Tag Archives: Preimplantation Genetic Diagnosis

Debate Over Genetic Screening of Embryos as New Tests Emerge

As more families opt for pre-implantation genetic diagnosis to screen embryos for inherited diseases, determining the regulatory and ethical guidelines to govern such screenings is “proving difficult,” the Chicago Tribune reports. Although the field of embryonic testing initially focused on identifying genetic defects that are certain to cause suffering or death early in life, it has broadened to include tests for genes linked to breast and ovarian cancer, which are not always fatal, occur later in life and affect 50% to 85% of those who carry the gene, according to the Tribune. The leading U.S. genetic diagnosis clinic, which is the largest in the world, conducted more than 1,800 screenings in 2008 “aimed at weeding out embryos that carried worrisome family conditions, from sickle cell anemia to cystic fibrosis,” the Tribune reports. Different countries vary in their regulation of PGD. In the U.S., doctors are allowed to select embryos for a particular sex, a practice that is not allowed in Great Britain, where each instance of PGD must be registered with the British Human Fertilization and Embryology Authority. BFEA has approved the use of PGD for about 70 genetic defects “after intensive public consultation about what is a serious enough problem to justify trying to eliminate it,” the Tribune reports. It is “significantly easier” to conduct PGD in the U.S. because the government only licenses clinics, not individual procedures, the Tribune reports. Mark Hughes, director of the Detroit-based Genesis Genetics Institute, said his company has tested for 171 genetic defects. In the U.S., “there is no approval mechanism,” Hughes said, adding, “No one is saying you can do this to save a sibling but you can’t do this for BRCA1,” a gene linked to breast cancer. According to a John Hopkins University study, nearly 40% of individuals surveyed believed that embryo screening should be regulated more closely for ethical reasons. An additional 19% said the screening should be banned altogether, for reasons ranging from the belief that discarding an embryo is immoral to concerns that selecting against certain diseases will devalue the lives of people already living with those conditions. Clare Williams, a bioethics specialist at Kings College London, said that during public hearings in Britain, “quite a lot of people felt there could well be treatment (for some conditions) by the time these children grow up, and then (their condition) won’t be an issue.” Some experts say it would be beneficial to place limits on the type of genetic defects doctors are allowed to screen for in the U.S., the Tribune reports. The Hopkins study found that, as of 2006, 65% of about 200 U.S. clinics offering embryo screenings allowed clients to choose the gender of the implanted embryo, regardless of the gender of existing children or whether the child was their first. The Tribune reports that such data and a California-based genetics lab’s recent announcement that it would be able to select eye and hair color have raised public concerns about genetic selection of embryos. The lab’s claims have been “disproved,” and many experts believe that expanded embryo screening “probably is not a slippery slope toward designer babies” because PGD is “costly and difficult,” there are a limited number of embryos to choose from and “finding one that includes a number of desired traits would be very difficult,” the Tribune reports. Hughes said the “things you might want to select for in a child — intelligence, athletic prowess, body stature — involve not single genes but many, many genes.” According to the Tribune, PGD, used in conjunction with in vitro fertilization, costs about $3,500 in the U.S. and twice that in Britain (Goering, Chicago Tribune, 3/25).


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Birth of first UK baby screened for genetic breast cancer

The first baby to be screened for alterations in the breast cancer-causing gene, BRCA1, was born last week. The child was at risk from inheriting the gene from her father, who has women in three generations of his family who have been diagnosed with breast caner in their twenties as a result of inheriting the defective gene.

breast_cancer22 Paul Serhal, the fertility expert who treated the couple at the Assisted Conception unit of University College Hospital, London, said: ‘This little girl will not face the spectre of developing this genetic form of breast cancer or ovarian cancer in her adult life. The parents will have been spared the risk of inflicting this disease on their daughter. The lasting legacy is the eradication of the transmission of this form of cancer that has blighted these families for generations.’

The BRCA1 gene, when properly functioning, can help prevent breast cancer, but abnormal variations can significantly increase the risk of developing breast cancer. Females born with the affected gene face a 50-80 per cent risk of contacting breast cancer and a 40-60 per cent chance of developing ovarian cancer.

In 2006 the UK’s Human Fertilisation and Embryology Authority (HFEA) permitted fertility clinics to perform pre-implantation genetic diagnosis (PGD) – a procedure whereby embryos are tested for various conditions, the healthy ones are re-implanted and those that are affected are discarded – to test for this type of gene that makes carriers susceptible to a disease but that does not necessarily lead to disease in all cases. BRCA1 and BRCA2 account for around five per cent of breast cancers and it is thought that roughly 37,000 women in the UK carry BRCA1.

pgd1The couple concerned, who wish to remain anonymous, underwent IVF despite being fertile. A single cell was removed from the 11 embryos created when they were at the eight-cell stage and tested for the defective BRCA1 gene, revealing that only five of the embryos were free from the gene. Two of these were implanted into the mother’s womb, of which one, a girl, pgd21 successfully implanted to develop until birth.  The remaining three healthy embryos were frozen in case the parents want more children in the future. The six embryos carrying the defective BRCA1 gene were discarded.

