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Genetic Testing of Embryos (PGS/PGD)

Genetic testing of embryos

It is well established that one of the main reasons causing miscarriage of the failure of embryos to implant is genetic (or chromosomal) abnormality.

 

 

Furthermore, the risk of genetic abnormalities being present increases with maternal age. Thus Down’s syndrome (a disorder of chromosome 21) is more prevalent in babies born to older mothers.

It is possible to increase the pregnancy rate, reduce the risk of miscarriage and reduce the risk of a child being born with a genetic abnormality by genetic testing of eggs or embryos, and only transferring embryos with no identifiable genetic abnormalities. Recent studies indicate that this benefit is significant:

  • A study on women under 35 years (Yang, Molecular Cytogenetics, 2012) showed that genetic testing increased the pregnancy rate from 42% to 69%
  • A study on women over 35 years (Forman, Fertility Sterility, 2013) showed that genetic testing increased the implantation rate from 40% to 58%.

Please note the exact benefit of genetic testing on pregnancy rate and miscarriage rate will vary based on your unique medical history.

Pre-implantation genetic screening (PGS)

PGS, also referred to as aneuploidy screening, is used to screen embryos so that only chromosomally normal embryos are transferred. PGS is often recommended for patients with recurrent IVF failure or unexplained recurrent miscarriage because it is thought that such patients are at increased risk of producing embryos with chromosomal abnormalities (aneuploid embryos).

DNA is a molecule that contains information (in the form of genes) on how each cell in the body should grow and function. DNA is wrapped up into structures called chromosomes that are present in every cell in the body. Humans usually have 23 pairs of chromosomes (22 autosomes plus 1 pair of sex chromosomes) in each cell of their body. Having extra or missing chromosomes (aneuploidy) can result in failure of an embryo to implant, miscarriage and conditions such as Down syndrome.

For PGS, we examine ALL chromosomes in the embryo to determine how many copies there are of each.

Pre-implantation genetic diagnosis (PGD)

Pre-implantation genetic diagnosis (PGD) is used to screen embryos when a couple is deemed to be at risk of passing on a genetic disease to their child. PGD patients may be fertile and capable of achieving a pregnancy naturally but they require IVF in order to produce sufficient embryos for genetic testing. PGD may be advised if:

  • You have had one or more terminations because your baby had a genetic condition
  • You already have a child with a serious genetic condition
  • You have a family history of a serious genetic condition

The HFEA must agree that a particular condition is sufficiently serious before clinics are allowed to test for that condition. Presently, there are over 300 conditions approved for testing by the HFEA – http://guide.hfea.gov.uk/pgd/

Even if the HFEA approves the genetic condition for testing, clinics must make their own judgment on whether PGD is the appropriate treatment for a particular patient. In doing this, they will use the guidance contained in the HFEA’s Code of Practice. This guidance requires the clinic to take into account the view of that patient of the seriousness of the condition to be avoided.

PGD is an area of medicine that is rapidly developing, so new tests often become available. If the condition you are looking for is not currently approved for testing by the HFEA, we advise you to get in touch with us because we may be able to apply to the HFEA on your behalf for permission to perform PGD on that particular condition.

Most of the genetic conditions approved by the HFEA can be carried out for any patient who requests it, after following the guidance in the Code of Practice. However, in cases involving HLA tissue typing, the HFEA only approves PGD on a case by case basis. In these cases, we must apply to the HFEA to authorise testing for a particular patient or family.

Gender selection

Some genetic diseases, such as Duchenne muscular dystrophy, are sex-linked disorders, which affect boys but not girls (girls may still ‘carry’ the gene for the disease but they will not suffer from it). In such cases the embryos are tested for their sex and only female embryos are transferred to the womb.

Gender selection is only allowed to avoid having a child with a serious medical condition, and is strictly prohibited for social reasons, e.g. to have a baby boy or girl to balance your family.

Procedure

Prior to undergoing any form of genetic testing we must ensure that you have been appropriately counselled with regards to the possible risks and benefits of the technique by a suitably qualified professional. In certain cases, we may refer you to a specialist genetics counsellor to discuss the possible implications.

