Preimplantation Genetic Testing for Single Gene Disorders or Chromosomal Structural Abnormalities
Preimplantation genetic testing (PGT) is a procedure in which genetic testing is performed on embryos produced by in vitro fertilization (IVF) before a clinical pregnancy is established. This procedure was previously termed preimplantation genetic diagnosis (PGD).
Who can benefit from PGT?
- Couples who are at higher than usual risk of having offspring with some genetic disorder, e.g. cystic fibrosis, hemophilia, Huntington’s disease, Fragile X, myotonic dystrophy, thalassemia, Tay Sachs disease, etc. In order for PGT to be possible, the genetic abnormalities called a mutation generally needs to be known. This type of PGT is termed preimplantation genetic diagnosis for monogenic disease (PGT-M).
- Couples who are at higher than usual risk of having offspring with chromosomal abnormalities. This type of PGT is termed preimplantation genetic diagnosis for chromosomal structural arrangement (PGT-SR).
- Couples with an offspring with genetic diseases that can be treated by bone marrow transplant from another sibling with specific tissue type matching called HLA matching.
- Couples who have a prior history of repeated miscarriages and would like to reduce their risk of having another miscarriage in their future pregnancies. Since a significant number of patients miscarry due to abnormal chromosomes in the fetus, the risk of miscarriages can be reduced by selecting embryos that are more likely to be chromosomally normal before embryo transfer. This process is called Preimplantation Genetic Testing for Chromosomal Aneuploidy (PGT-A) since instead of targeting a specific genetic diagnosis it screens the embryos to identify the ones with normal chromosomes for embryo transfer. Other terms that have also been previously used for this process is Preimplantation Genetic Screening (PGS) or Comprehensive Chromosomal Screening (CCS). The benefit of PGT-A in this group of patients is however often limited by factors that may reduce the chance of finding chromosomally normal embryos at the time of PGT-A.
Why is Genetic Counseling so important before PGT?
Before making the decision to do PGT, it is important that the couple understand well the risk and the implications of the genetic disease their offspring may have. During the genetic counseling, the following issues will be discussed:
- What is the risk of their offspring having the disease?
- What illnesses will their offspring have if they do inherit the disease?
- Do they have any options other than PGT to reduce the risk of having offspring with the genetic disease?
- What percentage of their embryos are likely to be abnormal?
- How reliable is the PGT testing? Is there a chance of error in the testing?
- Do they still need to do the routine prenatal tests such as amniocentesis to confirm the PGT result after they have achieved a pregnancy following PGT?
In order to ensure that each couple is fully informed before such an important decision is made, counseling is required prior to treatment. A referral will be made to a medical geneticist if this has not been done previously.
Each couple also needs to have a consultation with our PGT physician and to attend a PGT / IVF information session. Due to the complexity of the PGT process, some couples may find it necessary to return to the clinic for follow-up visits to address their concerns or questions before they feel comfortable that they have understood the process and feel ready to make an informed decision.
What does the PGT process involve?
Patients will be seen at the RFP for an initial PGT consultation in Calgary. For out of town patients, an attempt will be made to schedule the PGT and in vitro fertilization (IVF) information session in the evening before the consultation. During the first consultation, relevant medical histories will be reviewed. Please bring along a copy of all the reports and letters from prior genetic consultations if you have them. We will let you know which PGT laboratory in the U.S. will be performing your PGT and you will receive information on the laboratory.
If you decide to proceed with PGT, you will then contact the genetic counselor in the PGT laboratory for a phone consultation. The genetic counselor will further outline the process, rationale and limitations (including error rate) of PGT.
Depending on your situation, the particular type of PGT testing will be determined. In some circumstance, pre-treatment preparation work may be necessary. Once you are informed of all pertinent information and decide to proceed with treatment, the pre-treatment preparation work begins. In some situations, you and your partner may be told by the PGT laboratory to send blood sample or cheek swabs directly to the PGT laboratory so they can perform the preparation work. The amount of time the laboratory will need to complete your preparation work varies. Once the preliminary work has been done, the lab will notify our clinic. We will proceed to schedule your PGT treatment.
In order for PGT to be done, IVF must also be performed. The IVF process will be explained in detail at the IVF evening session. In essence, the female partner’s ovaries will be stimulated so that a number of eggs will mature. The eggs are then retrieved while the patient is under an intravenous sedation. The physician will use an ultrasound guided needle to collect the eggs.
Following fertilization of the eggs in the IVF lab by injecting a sperm into each egg, a process called intracytoplasmic sperm injection (ICSI), the embryologists will monitor the growth of each embryo. On the fifth day (and occasionally on the third day) of embryo development, the embryologist will remove cell(s) from each embryo, a process known as embryo biopsy.
Day 3 Embryo Biopsy
Based on your situation and the type of genetic testing that will be done for your PGT, the timing of your embryo biopsy will be decided. The cell(s) will be sent to the appropriate PGT laboratory for genetic testing. It also should be noted that in routine genetic analysis done on children or adults, there are usually hundreds of cells available for processing. However, with embryo biopsy only one or a few cells will be available for the genetic testing.
The biopsied cells are then sent to one of the PGT laboratories by overnight courier and analyzed to determine which embryos are abnormal and which embryos are “normal”. If your embryo biopsy is done on day 3 of embryo development, your embryos will be kept in the incubators in our IVF laboratory while we are waiting for the PGT results. As long as the PGT results are available by day 5 or 6 of embryo development and embryos suitable for transfer are identified, we can perform a fresh embryo transfer. On the other hand, if your embryo biopsy is done on day 5 of embryo development, all your embryos will need to be cryopreserved while we wait for the PGT results. Your embryos will be transferred in a frozen embryo transfer (FET) cycle, which is usually two and sometimes three months after the completion of your fresh cycle. For the majority of the PGT, the embryos will be biopsied on day 5 and frozen to allow sufficient time for the PGT to be completed.
You will be given further instructions on the day of the transfer when to check your pregnancy test, in general the test should be performed 16 days after embryo transfer if done on day 3 embryos or 14 days post transfer if done on day 5 embryos.
What is the Risk of Misdiagnosis?
When PGT is done for chromosomal testing, misdiagnosis can occur due to a phenomenon called chromosomal mosaicism within the embryo. Each human cell has its own DNA package. An embryo may contain cells that have normal chromosomes and other cells that have abnormal chromosomes. This is called mosaicism. For this reason, a diagnosis may be incorrect because the cell(s) that are biopsied and tested do not reflect the status of chromosomes of the rest of the embryo. This may result in the transfer of an embryo carrying a chromosome abnormality or the failure to transfer a normal embryo. Experimental error can also account for a misdiagnosis. During the phone consultation with the PGT centre, the issue of misdiagnosis will be further discussed. It is important that you understand this issue prior to signing the consent form.
Due to the possibility of misdiagnosis, PGT cannot be considered as a replacement of prenatal diagnosis by chorionic villus sampling (CVS) or amniocentesis. The recommendation after PGT is to still have prenatal diagnosis to confirm the genetic diagnosis to ensure that the fetus is not affected by the genetic disease of concern or that the chromsomes are normal.
We hope the above information will assist you in making the decision whether to proceed with PGD consultation or treatment. We understand that it is not an easy decision. Please contact our clinic if you have any further questions.