA in the culture media is not entirely understood. It may be that aneuploid cells are preferentially eliminated by the embryo and are overrepresented in the culture media.
Preimplantation Genetic Testing (PGT) Blog Posts
Preimplantation Genetic Testing for Monogenic Conditions (PGT-M) Blog Posts
Resources:
Sousa, Larissa Nogueira, and Paula Bruno Monteiro. “Non-invasive preimplantation genetic testing: a literature review.” JBRA assisted reproduction vol. 26,3 554-558. 4 Aug. 2022, doi:10.5935/1518-0557.20210102
"Preimplantation genetic testing." ACOG Committee Opinion No. 799. American College of Obstetricians and Gynecologists. Obstet Gynecol 2020;135:e133–7.
Viotti, Manuel et al. “Using outcome data from one thousand mosaic embryo transfers to formulate an embryo ranking system for clinical use.” Fertility and sterility vol. 115,5 (2021): 1212-1224. doi:10.1016/j.fertnstert.2020.11.041
Lázaro-Muñoz, Gabriel et al. “Screening embryos for polygenic conditions and traits: ethical considerations for an emerging technology.” Genetics in medicine : official journal of the American College of Medical Genetics vol. 23,3 (2021): 432-434. doi:10.1038/s41436-020-01019-3