Given that the breast cancer is increasingly curable and that carriers of the gene do not necessarily develop the disease (and vice versa), questions have been raised over the ethics of the procedure. Josephine Quintavalle, of the campaign group Comment on Reproductive Ethics (Core), told the BBC that she believes the procedure is a step too far, as it gives the message that ‘you are better off dead, than being born with this gene’. She added: ‘I hope 20 years down the line we will have eradicated breast cancer – not eradicated the carriers’.

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Applications of PCR

The Polymerase Chain Reaction (PCR) has found widespread application in many areas of genetic analysis. This is a list of some of these applications:

1 Medical applications
2 Infectious disease applications
3 Forensic applications
4 Research applications

Medical applications

PCR has been applied to a large number of medical procedures:

The first application of PCR was for genetic testing, where a sample of DNA is analyzed for the presence of genetic disease mutations. Prospective parents can be tested for being genetic carriers, or their children might be tested for actually being affected by a disease. DNA samples for Prenatal testing can be obtained by amniocentesis, chorionic villus sampling, or even by the analysis of rare fetal cells circulating in the mother’s bloodstream. PCR analysis is also essential to Preimplantation genetic diagnosis, where individual cells of a developing embryo are tested for mutations.

PCR can also be used as part of a sensitive test for tissue typing, vital to organ transplantation. As of 2008, there is even a proposal to replace the traditional antibody-based tests for blood type with PCR-based tests.
Many forms of cancer involve alterations to oncogenes. By using PCR-based tests to study these mutations, therapy regimens can sometimes be individually customized to a patient.

Infectious disease applications

Characterization and detection of infectious disease organisms have been revolutionized by PCR:

The Human Immunodeficiency Virus (or HIV), responsible for AIDS, is a difficult target to find and eradicate. The earliest tests for infection relied on the presence of antibodies to the virus circulating in the bloodstream. However, antibodies don’t appear until many weeks after infection, maternal antibodies mask the infection of a newborn, and therapeutic agents to fight the infection don’t affect the antibodies. PCR tests have been developed that can detect as little as one viral genome among the DNA of over 50,000 host cells . Infections can be detected earlier, donated blood can be screened directly for the virus, newborns can be immediately tested for infection, and the effects of antiviral treatments can be quantified.

Some disease organisms, such as that for Tuberculosis, are difficult to sample from patients and slow to be grown in the laboratory. PCR-based tests have allowed detection of small numbers of disease organisms (both live or dead), in convenient samples. Detailed genetic analysis can also be used to detect antibiotic resistance, allowing immediate and effective therapy. The effects of therapy can also be immediately evaluated.

The spread of a disease organism through populations of domestic or wild animals can be monitored by PCR testing. In many cases, the appearance of new virulent sub-types can be detected and monitored. The sub-types of an organism that were responsible for earlier epidemics can also be determined by PCR analysis.

Forensic applications

The development of PCR-based genetic (or DNA) fingerprinting protocols has seen widespread application in forensics:
In its most discriminating form, Genetic fingerprinting can uniquely discriminate any one person from the entire population of the world. Minute samples of DNA can be isolated from a crime scene, and compared to that from suspects, or from a DNA database of earlier evidence or convicts. Simpler versions of these tests are often used to rapidly rule out suspects during a criminal investigation. Evidence from decades-old crimes can be tested, confirming or exonerating the people originally convicted.

Less discriminating forms of DNA fingerprinting can help in Parental testing, where an individual is matched with their close relatives. DNA from unidentified human remains can be tested, and compared with that from possible parents, siblings, or children. Similar testing can be used to confirm the biological parents of an adopted (or kidnapped) child. The actual biological father of a newborn can also be confirmed (or ruled out).

Research applications

PCR has been applied to many areas of research in molecular genetics:

PCR allows rapid production of short pieces of DNA, even when nothing more than the sequence of the two primers is known. This ability of PCR augments many methods, such as generating hybridization probes for Southern or northern blot hybridization. PCR supplies these techniques with large amounts of pure DNA, sometimes as a single strand, enabling analysis even from very small amounts of starting material.

The task of DNA sequencing can also be assisted by PCR. Known segments of DNA can easily be produced from a patient with a genetic disease mutation. Modifications to the amplification technique can extract segments from a completely unknown genome, or can generate just a single strand of an area of interest.

PCR has numerous applications to the more traditional process of DNA cloning. It can extract segments for insertion into a vector from a larger genome, which may be only available in small quantities. Using a single set of ‘vector primers’, it can also analyze or extract fragments that have already been inserted into vectors. Some alterations to the PCR protocol can generate mutations (general or site-directed) of an inserted fragment.

Sequence-tagged sites is a process where PCR is used as an indicator that a particular segment of a genome is present in a particular clone. The Human Genome Project found this application vital to mapping the cosmid clones they were sequencing, and to coordinating the results from different laboratories.

An exciting application of PCR is the phylogenic analysis of DNA from ancient sources, such as that found in the recovered bones of Neanderthals, or from frozen tissues of Mammoths. In some cases the highly degraded DNA from these sources might be reassembled during the early stages of amplification.

