PGS, PGT-A, PGT-M, PGD… what does it all mean?

Within the IVF sector, there are many different terms that all mean the same or similar procedure.  When clinics refer to PGS (Pre-implantation Genetic Screening) or PGT-A (Pre-implantation Genetic Testing – Aneuploidy), they are talking about checking suitable embryos to see if they have the correct genetic make-up.  To really understand this though we first need to understand a little more about human genetics. 

We as humans contain 23 pairs of chromosomes; these chromosomes contain all of the instructions that the cells in our bodies need to be able to function normally.  Each of the chromosomes contains many thousands of genes which are the specific instructions.  When PGS or PGT-A is completed on an embryo, we are checking to see if the embryo contains a full set of chromosomes.  Sometimes the embryos can have extra copies (three times more) of any one of the chromosomes.  There can also be copies missing or there can be additional/missing segments of the chromosomes.  These embryos would all be considered abnormal and not suitable for treatment.  This is because many would not be able to establish a pregnancy; some would result in a miscarriage, others in a stillbirth.  Some of the embryos considered abnormal may result in a live birth; however, the child would have a genetic abnormality that, depending on the chromosomes involved, will have a range of impacts on the child.

The method of genetic laboratory testing that is performed when using PGS/PGT-A is a process called next-generation sequencing.  This type of testing looks for a very large amount of information on the embryo.  Due to the vast amount of genetic information that is analysed, very small changes in the embryo’s genetics are not able to be identified. Something called a single gene disorder (e.g., Cystic Fibrosis) is a very small change in one of the genes located on the chromosomes.  This type of genetic change is not able to be detected through standard next-generation sequencing.  However, we do also have specific testing that can be done to identify these types of disorders, this type of testing is referred to as PGD (Pre-implantation Genetic Diagnosis) or PGT-M (Pre-implantation Genetic Testing – Monogenic).  Only patients that are known to be carriers or have a family history of a single gene disorder will be referred to have PGD/PGT-M.  Often these patients will also have PGS/PGT-A completed on the embryos at the same time as PGD/PGT-M.  These patients may have embryos that are affected by the single gene disorder, but no abnormalities are detected by PGS/PGT-A.

But what are the risks?
With any laboratory procedure, even though every precaution and care is taken to protect the embryo/patient material, there are always risks associated with it.  The first hurdle that the embryo needs to overcome with any type of genetic testing is the biopsy procedure.  Even though only the ‘top quality’ embryos are selected to undergo embryo biopsy, the embryos don’t always respond the way the embryologist would expect them to.  There is around a 2-5% chance that the biopsy procedure could damage the embryo and reduce the embryo’s potential for pregnancy (even if there are no abnormalities detected following genetic testing).

The next hurdle is that the cells need to be able to give a result.  In less than 5% of cases, there may be no, or insufficient genetic material (DNA) detected in the tube by the genetics laboratory.  This can arise because the quality of the DNA from the cells was poor, which can be caused by the cells starting to break down (lyse) prior to them being frozen and shipped. Unfortunately, this is not something that can be predicted; the IVF laboratory tries to control for this by only performing biopsy on good quality embryos.  It can also arise because while every care is taken, something has gone wrong with the cell transfer. The cells from the embryo have not survived the process, meaning the genetics laboratory cannot detect any DNA from the embryo.

The final hurdle for the embryo is that it needs to survive the freezing and thawing process.  While the majority of laboratories experience embryo survival rates of around 90-95%, there are still some cases where the embryo does not survive the freezing and thawing.  Again, the IVF laboratory will take every care to protect the embryo, but sometimes, for reasons that are not always understood, even good quality embryos do not survive the process.

There is also risk associated with the genetic results:

1. A patient may go through the process of PGT-A/PGS/PGT-M/PGD and result in no embryos that are suitable for transfer either because no embryos were suitable for biopsy or because all of the embryos biopsied had abnormalities detected.  This is a very upsetting result but is something all patients should be prepared for.  The risk of this occurring increases as maternal age increases. 
2.  A false positive/negative result may be given, which occurs in 1-2% of cases.  This is when the genetic laboratory reports that an embryo is abnormal when in actual fact, it has no detectable abnormalities.  This can also happen in reverse, where an embryo is reported as having no abnormalities detected but does contain abnormalities.
3. The genetic condition called mosaicism may occur.  Mosaicism is a difficult concept to explain – however, at its most basic explanation, it means that not all of the cells in the embryo contain the same genetic make-up.  This is reported by the genetics laboratory generally as a percentage of the embryo that has an abnormal genetic make-up (e.g., 40% mosaic for trisomy 21 – means 40% of the cells had an extra copy of chromosome 21).  Mosaicism can occur in the embryo in a few different ways as follows:

If an embryo is in the category of example two above, this embryo would be considered suitable for transfer.  However, depending on the chromosome/s involved in the abnormality may not result in a healthy live birth.  If the embryo is in the category of example three, it would be considered abnormal and would be discarded; however, it could have resulted in a healthy live birth.  The embryos that arise from example one generally require further discussion with your clinician or a genetic counsellor to consider the possible outcomes that could occur and will be related to the level of mosaicism detected and the chromosome involved.

Due to all of the risks associated with genetic testing of embryos it is always strongly recommend that should an ongoing pregnancy be established, routine obstetric checks and testing is also completed to confirm the genetic results obtained from the embryo.