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PGD Team

PGD Team

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Further information about PGD

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Dr Joyce C Harper
UCL Centre for PGD
University College London
joyce.harper@ucl.ac.uk

General information (lay terms)

Preimplantation genetic diagnosis (PGD) was developed as an alternative to prenatal diagnosis, for couples at risk of transmitting an inherited disease to their offspring.  In prenatal diagnosis (either chorionic villus sampling (CVS) or amniocentesis) the diagnosis is performed when the pregnancy is already established.  If the test finds that the fetus is affected with a genetic disease, the couple have to decide if they with to continue with the pregnancy or undergo a termination.  For most couples, a termination of pregnancy is a difficult option.  With PGD, the couple undergo routine IVF procedures so that the embryos are produced outside the body.  Embryo biopsy is usually undertaken when the embryo is at the 6-8 cell stage, and 1-2 blastomeres are removed.  Single cell diagnosis is performed using the polymerase chain reaction (PCR) or fluorescent in situ hybridisation (FISH), depending on the disease being diagnosed.  Unaffected embryos are then transferred to the uterus so that the pregnancy is started knowing that the fetus is unaffected.

The patients that come forward for PGD are often fertile.  They may have already experienced a termination of an affected pregnancy, may have moral or religious objections against termination, or may be experiencing repeated miscarriages due to chromosomal abnormalities. 

The majority of clinics performing PGD use cleavage stage embryo biopsy on day 3 (see figure in next section).  There are two stages to this procedure;  zona drilling, which is usually performed using acid Tyrodes solution but more recently using a non-contact laser, and then blastomere aspiration.  Polar body biopsy has also been used for PGD by two groups.  Usually both the first and second polar body are taken to be sure of an accurate diagnosis.  Blastocyst biopsy has been proposed, but no reports of using this procedure clinically have been published.

PCR is used for the diagnosis of single gene defects, including recessive and dominant disorders, triplet repeat diseases, and sexing for X-linked disease (but FISH is the usual method for sexing).  PCR involves amplification of a specific region of DNA many thousands of times and techniques such as fluorescent PCR have made PGD more versatile.  However, each mutation or disease requires a new PCR to be developed.  PCR in PGD is hampered by two things:  contamination and a phenomenon known as allele dropout (ADO) (for review see Wells and Sherlock, 1998). 

FISH is used for the diagnosis of sex for X-linked disease, chromosomal abnormalities and more recently for aneuploidy screening to try and improve IVF pregnancy rates.  Sexing by FISH is a relatively easy PGD procedure and is usually only used for patients at risk of X linked disease, but has recently also been used for patients who wish to choose the sex of their child.  Using PGD for social sexing is illegal in the UK and there is much controversy about using PGD for non-medical reasons (see end of this article).  PGD for chromosomal abnormalities, such as translocations, etc, is more difficult.  One of the couple will be carrying a translocation involving two chromosomes and FISH probes have to be used for these chromosomes.  The right probes are not always available commercially, or may not work well together, and so these diagnoses can take some time to workup.  Aneuploidy screening has been used to try and increase the pregnancy rate for certain patients undergoing PGD, usually older women. 

PGD may seem like the ideal option for patients carrying genetic or chromosomal diseases, but realistically, PGD does have some problems.  The first is that the patients have to go through IVF, and for the fertile couple, this may be difficult.  For PGD to be successful, a good number of embryos are required, ideally around 10, so that after PGD, some good quality, unaffected embryos are available for transfer.  In some cases, all the embryos may be affected, or there may only be morphologically poor embryos to transfer.  Also, the pregnancy rate after PGD seems to be lower than the IVF pregnancy rate, probably as not always the morphologically best embryos are transferred. 

In 1997, we established the ESHRE PGD Consortium, to collate data on PGD referrals, cycles, pregnancies and babies born.  To date two reports have been published, both in the December issues of Human Reproduction (1999 and 2000).  The pregnancy rates over the two years of data collection have been 17% and 19% respectively.  There are also hurdles with PGD relating to the diagnosis.  Single cell diagnosis is still a technically challenging procedure, and there have been several reports of misdiagnosis (reviewed in Harper and Delhanty, 2000).   Due to the complex nature of the diagnosis used in PGD, working up a diagnosis for new diseases is time consuming and expensive.  As a result, only a handful of diseases have been diagnosed by PGD.

What does the future hold for PGD?  Importantly, methods have be to used to try and increase the information gained from a single cell, so that more accurate and a wider of spectrum of diseases can be diagnosed.  For PCR, the use of fluorescent PCR is being widely used, as this is a very sensitive technique and more than one segment of DNA can be examined at one time (multiplex PCR), which is essential when there are only 1 or 2 cells for analysis.  This technique has been used to look at mutations, and DNA markers (similar to those used in DNA fingerprinting), which vary between the mother and father and so can be used to eliminate contamination.    Advances in FISH are concentrating on examining more or ideally all of the chromosomes.  One method is comparative genomic hybridisation (CGH), which has been applied to human embryos by our own group and Leeanda Wiltons group in Melbourne (reviewed in Harper and Delhanty, 2000).   However, CGH is a time consuming procedure that currently takes many days and so it has not been applied to PGD.

A discussion on PGD will not be complete without mentioning the ethics involved in this procedure.  PGD has already been used for social sexing in Australia and Jordan, and as the genetic basis of more characteristics are understood, there is the worry that PGD will be used for designing the perfect baby.  With the reports that the Italians are trying to clone humans, who will be the first to take PGD into the Brave New World?  Luckily in the UK we have strict legislation which only allows PGD to be used for serious diseases.

Further reading

Book on PGD:  Preimplantation genetic diagnosis, edited by Harper, Delhanty and Handyside, published by Wiley, due out Summer 2001 (see web page).

Review on PGD: Preimplantation genetic diagnosis, Harper and Delhanty, 2000, in Current opinions in Obstetrics and Gynaecology, Apr;12(2):67-72

Review on PCR diagnosis:  Wells D, Sherlock JK. Strategies for preimplantation genetic diagnosis of single gene disorders by DNA amplification. Prenat Diagn 1998; 18:1389–1401.

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