Preimplantation Genetic Diagnosis (PGD)

"Preimplantation Genetic Diagnosis Using Embryo Biopsy and Fluorescence in situ Hybridization (FISH), or Other Procedures Including PCR Single Gene Analysis."

PGD involves procedures that allow for the study of specific cells, taken from embryos in the laboratory, as a method of detecting chromosomal abnormalities, prior to the time that such embryos are transferred to the uterus for the possible establishment of a pregnancy. Since both analyses require examination of the embryos in vitro (in a laboratory dish), PGD requires the use of in vitro fertilization (IVF).

After genetic analysis, the patient and physician discuss the results and what they may mean for the future development of such embryos to assist the patient in making an informed decision as to whether to undergo embryo transfer, and -- if so -- which embryos to select for use in such transfer.

The purpose of PGD is to attempt to detect chromosomal abnormalities and potentially avoid the transfer of an embryo that has certain abnormal chromosomes, hopefully preventing a pregnancy with an abnormal fetus, or the possible delivery of a child with genetic defects. Also, by selecting embryos for transfer, which, according to the test results, appear to have the best chance for acceptable development, it is possible that the rate of implantation may be increased and the number of miscarriages may be reduced.

Not all genetic defects are ascertainable using PGD, and when undergoing PGD, there is the risk of inaccurate results. PGD offers no guarantee that a diagnosis can be made, that pregnancy will occur, or that a healthy child (free from genetic defects) will result. If you elect to proceed with PGD, you must acknowledge these risks.

Any understanding of the purposes of PGD or its methods requires some knowledge of the genetic conditions that form the basis for the need for PGD. Please note that The Center for Reproduction & Women's Health Care strongly recommends that you discuss potential genetic abnormalities with a geneticist and/or with your physician prior to performing the genetic diagnosis on your embryos and again after the diagnosis has been made.

Information Concerning Genetic Abnormalities that May Affect the Health of a Developing Embryo.

During fertilization, the egg provides a set of chromosomes and the sperm provides another set, resulting in two of each chromosome. However, sometimes genetic abnormalities occur in the formation of the sperm or eggs (or both) resulting in embryos with too many or too few chromosomes (aneuploidy), or too many or too few parts of specific chromosomes (translocation or inversion). For example, the embryo should contain two copies of chromosome 21. When there is an extra copy (three chromosome 21's), the embryo may result in an individual with Down Syndrome (Trisomy 21).

There are essentially three types of genetic conditions which can have significant effects on the development of an embryo: (1) aneuploidy, (2) translocation, or (3) inversion.

Aneuploidy

Aneuploidy is a condition where there are either extra, or too few, chromosomes. When the normal number of chromosomes is present, it is referred to as euploidy. Chromosomes are "numbered" and at least five (5) chromosomes will be tested with PGD, because such chromosomes account for most of the chromosomal abnormalities (aneuploidy) seen in newborns or in the tissue of miscarriages.

These abnormalities are also found in up to approximately 50% of human embryos and may contribute to failure of some embryos to implant in the uterus following IVF and embryo transfer. Aneuploidy for these chromosomes can also lead to embryo death, miscarriage, or the live birth of an infant with substantial medical problems. In fact, aneuploidy in a developing embryo may be associated with the following:

• Failure to achieve a pregnancy. Studies have demonstrated that the majority of embryos obtained following IVF that fail to implant in the uterus or miscarriage are aneuploid or "unbalanced."
• Loss of a pregnancy. Chromosome abnormalities are the most common reason for spontaneous miscarriages (loss of a pregnancy after it has been established in the uterus).
• Offspring born with aneuploidy or an "unbalanced state."

The chance of having a miscarriage or having embryos that fail to develop into a pregnancy increases as the age of the woman increases. There is evidence that the relationship between these two conditions and maternal age may be explained a higher incidence of aneuploidy in the offspring of older women.

While there are many chromosomal aneuploidies, the most common that occur are with chromosomes 13, 16, 18, 21, X and Y, and include the following:

• TRISOMY 21 (one extra chromosome 21, also known as Down's syndrome) is the most common chromosome aneuploidy found in live births. Approximately 1 in every 800 babies has it. It is associated with advanced maternal age. Children who have Down syndrome can have varying degrees of developmental delay. Some may be mildly affected, while others may be more severely delayed. Some children with Down syndrome have other associated medical problems, like heart defects or leukemia that may require medical management.
  
