A Guide to Preimplantation Genetic Testing (PGT)

Preimplantation genetic testing at a glance

Preimplantation genetic testing (PGT) examines embryos during in vitro fertilization (IVF) before possible transfer to a woman’s uterus for a range of genetic problems that can cause implantation failure, miscarriage and birth defects in a resulting child.
These genetic defects include a missing or an extra chromosome in the embryo (for example, Down syndrome), single gene disorders (like sickle cell anemia), or the rearrangement of genes, which can cause pregnancy loss and birth defects.
We use three specific types of PGT, which is a new term encompassing the same functions as the previously named and more well-known preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS) embryo genetic tests.
Embryologists use PGT to find genetic defects in embryos during IVF, so those embryos will not be transferred to the woman’s uterus to achieve a pregnancy.

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What is preimplantation genetic testing (PGT) for embryos?

Preimplantation genetic testing refers to the three types of tests that may be performed on embryos during IVF:

Preimplantation genetic screening for abnormal chromosome number (PGT-A)
Preimplantation genetic testing for monogenic (individual) disease (PGT-M)
Preimplantation genetic testing structural rearrangement (PGT-SR) for known chromosomal mis-arrangements such as inversion and translocation.

Fertility specialists conduct these tests for two important reasons. One is to determine if embryos have genetic abnormalities that often cause failed implantation and miscarriage, resulting in unsuccessful IVF. The second is to identify embryos with genetic defects that can result in a child with a genetic disorder that could cause death or such inheritable conditions as muscular dystrophy.

Embryos found to have such flaws are excluded from being transferred to the mother’s womb for a pregnancy. Research has shown that genetic errors in embryos are a major cause of failed pregnancy and live birth. A fertility specialist can consult with couples interested in PGT testing to discuss available procedures.

The three types of PGT are new terms the medical community is moving toward that replace the previous terms of preimplantation genetic screening (PGS) and preimplantation genetic diagnosis (PGD). The function of PGS is now accomplished through PGT-A. PGD’s function is now either performed by PGT-SR or PGT-M. The tests themselves are still executed in the same or similar manner.

Preimplantation genetic testing for aneuploidy (PGT-A)

PGT-A is an analysis of embryo cells to determine if there is the normal amount of chromosomes. An unequal division of either sperm or egg cells can result in an embryo having too few or too many chromosomes.

Most people have 46 chromosomes because they inherit 23 chromosomes from each parent. If an embryo or a cell is missing a chromosome or has an extra one, it is called aneuploidy. Monosomy is a missing chromosome and trisomy is an extra chromosome.

A child can only survive one type of monosomy, Turner syndrome, which is the absence of one of the X chromosomes. Trisomy of chromosome pairs can sometimes result in live birth, Down syndrome, also called trisomy 21 (an extra chromosome in normal pair # 21), Turner syndrome (trisomy 18) and Patau syndrome (trisomy 13). Down syndrome affects 1 in 700 babies, according to the Centers for Disease Control and Prevention.

Aneuploidy is one of the greatest causes of failed implantation for pregnancy and miscarriage, as well as a major cause of birth defects in children.

Candidates for PGT-A include:

Couples who have had a previous pregnancy with aneuploidy
Women who have had two or more miscarriages
Women who have experienced previously failed embryo implantation
Women diagnosed with unexplained infertility
Women older than age 35
Women who have undergone numerous unsuccessful fertility treatments

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Preimplantation genetic testing for a monogenic disease (PGT-M)

PGT-M analyzes for specific gene mutations that one (or both) of the parents is known to carry. A family background of genetic disorders in one or both parents can increase the possibility for a child to be born with a genetic mutation.

A disorder involving a single specific gene is due to a mutation in the DNA sequence. This results in diseases such as cystic fibrosis and sickle cell anemia. It can also cause an inherited genetic mutation such as the BRCA1 and BRCA2 mutations that greatly increase a woman’s risk of breast cancer and ovarian cancer.

