Pre-implantation Genetic Testing

Pre-implantation genetic testing is a method of early oocyte or embryo testing, with the aim of preventing the birth of children with genetic defects. It combines assistive reproduction technologies, embryology, and genetics. Every healthy embryo contains 46 chromosomes, 23 of whom stem from the oocyte, the other 23 – from the sperm cell. The chromosomes are made up of genes that act as chemical messengers that instruct the cell on how to grow and function in different processes in the human body. There are more than 30 000 different genes that are made up of DNA, ordered in a certain row and contain the “code” for every single gene and its function. The destruction of the normal structure (code), as well as the discrepancies in the number of genes / chromosomes can have terrible consequences.

Pre-implantation genetic testing is divided into two main groups - pre-implantation genetic diagnosis (PGD) and pre-implantation genetic screening (PGS). PGD ​​is applicable to families in which one or both parents have a proven genetic abnormality (chromosomal abnormality, monogenic defect, or hereditary disease in the lineage transmitted by the X chromosome) and the embryo is tested for the specific mutation. In PGS, embryos of parents with normal karyotype are screened for aneuploidy (incorrect chromosome count). Indications for PGS are advanced female reproductive age, multiple spontaneous abortions, unsuccessful attempts from previous IVF procedures, severe male infertility.

Pre-implantation genetic diagnosis (PGD)

PGD is used for determining translocations, i.e. changes in the chromosome structure. In patients with “balanced” translocations, no changes are usually observed, as there are is extra or missing chromosome material, and the discrepancy usually does not disturb gene function. It is typical for such patients that they do not have any medical problems, although some of them have a reduced fertility. If there is missing or extra chromosome material, such translocations are considered as “unbalanced”. The probability for embryo implantation in an unbalanced translocation is slim, as the abortion chances get higher. However, if a pregnancy does occur, it can lead to the birth of a child with physical or mental problems. Reciprocal translocations occur in about 1 in 625 people. Such translocations disturb the structure of two different chromosomes. About 1 in 900 have Robertson’s translocation, which entails chromosomes 13, 14, 15, 21, or 22. Those chromosomes have larger bottom ends that can blend into one-another. The risk of recurring spontaneous abortions or the birth of a child with malformations in the included chromosomes and the size of the interchanged fragment. The application of PGD enables the possible diagnostics of different single gene defects. Those are diseases that are caused by the inheritance of a single defect gene. There are two types of single gene defects:

  • Recessive: two copies of the defect gene are necessary, one from each parent, for the disease to manifest;
  • Dominant: only one copy of the defect gene is necessary for the disease to manifest.

Preliminary screening for some of the most common single genetic defects (such as cystic fibrosis, Tay-Sachs disease) is advised for populations at risk.

Pre-implantational Genetic Screening (PGS)

Indications for PGS are advanced female reproductive age, multiple spontaneous abortions, unsuccessful attempts from previous IVF procedures, severe male infertility.

In PGS, the embryos are analyzed to determine the number of chromosomes. Aneuploidy is the most common chromosome anomaly. It is either the presence of an additional chromosome (trisomy), or the absence of a chromosome (monosomy). When there are additional or missing chromosomes, the probability of a successful implantation is reduced, and the percentage of spontaneous abortion risk increases. When chromosomes 13, 18, 21, X, or Y are affected, implantation and subsequent pregnancy can still occur, but the offspring will have a genetic disease. The most common trisomy is Trisomy 21, or Down syndrome. Other aberrations include Patau syndrome (trisomy 13), Edward syndrome (trisomy 18), Klinefelter syndrome (47 XXY), Turner syndrome (45 X, missing a gamete chromosome). In spontaneous abortions, the affected chromosomes are usually 15, 16, 21, and 22. The most common aneuploidies in 3-day-old embryos are 15, 16, 17, 21, and 22. The aneuploidy probabilities increase with increasing age of the mother. As women are born with their ovarian reserve for whole life, it is widely believed that the oocytes of women in advanced reproductive age are more likely to make mistakes in the chromosome division. This would mean an increase of defect oocytes (due to a missing or an additional chromosome, for example). Studies show that more than 20% of the embryos of women of 35-39 years of age and 40-60% of the embryos of women of ages above 40 suffer from aneuploidy. At least 85% of aneuploidy cases in the embryo occur in the oocyte. Sperm aneuploidy cases are a much smaller percentage, around 7-8%. The rest of the chromosomal aberrations occur during cell division in the early embryo phase.

The advantages of PGS are:

  • Selection and embryo transfer of healthy embryos that do not have any concrete data for chromosome abnormalities;
  • A reduction of spontaneous abortions;
  • A reduction of multiple-embryo pregnancies;
  • An increase of the degree of embryo implantation;
  • An increase of the chances to birth a healthy child.

The risks of PGS include:

  • Embryo damage (< 1%);
  • Incorrect diagnosis (false positive or false negative) due to natural embryo mosaicism or technical limitations (< 5%);
  • No embryotransfer if 100% of the embryos turn out to be abnormal (< 20%).
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