• TRISOMY 13 (one extra chromosome 13) In the general population, 1 in every 5,000 babies born has trisomy 13. Trisomy 13 is associated with advanced maternal age. These babies have multiple system abnormalities, including abnormalities of the heart, brain and cleft lip/plate. Babies with trisomy 13 have limited life span. Most of them die within the first few months of life, and those that do survive are severely delayed in growth and development.
• TRISOMY 18 (one extra chromosome 18) Approximately 1 in every 3,000 live births results in trisomy 18. It is associated with advanced maternal age. Most babies with trisomy 18 have multiple abnormalities including heart, brain, mental retardation and delayed growth. Most of the babies do not survive more than a few months.
• XXX (one extra X chromosome resulting in three X chromosomes) Incidence of XXX is approximately 1 in 1,100. XXX is also associated with advanced maternal age. These are normal appearing, fertile females who may present with learning disabilities.
• XXY (one extra X chromosome in a male) this occurs in about 1 in 1,100 births. These males are normal in appearance and are often taller than other male siblings. There are some studies suggesting that these males may have behavioral problems but generally have a normal IQ.
• XO (missing one X chromosome; also referred to as Turner's syndrome) this occurs in about 1 in every 5,000 live births. These females have normal IQ, but generally are shorter than expected and may have other physical abnormalities, such as congenital heart defects. Growth can be enhanced with hormone therapy. These women are usually infertile; however, they do have a uterus and can conceive and carry to term with the help of IVF using donor eggs.
  
• Monosomes for Chromosomes 13, 15, 16, 17, 18, 21, 22, X and Y (Only one of a particular chromosome is present instead of the typical two chromosomes) Monosomy 21 (one chromosome 21) is only seen in tissue from miscarriages. The other monosomies have never been seen in miscarriages or in children. It is therefore, believed that embryos that are missing one of these chromosomes are not able to implant into the uterus.

Translocation or Inversion ("Unbalanced State")

An "unbalanced state" may result from either translocation or inversion:

a. Translocation is the presence of a translocation chromosome (chromosomal rearrangement) that can cause the embryo to have too many copies or parts of one chromosome and too few copies or parts of the other. This results in too many or too few normal genes on a chromosome. This is called an "unbalanced state", meaning that the embryo does not have the proper amount of genetic material.

Where one of the patients is known to carry a translocation chromosome involving specific chromosome(s), those chromosomes will be tested utilizing PGD.
An "unbalanced state" or translocation in an embryo may lead to embryo death, miscarriage, or the live birth of an infant with substantial medical problems. Listed below are very brief descriptions of some of the possible abnormalities that are found when there is the transfer of a balanced or unbalanced translocation or inversion chromosome to one's offspring.

b. Inversions B occur when a single chromosome breaks in two places and the material in-between is reconstituted upside down. The presence of this inversion chromosome in eggs or sperm can result in an embryo with too many or too few copies of genes located on particular chromosomes.

This can also be considered an "unbalanced state." Where one of the patients is known to carry an inversion of a particular chromosome(s), those chromosomes will be tested utilizing PGD. A pregnancy involving an embryo with too many or too few copies of genes (from this inverted chromosome) may result in the failure of the embryo to grow, miscarriage, or the birth of a severely-affected child with substantial medical problems.

Translocation or Inversion ("Balanced State")

There may also be "balanced" translocations or inversions, which means that there is a translocation (rearrangement) or inversion (material upside down) but there are the right number of copies of genes. When one partner carries a balanced translocation or inversion chromosome, this intact chromosome can be transferred to their offspring.

While the child would be "normal", that child may transmit this abnormal chromosome to his/her offspring. The FISH technique of analysis (described later) cannot differentiate between the presence of a balanced translocation chromosome and a normal chromosome.

When one partner carries a balanced translocation or inversion chromosome, this chromosome can separate and transfer too few or too many copies of a chromosome to the embryos, which can lead to abnormal genetic conditions. There may be a resultant failure to conceive, miscarriage, fetal death or the birth of a severely affected child with a genetic disorder. Please read our PGD Patient Handout.

 

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