During PGT-M, the fertility specialist will test the embryos for specific genetic disorders before the embryo is possibly transferred to the woman’s uterus.

PGT-M examines common disorders including:

Huntington’s disease
Sickle cell anemia
Muscular dystrophy
Cystic fibrosis
BRCA1 & BRCA2 mutations
Fragile-X syndrome
Tay-Sachs disease

PGT for chromosome structural rearrangement (PGT-SR)

PGT-SR analyzes embryos of patients known to have a chromosomal structural rearrangement, such as an inversion or translocation. Patients who have a known structural rearrangement are more at risk for producing embryos that do not have the correct amount of chromosomal material. The affected embryos are less likely to result in a live birth. Patients with these problems often have repeated miscarriages.

PGT-SR examines disorders including:

Robertsonian translocations
Reciprocal translocations
Nonreciprocal translocations

How are PGT-A, PGT-SR and PGT-M performed on embryos during IVF?

The two main steps to the three types of PGT are the same. The first step is an embryo biopsy. The second step is analysis of the biopsy by a laboratory to conduct genetic testing on DNA.

In both forms of testing, the biopsy is at the blastocyst (day 5 or day 6 of embryo culture) stage of development. The blastocyst consists of two cell types, trophectoderm (TE) that allows the placenta to develop and the inner cell mass (ICM) that later develops into the baby.

The biopsy removes 3-10 cells from the trophectoderm (pre-placenta) for laboratory testing for genetic disorders. The cells that are destined to make the baby are not disturbed. Results are usually available within 7-10 days following the biopsy. The blastocyst is frozen right after it is biopsied to wait for the results of the testing and then is thawed and transferred to the woman in a subsequent cycle.

NGS (next generation sequencing) now identifies mosaicism in embryos

The laboratory testing of the embryo biopsy is accomplished with next generation sequencing (NGS), which uses molecular evaluation and powerful computing to spot a likelihood of chromosomal abnormality. Until recently, the NGS results were only considered to be abnormal or normal, providing an embryo evaluation of good or bad.

But there is a gray area in between those absolutes, called mosaicism. NGS can now identify such mosaic embryos that have a different proportion of abnormal and normal cells. An embryo at the blastocyst stage has more than 100 cells, and in a mosaic embryo some are abnormal, some are normal. A high-level mosaic embryo will have predominately abnormal cells and a few normal ones. A low-level mosaic will have mostly normal cells.

Previously, preimplantation genetic testing could not identify mosaicism. Now NGS can pinpoint the level of mosaicism, giving physicians and patients a more complete analysis that can increase the chances of successful pregnancy and birth. We have guidelines on whether or not to implant an embryo with mosaicism present after consultation with a genetics counselor.

Embryo preimplantation genetic testing considerations

PGT risks

There are no documented health risks for children born after PGT testing beyond the normal health risks to mother and child through IVF. Handling of the embryo, its biopsy, freezing, and thawing results in a small risk of damage leading to an embryo that does not implant. Generally, around 5% of embryos evaluated by PGT are lost due to such damage.

Another risk of PGT is inaccuracy in test findings, as the testing is not 100% accurate. For this reason, it is recommended that the patient undergo typical prenatal testing when she is pregnant, such as amniocentesis.

Ethical issues of PGT

As PGT testing evolves, the prospect of selecting traits to pass on to a child through embryo selection might become another use of the technology. It was originally just used to increase healthy IVF births, and that is still the predominant reason for its use. PGT will undoubtedly be used more often in the future by parents to look for traits in embryo genetics they want to pass on to their children and selecting to not pass on other traits.

This puts PGT in the moral ground of eugenics, a past scientific attempt to improve the human population through selective breeding for desired characteristics. PGT experts see this as an increasing issue for clinics offering the service and for patients deciding on whether or not to use it. Debate is ongoing about which genetic traits should be identified, as well as on the need for laws to guide clinics and patients.

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Preimplantation Genetic Testing (PGT)