Preimplantation Genetic Diagnosis (PGD) or Preimplantation Genetic Testing in Monogenic Diseases (PGT-M), is a procedure offered to couples who are known to have a risk of conceiving a child who will be affected by a hereditary genetic medical condition.

At times, one of the parents is affected by the condition, while in other cases the parents are only carriers of a genetic condition but not affected by it. In such cases the couple may find out about their carrier status only after having a child affected by the condition or when the risk that one of them is a carrier is flagged up by a relative (parent or sibling) affected by the condition. In some cases the carrier status is diagnosed by pre-conception expanded screening tests. This refers to a battery of genetic tests that the couple elect to have before they try conceiving. The battery checks for a possibility that they may carry any of an array of genetic mutations which may lead to a significant medical condition.

There are many patterns of genetic inheritance which may lead to the birth of a child affected by a medical condition with potential significant implications on longevity or quality of life. Yet, PGT-M is mostly aimed at pre-conception diagnosis of conditions which occur due to a mutation in a single gene (mono-genic conditions). Our genome consists of two copies of each gene – one we inherit from the father and one we inherit from the mother. Therefore mono-genic genetic disorders may have 3 main patterns of inheritance:

Autosomal dominant conditions

Dominant inheritance means an abnormal gene from one parent can cause a disease. This happens even when the matching gene from the other parent is normal. The abnormal gene dominates. Normally, under such circumstances, the parent who passes the mutation is affected by the condition. Once one parent is diagnosed with a medical condition due to an autosomal dominant genetic mutation the risk of having a child affected by the condition is 50%.

Examples of medical conditions with autosomal dominant inheritance are Myotonic Dystrophy, Marfan syndrome and neurofibromatosis type 1.

Autosomal recessive

These conditions occur only when both genes – the one inherited from the father and the one inherited from the mother - carry a mutation rather than a normal copy. Under such circumstances the parents are often not affected by the condition as they each carry one normal gene and one gene with a mutation - the presence of a normal gene is sufficient to ‘compensate’ for any effect that the second copy with the mutation may have.

Very often couples are made aware of their carrier status only when they already have a child affected by the condition. At times one partner is diagnosed with a carrier status when his/her parent or sibling is affected by the condition. Their spouse is then tested secondary to their diagnosis and at times the spouse happens to carry the genetic mutation too. Finally, there is a growing trend of pre-conception genetic screening tests which couple have before they attempt conceiving and in a small percentage of cases they may be both found to carry a mutation on genes encoding for the same medical condition.

Once both parents are diagnosed as carriers of an autosomal recessive genetic mutation the risk of having a child affected by the condition is 25%.

Examples of such conditions are Cystic-Fibrosis and Sickle Cell disease.

X linked

The X chromosome is one of the sex chromosomes. Women have 2 copies of the X chromosome (XX) while men have a single copy of X chromosome and a single copy of Y chromosome (XY). The X chromosome is much larger than the Y chromosome and carries more genes. If the mother carries a mutation on a single copy of a gene appearing on her X chromosomes, any boys inheriting this gene will be affected by the condition as they will not have a second copy to ‘compensate’ for the mutation (they have only one X chromosome which they inherit from their mothers). Any girls who inherit the X chromosome carrying the mutation from their mothers will have an extra X chromosome with a normal gene inherited from their fathers and will therefore remain medically unaffected. Hence, with X-linked inheritance the condition is passed from (healthy) mothers to their male babies. If a prospective mother is carrier of an X linked mutation there is 50% risk that her son will be affected by the genetic condition.

Examples of X-inked inherited conditions are haemophilia or Duchenne muscular dystrophy.

PGD can help parents to conceive through IVF treatment with a baby who is significantly less likely to be affected by the serious genetic condition which runs in their family (or they were randomly found to be carriers of). As PGD is mostly aimed at diagnosis of conditions resulting from a mutation in a single gene (mono-genic conditions) it has been recently named as Preimplantation Genetic Testing – Monogenic or PGT-M.

PGD/PGT-M testing can only be carried out in conjunction with in vitro fertilization (IVF) cycle. Below, we explain IVF combined with preimplantation genetic diagnosis in more detail.

Step 1: Initial assessment

Once the couple are found to be at a risk of conception with a child affected by a genetic disorder they will be referred to see a Geneticist for genetic counseling. After taking your detailed medical history and exploring the medical history of your families the Geneticist will discuss issues such the genetic pattern of the condition, the risk of genetic transmission and the implication of the genetic condition on the longevity and quality of life of your future children.

You will also need to be assessed by one of our Fertility Specialist to check the feasibility of having a PGD cycle. To give you a good chance of conception with PGD you need to have a reasonable ovarian reserve. Women with very low ovarian reserve produce a limited number of eggs in response to to the stimulation[SW8]  drugs they are given during the PGD cycle. Fewer eggs lead to fewer embryos suitable for pre-gestation genetic diagnosis and hence a lower chance of ending up with an embryo which is unaffected and suitable for transfer.

Step 2: Creating a pathway in the genetic lab (a ‘Probe’) for your genetic diagnosis.

Each PGD test is custom-designed for the specific pattern of inheritance of the mutation in the family of the prospective parents. Please note that this process of creating the ‘probe’ is needed even if you already know the exact nature of the mutation that you are a carrier of. Indeed, the genetic lab in which your embryos will be tested will ask for the details of the diagnosis of your carrier status. The lab will then review the results you forward to them and accept the case if PGD is possible. Yet, to be able to diagnose your embryos, an additional step of creating a probe for the diagnosis will be required. For this purpose the lab will require DNA samples (blood samples) from the egg source, sperm source, and additional family members such as parents, siblings or children. This process typically takes a few weeks.

