Genetic Screening/Testing

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Brave New World is Here: Pre-implantation Genetic Diagnosis

By Michael A. Feinman, MD
Published in Resolve for the journey and beyond, Winter 2011

Since the time of the first IVF success, scientists and ethicists have understood that the potential of preventing chromosomal and genetic diseases before pregnancy was possible. The process known as pre-implantation genetic diagnosis (PGD) has now been available for over a decade, and the technology has progressed rapidly.

PGD is used to identify genetic defects in embryos created through in vitro fertilization (IVF) before implantation and pregnancy. PGD can be used to select embryos that have less risk of having a genetic disorder, increased chances of resulting in a successful pregnancy, less cancer predisposition, and for sex selection.

There are three basic indications for PGD: 1) aneuploidy screening, 2) translocation analysis, and 3) single gene disorders. In all cases, a woman goes through the whole IVF process, including ovarian stimulation, egg retrieval, and fertilization. However, on day three after retrieval, a single cell is removed from the embryo for analysis. If the analysis is good, then the doctor will proceed with an embryo transfer on day five.

Aneuploidy: Test for Chromosomal Abnormalities in Embryo

The most common type of PGD performed is aneuploidy, which tests to see if an embryo has chromosomal abnormalities that result in failed implantation, miscarriages and chromosomal disorders such as Downs Syndrome (an extra copy of the #21 chromosome). The initial technique of looking at chromosomes is called fluorescent in-situ hybridization or FISH. With FISH, special probes are created that uniquely bind to specific chromosomes. When placed under a UV light, the chromosomes can be identified under a microscope by the color they emit. Since the human eye can only discern a certain number of colors, this technique is limited to studying 5-10 chromosomes. The original protocol identified the 10 most common chromosomal abnormalities found in miscarriages.

Limitations of aneuploidy include not detecting a chromosome due to failure to pick up the dye or two chromosomes lying on each other. Another problem that plagues all PGD is called mosaicism – when an early embryo can actually have two groups of cells with different numbers of chromosomes. If one cell shows abnormalities, but the majority of the cells are normal, the embryo may be falsely diagnosed as abnormal.

Over the years, most studies have failed to show a benefit to aneuploidy screening with FISH in either pregnancy rates or miscarriage rates. This is probably due to the limitations mentioned above. For this reason, the American Society for Reproductive Medicine (ASRM) has renamed this process pre-implantation genetic screening (PGS) and is recommending that physicians do not do PGS.

New Advances in Aneuploidy

Two new techniques have reignited interest in aneuploidy screening. One is called CGH for comparative genomic hybridization. With CGH, flourescent probes are used too, but here, thousands of probes are used and all 23 chromosomes can be studied. The analysis is not done with the human eye, but with a computer-assisted microarray that allows for the complex analysis.

The second technique is single nucleotide polymorphism or Snp analysis. Each person has unique areas on their chromosomes that can be used for indemnification. Using DNA samples from each parent, all 23 chromosomes can be accurately identified. Snp technology may be slightly more accurate than CGH, but there are no large randomized studies that compare the two, or show that either technique significantly improves implantation rates or lowers miscarriage rates.

Some clinics have been using Snp technology for a few years, and some believe that it does accomplish the two goals of improving implantation rates and lowering miscarriage rates, but comparative trials are still needed to prove it. Women aged 35-40 may benefit from aneuploidy screening to allow selection of a small number of normal embryos, thus reducing the multiple pregnancy potential of transferring several embryos, without compromising success rates. For younger women and egg donors, results with single embryo transfers may be improved. Finally, women with repeat miscarriages may benefit from current aneuploidy screening.

Translocation Analysis: Tests for Risks of Implantation Error and Miscarriage

The second type of PGD is translocation analysis. Here, one of the parents has a re-arrangement of the chromosomes that leaves him/her normal, but the person has high chance of transmitting an abnormal amount of DNA to the eggs or sperm (gametes). This results in a high rate of infertility, a very high miscarriage rate, and in some cases an increased risk of having a child with abnormal chromosomes. Fortunately, PGD is quite effective at eliminating these risks and helping couples conceive healthy pregnancies.

Single Gene Disease Disorders: Tests for Cystic Fibrosis, Tay-Sachs, Sickle Cell Disease and More

Finally, the most intriguing and controversial type of PGD is single gene disease prevention. Roughly 1/1000 couples carry recessive genes that give them a 25% chance of having an affected child. Well-known examples are cystic fibrosis, Tay-Sachs, and sickle cell disease. If a couple knows they are carriers, embryos can be tested to prevent pregnancy with affected embryos. For couples who have seen their children die from such conditions, this is a miracle. For some ethicists, there are concerns about the eugenic implications of perception of creating “designer babies.”

Benefits, Risks and Questions

In conclusion, with all its shortcomings and controversy, PGD is here to stay. PGD for translocations and single genes have been shown to be effective and offer couples new hope of having healthy children and preventing the painful decisions regarding pregnancy termination of affected fetuses. Current methods of aneuploidy screening may improve embryo selection and reduce miscarriages, but controlled studies are still needed to prove this.

To determine if you are a candidate for PGD, talk with your doctor. If you are considering PGD ask your doctor or reproductive endocrinologist about potential risks associated with this technique. Not all disorders can be detected with PGD, and not all clinics utilize PGD resources.

Michael A. Feinman, MD, FACOG, is the Medical Director, HRC Fertility, with centers in Southern California. Dr. Feinman performed one of the first transvaginal ultrasound guided egg retrievals in America and the first in New York. He developed one of the first anonymous egg donor programs in the world, at the Albert Einstein College of Medicine in New York in 1987. Dr. Feinman has been featured on the cover of the New York Times and on ABC Evening News.

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