Preimplantation Genetic Diagnosis

Preimplantation genetic diagnosis (PGD) is a procedure in which genetic testing is performed on embryos produced by in-vitro fertilization (IVF) before a clinical pregnancy is established. It must be done in conjunction with IVF and is an alternative to prenatal diagnosis. PGD has been mostly applied to women with recurrent miscarriages, patients with chromosomal disorders such as translocations and patients who have genetic diseases or are carriers of genetic diseases. The number of single gene disorders that have been diagnosed in preimplantation embryos has continued to grow. Families in search of a bone marrow donor for an offspring with some genetic diseases may be able to use PGD to bring a child into the world that can provide matching stem cells.

Who can benefit from PGD?

• Carriers of single gene disorders: PGD can reduce the risk of conceiving an affected baby. (e.g. cystic fibrosis, fragile X, myotonic dystrophy, thalasaemia, hemophilia and Tay Sachs disease)
• Carriers of chromosome translocations or other chromosome abnormalities
• 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
• Women with a prior history of repeated miscarriages. Since a significant number of patients miscarry due to abnormal chromosomes in the fetus, they can benefit from PGD with higher implantation rates, reduced spontaneous rates, and reduced risk of chromosomally abnormal conceptions. The benefit of PGD in this group of patients is however controversial, since even though theoretically it should help, there has not been clinical data to prove that it is beneficial.

Why is Genetic Counseling so important before PGD?

In order for you and your partner to make the decision as to whether to proceed with PGD, it is important for you to have a good understanding of the nature of the genetic disease that your future offspring are at risk for as well as the probability of your offspring being born with the disease. Many of you have been referred to us by Medical Genetics and therefore have already gone through the counseling. For those of you who have not done this, we may refer you to your local geneticist for a consultation. Some issues that are routinely discussed are:

• genetic risk assessment of the disorder,
• reproductive options and alternative to PGD,
• proportion of embryos expected to be affected,
• reliability of PGD,
• risk of premature birth, and
• the need for antenatal genetic screening following PGD.

For infertility patients in Canada, counseling before treatment will be mandatory.

What does the PGD process involve?

We, as an IVF clinic, work with a PGD laboratory to offer PGD as an option to couples in situations mentioned above. You and your partner will be seen in our clinic for an initial PGD consultation in Calgary. If you are from out of town, we will try to schedule you for IVF information session the evening of or before your consultation. During this consultation, your medical histories will be reviewed. Please bring along a copy of all the reports and letters from your prior genetic consultations. Depending on the reason for PGD in your situation, we will let you know which PGD laboratory in the U.S. will be performing your PGD and you will receive information on the laboratory. If you decide to proceed with PGD, you then contact the genetic counselor in the PGD laboratory for a phone consultation. The process, rational and limitation (including error rate) of PGD will be reviewed.

Depending on the genetic disorder, pre-cycle workup may be necessary. Once the patient is informed of all pertinent information relative to them, the cycle preparations begin. In some situations, your and your partner may be told by the PGD laboratory to send blood directly to them so they may test the genetic probe needed to detect the disorder. Some cases require the lab to design a probe "from scratch" that is tested on the DNA from the blood sample to ensure the probe will work on the cells from the embryos. (You will find the prescription for drawing blood, the address for the PGD laboratory, a blood specimen information form and a U.S. Customs Declaration letter in your PGD package). Once the preliminary work has been done, the lab will notify our clinic. You will be set up for treatment based on your position of the PGD waiting list. Confirmation of your payment to the PGD laboratory is required before you are set up for treatment. You and your partner will also be required to sign all consent forms for PGD and IVF before IVF treatment.

The IVF process will be explained in great detail at the IVF evening session. In essence, medication is given to "down regulate" the woman's hormones so that other medications can be used to stimulate the production of multiple eggs. The eggs are then retrieved while the patient is under a very light anesthetic. The physician will use an ultrasound guided needle to collect the eggs.

Following fertilization of the eggs in the IVF lab, the embryologists will monitor the growth of each embryo. On the third day of development, the embryologist will remove a cell from each embryo (embryo biopsy) which will be sent to the appropriate lab for genetic testing. The biopsy method is relatively straightforward, but this does not mean that it is an easy procedure to undertake. It also should be noted that in routine genetic analysis, there are usually hundreds of cells available for processing, however, with embryo biopsy only one cell (occasionally two) will be available for testing. The removal of up to a quarter of an embryo is not known to be deleterious to the further development of that embryo, as the embryo as this early stage of development can compensate for this loss of cell material. All cells at this stage are still fully capable of directing further embryonic development.

Once a single cell (a blastomere) is removed, the biopsied cells are then sent to the PGD laboratory by overnight courier and analyzed to determine which embryos have inherited the disease and which embryos are free of the disease. The cells are analyzed using techniques called fluorescence in situ hydridization (FISH) or DNA analysis (PCR). Your embryos stay in our IVF laboratory while we are waiting for the PGD results. During the genetic analysis, the growth of the embryos is monitored by the embryologists. Once available, the genetic results are faxed to our clinic. Hopefully, embryos suitable for transfer are identified and you will be notified to come in for a blastocyst transfer (usually day 5 or 6 following egg retrieval). You will be given further instructions on the day of the transfer regarding when to do your pregnancy test.

What is the Risk of Misdiagnosis?

Misdiagnosis can occur due to mosaicism within the embryo. Each cell has its own DNA package. Some embryos may contain cells which are genetically normal and, within the same embryo, other cells which are abnormal. This is called mosaicism. For this reason, a diagnosis may be incorrect because only one cell is tested. 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 PGD 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, PGD cannot be considered as a replacement of prenatal diagnosis by choronic villus sampling (CVS) or amniocentesis. The recommendation after PGD is to still have prenatal diagnosis to confirm the genetic diagnosis to ensure that the fetus is not affected by the disease.

We hope the above information will assist you in making the decision whether to proceed with PGD treatment. We understand that it is not an easy decision. Please contact our clinic if you have any further questions.