In order to perform PGS or PGD you will first need to undergo IVF or ICSI treatment to generate multiple embryos for testing. It is therefore important that you read the information pertaining to IVF and/or ICSI.

Embryo biopsy

The treatment cycle will proceed as per conventional IVF or ICSI. After fertilisation of the eggs by conventional IVF or ICSI, cellular material can be removed from the embryos (biopsy) for testing at one of three time points:

  1. Day 0 or day 1: at this stage the embryologist can biopsy a structure known as a polar body. The limitation with this option is that only maternal DNA is tested.
  2. Day 3 (cleavage stage): at this stage an embryo typically contains 8 cells and the embryologist will biopsy one of the blastomeres. Cleavage stage biopsy allows testing of both maternal and parental DNA. The main limitation with this option is that less genetic material can be removed for testing compared to blastocyst biopsy (Day 5).
  3. Day 5 or 6: at this stage embryos will develop into blastocysts, which contain two distinct cell lineages: the inner cell mass (this develops into the foetus) and the trophectoderm (this develops into the placenta and amnion). The benefit of blastocyst biopsy is that cells are removed from the trophectoderm, which does not contribute to the foetus. Additionally, more cellular material can be safely biopsied at this stage (since the embryo is larger: containing approximately 100 cells), thereby increasing the accuracy of the test results, while a lower proportion of the embryo as a whole is removed for testing. The disadvantage of blastocyst biopsy is that not all embryos will develop into blastocysts in the laboratory and so there may be fewer embryos to test.

Please note that genetic results for embryos biopsied on day 6 will not be available in time for a fresh transfer and so those embryos must be frozen and transferred in a subsequent frozen embryo transfer (FET) treatment cycle.

Testing

Following embryo biopsy, the biopsied cells are washed and transferred into small test tubes that are sent to an external reference laboratory for analysis.

For PGS, and certain PGD conditions, testing can be performed on a high resolution micro-array using a technique called comparative genomic hybridisation (aCGH), which allows full testing of the 22 chromosome pairs and X|Y chromosomes. Hence, PGD conditions tested by aCGH will also be screened for aneuploidy.

For single gene disorders, a specific test must be developed for that particular disorder. Traditionally, the development of such a test can take up to six months for certain rare disorders and patients will not be able to start their fertility treatment until we receive confirmation from the external lab that test development and verification is complete.

As mentioned above, certain PGD conditions can be tested for using aCGH, which does not require test development and so there is no delay in starting treatment.

Recently, a new technique called Karyomapping allows testing of any licensed single gene disorder without the need to develop a specific test for that disorder. Karyomapping uses next generation sequencing technology to establish a genetic fingerprint of each embryo and compare it to reference samples (provided by the parents and possibly other relatives depending on the condition).

Risks

Embryo biopsy

There is no guarantee that embryos will be suitable for the biopsy procedure. If the biopsy does not take place, genetic testing cannot be performed.
As with any invasive procedure, there is a risk of damage to the embryo from the biopsy procedure. It is estimated that the risk of accidental damage due to biopsy is less than 1%.
The first births following embryo biopsy for PGD were in 1990.

Misdiagnosis

The risk of a clinical misdiagnosis resulting in a baby with genetic abnormalities after PGS or PGD procedure is 1-2%. This could be as a result of mosaicism within an embryo (cells with a different chromosomal pattern). As such, should a pregnancy result, prenatal testing and/or diagnosis is advisable should your physician recommend it.

No embryos for transfer

Genetic testing may reveal that all of the embryos are genetically abnormal, in which case there will be no embryo suitable for transfer into the uterus. The risk of this occurring is influenced by a variety of factors, the most important of which are family history (for PGD), maternal age and the number of eggs retrieved.

No diagnosis

A small number of embryos may have no diagnosis due to poor DNA quality (often found in damaged or dying cells). Embryos without a result can still be transferred, but the benefits of genetic testing will not apply in such cases.

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