A common application of PCR is the study of patterns of gene expression. Tissues (or even individual cells) can be analyzed at different stages to see which genes have become active, or which have been switched off. This application can also use Q-PCR to quantitate the actual levels of expression.

The ability of PCR to simultaneously amplify several loci from individual sperm has greatly enhanced the more traditional task of genetic mapping by studying chromosomal crossovers after meiosis. Rare crossover events between very close loci have been directly observed by analyzing thousands of individual sperms. Similarly, unusual deletions, insertions, translocations, or inversions can be analyzed, all without having to wait (or pay for) the long and laborious processes of fertilization, embryogenesis, etc.

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UK Couple to Test Embryos for high Cholesterol disorder

UK doctors are expected to receive permission to help a couple avoid passing on a hereditary condition that causes very high blood cholesterol to their children, according to the Times. The newspaper reports that a team lead by Paul Serhal, of University College London, will be granted a license by the Human Fertilisation and Embryology Authority (HFEA) this week. This will enable them to use preimplantation genetic diagnosis (PGD) to select embryos free from the gene mutation that causes both the mild and severe forms of familial hypercholesterolaemia (FH). One in 500 people in the UK has inherited the mild form of FH, although many of those with the condition are thought to remain undiagnosed. The condition can increase the risk of a heart attack in men under fifty by ten-fold. However, if treated through diet, exercise, lifestyle changes and – in some cases – with statin drugs, this risk can be drastically reduced. FH also increases the risk of strokes and blood vessel failure, which can lead to limb amputations. In contrast to the mild form of the condition, which affects people who inherit just one copy of the faulty gene, there is also a severe form of FH that affects children who inherit a ‘double dose’ of the mutation. This ‘homozygous’ form of the disease leads to very high levels of cholesterol from the age of around five, and can often cause death in childhood. Unlike the mild form, it does not always respond well to treatment with statins or other drugs.

The couple seeking treatment at UCL both have mild FH, which they discovered only after having a daughter with the homozygous, severe form of the disease. There is a 25 per cent risk that any subsequent child will also inherit the severe form of FH, who, unlike their first child, may not respond well to treatment. There is also a 50 per cent chance that they will pass on the mild form of the condition to their next and subsequent child, and a 25 per cent chance that each will be unaffected.

PGD involves taking a single cell from a 2-4 day old IVF embryo, performing a genetic or chromosome test on that cell, and then returning one or two unaffected embryos to the womb. In the UK, the use of PGD is regulated by the HFEA, which licenses the procedure on a case-by-case basis. The couple approached Mr Serhal after learning that his clinic offered PGD for hereditary breast cancer. If the procedure is successful, then the couple will be able to select one or more unaffected embryos to implant. However, if there are no unaffected embryos, then the couple will have to decide whether or not to select embryos that have the milder form of FH. Mr Serhal told the Times: ‘This obnoxious disease can cause cardiovascular accidents at a very young age. Ideally, we will find embryos with no FH genes, but it is possible we will not and it will be up to the patients to choose. Some people would think twice about using embryos that they know have a risky gene, and others would say you shouldn’t screen out a condition that can be managed so people can live with it. It will be an awkward choice’.

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Couple suing over child selection “blunder”


An Australian couple has launched an action in the Supreme Court of Victoria against the health services involved in an embryo testing procedure, after the mother gave birth to a boy instead of a girl. The couple had undergone IVF and PGD (preimplantation genetic diagnosis) at Melbourne IVF to enable doctors to select only female embryos to be re-implanted in an attempt to avoid haemophilia, an inherited disorder that only affects males. Instead,the mother gave birth to a baby boy, Jess, who doctors later confirmed is affected by the blood clotting condition. The couple are alleging that in no point during the pregnancy were they informed that the child was not a girl, and are now seeking compensation and
damages to pay for the child’s care costs and other losses they will incur.
If the couple had been informed of the true sex of their child, they say they would have considered terminating the pregnancy. It is reported that the defendants will contest the action on the grounds that the couple did not make inquiries as to the sex of their child after ultra-sound scans and that the boy may have been conceived naturally.
Sex selection is permitted in Victoria only to reduce the risk of a serious genetic condition being passed to the child. The couple opted for the procedure to avoid passing on hameophilia, which also affects the boy’s uncle. ‘By choosing the IVF procedure, we hoped to never see a child suffer in this way again’, the parents told reporters. ‘At no stage did we want a
designer baby, we just wanted a healthy baby.”We love our little boy, but we are very sorry he has to go through so
much in his life’, the couple said. ‘We tried everything to avoid this situation, and now our boy has to go through all the pain and treatment in order to survive. We now face the fact that Jess will require treatment for the rest of his life’.
The action is being taken against Melbourne IVF, Ballarat Health Services, the couples’ obstetrician and Bendigo Radiology. In documents lodged with the court, lawyers for Melbourne IVF say that a counsellor told the couple in 2003 that there was a risk of misdiagnosis with the PGD method. They also claim the couple signed consent forms, including one that stated ‘If a pregnancy is achieved from biopsied embryos, we understand that further diagnostic tests are recommended to confirm the early embryo diagnosis’. No date has been set for the trial.

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