Step 3: Stimulation of the Ovaries

When the genetic lab inform us that the probe for diagnosis of your embryos is ready we will start your cycle of ovarian stimulation. You will be prescribed stimulation drugs which you will administer daily. The stimulation typically takes 9-14 days and is aimed at maturing 10-20 eggs (ideally) rather than the single egg you mature in a natural cycle when no drugs are used. During this period of ovarian stimulation you will be asked to come to the clinic for ultra-sound scans to monitor the development of your eggs. At times monitoring blood tests (hormone levels) will be requested too.

Step 4: Egg Collection

At the end of the stimulation period, once your monitoring shows that you are ready, you will have an egg retrieval procedure. This is a day-case procedure during which a needle, guided by trans-vaginal ultrasound, will be used to aspirate the eggs from the ovaries. The egg collection is carried out in theatres under light sedation. It takes approximately 30 minutes to complete. Any discomfort you may have after the procedure is normally mild and should be effectively controlled by simple pain-killers. A scientist (embryologist) will be given the eggs collected by the surgeon so that they can be fertilized in the embryology lab.

Step 5: Fertilisation

Next, the embryologists will fertilise your eggs. Fertilisation may be achieved either by standard IVF - by incubating the eggs with sperm overnight, or by intracytoplasmic sperm injection (ICSI). If the semen sample has low sperm cell count or the sperm cells have low motility, ICSI is used to improve the chances of fertilisation. With ICSI the embryologist injects a single sperm cell into each egg under a microscope using a microscopic glass needle.

Step 6: Culture and Biopsy

The morning after your egg collection procedure the embryologist will check how many eggs fertilised successfully. Please note that some of your eggs may not fertilise and that 100% fertilisation rate is rather uncommon. On day 2 after egg collection the embryologist will check how many of your fertilised eggs started dividing to 2-4 cells.

Again some fertilised eggs may fail to cleave and produce embryos. On day 3 after egg collection further cell divisions should lead to the formation of embryos containing 6-8 cells. In the past the biopsy on the embryos was performed at this stage – removing 1-2 cells from each embryo for the sake of genetic diagnosis. However, with experience gained through the years, it transpired that waiting until day 5-6 after egg collection before the biopsy was carried out was advantageous. A blastocyst embryo is no longer a clump of a few cells surrounded by a shell but rather a structured embryos. It typically contains about 100-150 cells set in 2 distinct sites within the embryo. A layer of cells on the periphery of the embryo, the trophectoderm (TE) is destined to form the placenta and membranes during pregnancy while an inner tight group of cells, the inner cell mass (ICM) will form the foetus.

Please note that not all the embryos you have on day 3 will successfully reach the blastocyst stage. Any embryos which successfully achieve a blastocyst stage by day 5-6 after egg collection, will be suitable for a biopsy. During the biopsy our embryologist will remove approximately 4-10 cells from the trophectoderm layer of the embryo. The blastocyst will be frozen and remain at the clinic, while the cells from the biopsy are placed in a test tube and sent to the genetic lab for PGD testing.

Step 7: PGD Testing

Once the genetic lab receives the biopsy samples, the lab will use the probe that was developed to test embryos for the inherited mutation. It is also possible to use the same biopsy sample to test for chromosomal errors in embryos. The PGD lab will provide results for each embryo to the clinic.

Step 7: Embryo Transfer

Next, the patient will discuss the results of their IVF + PGD cycle with their doctor. If the patient has normal embryos that are unaffected with the condition, they may decide to proceed with transferring an unaffected embryo. They may also decide to undergo additional retrievals and IVF cycles to create more embryos.

Step 8: Pregnancy

Ten to twelve days after the embryo transfer procedure, the patient who underwent the embryo transfer will be given a pregnancy test. If the test is positive, the implantation has been successful.

Q & A

Can you do PGD for any genetic condition?

No. In the UK our regulatory body, the HFEA, created a list of genetic conditions which are ‘licensed’ for pre-implantation genetic diagnosis. When patients are at risk of conceiving with a child who will be affected by a genetic condition which is not included in this list, a special application is needed. The HFEA may approve PGD if indeed the condition is likely to have significant implications on longevity or quality of life of the affected child.

Is PGD the only route that prospective parents can take if they are at a risk of conception with a child affected with a genetic condition?

No. Prospective parents may have different approaches to life with disability and they may have different sets of ethics and different religious inclinations. At times after receiving Genetic Counselling and after learning about the pathway of PGD treatment prospective parents decline PGD. They may decide that they wish to conceive and accept the risk of parenting a child with a genetic condition or that they may decide to conceive and have pre-natal genetic screening with chorionic villus sampling (CVS) or amniocentesis so that they can consider termination. At times prospective parents elect to have gamete donation so that the genetic condition is not passed on to their child.

Is PGD testing always successful?

It is almost common knowledge that IVF does not always result in successful pregnancy. As PGD can only be carried out in conjunction with IVF it follows the same statistical predictions as IVF does. Factors such as age of the person who contributes the eggs, ovarian reserve, sperm quality and other con-current fertility issues may affect the chances of conception. An estimated chance of success will be given to you after an assessment by a fertility specialist when your individual circumstances have all been considered.

How accurate is PGD testing?

For most single gene conditions PGD testing is approximately 98% accurate. Yet, testing during pregnancy has an even higher accuracy than PGD has for these conditions. Therefore, doctors recommend testing during pregnancy to confirm the results of PGD.