Fertility and Preimplantation Genetic Testing

PGT stands for preimplantation genetic testing (PGT).  Previously referred to as preimplantation genetic diagnosis (PGD), PGT is the process of screening embryos for genetic abnormalities. The goal of PGT is to reduce the chance of having a child who is a carrier of a genetic mutation that causes a genetic disease.  While there are several kinds of PGT (PGT-M, PGT-A, and PGT-SR), we will mainly be discussing PGT-M.

PGT for monogenic disorders (PGT-M): This type of PGT is used to screen embryos for mutations that cause monogenic disorders or genetic conditions attributed to mutations in a gene. This includes both autosomal dominant conditions, which are caused by one gene mutation, like BRCA1 or BRCA2, and autosomal recessive conditions, which are caused by two gene mutations, such as Tay-Sachs Disease or cystic fibrosis.         

PGT for aneuploidy (PGT-A): This type of PGT is used to screen embryos for different chromosome abnormalities, or aneuploidies. Aneuploidy is defined as the presence of extra or missing chromosomes. A common aneuploidy is Trisomy 21, or Down’s Syndrome. An individual with Down’s Syndrome has three copies of chromosome 21 instead of the expected two. PGT-A screens embryos for different aneuploidies, including Down’s Syndrome, to check for extra or missing chromosomes, or even extra or missing pieces of a chromosome, that may cause an increased risk for failed embryo transfer, miscarriage, or a child affected by a chromosome abnormality.

PGT for structural rearrangements (PGT-SR): This type of PGT screens embryos to see if they have inherited the same rearranged chromosome as their affected parent. Sometimes an individual has all 46 of their chromosomes, but one is abnormally structured. This is unlikely to cause any health issues for the individual themselves, but can become problematic when they attempt to have children. This is often identified with specific genetic testing. These individuals have elevated risks for reproductive and fertility issues, such as recurrent miscarriage and stillbirth due to passing on a chromosome that has extra or missing genetic material.

Embryos are developed through in-vitro fertilization (IVF) and then screened in a laboratory before they are transferred into a uterus.

Humans typically have 46 chromosomes, 23 from each biological parent. Any extra or missing chromosomes or small parts of chromosomes that are duplicated or deleted can cause an individual to be affected by a genetic condition.

On each chromosome, there are segments called genes that are responsible for an individual’s growth and development. An individual has two copies of every gene, one from each parent. An inherited mutation in one copy of the gene can cause an individual to have a genetic condition or disease. Both male and female mutation carriers have a 50% chance of passing these mutations to each of their children. An individual who carries a mutation may be able to use IVF and PGT to screen embryos to avoid passing a mutation to the next generation.

Autosomal dominant (AD) – There are genetic conditions that require only one mutation in a gene from either parent to cause the condition. Most cases of hereditary cancer result from autosomal dominant gene mutations like BRCA1 or BRCA2 – having one mutation in a gene from either parent is enough to cause the predisposition. When one parent is an autosomal dominant gene mutation carrier, every one of their children has a 1 in 2, or 50%, chance of carrying that same mutation and having an elevated risk of developing cancer.

Autosomal recessive (AR) – Other genetic conditions require two mutations in a gene, one from each parent, to cause the condition. Some examples include Tay-Sachs disease and cystic fibrosis. Many Jewish individuals are screened for these types of conditions before planning a pregnancy. A carrier of an AR condition does not have the disease. If a couple carries the mutations in the same gene, their chance of having an affected embryo is 1 in 4, or 25%. Only the embryos with two mutations will be affected.

Most laboratories that perform PGT-M on embryos quote an accuracy rate of over 99%. This means that over 99% of the time, the laboratory will be able to accurately predict that an embryo will have a genetic or chromosomal condition.

Embryos can be screened for most genetic disorders based on an individual’s personal and family medical history.  However, PGT-M is only able to test for a mutation that has been identified in one of the parents.

It is possible to use prenatal screening, sometimes by bloodwork and sometimes by sampling fetal cells in amniocentesis, to do further genetic screening.  You may wish to discuss with your obstetrician what types of testing may be beneficial for your specific circumstances.

Prime candidates for PGT include:

• Individuals who carry genetic mutations such as BRCA, CHEK2, PALB2, ATM, Lynch Syndrome, and others that could be passed on to their children, thereby elevating their children’s risk of a hereditary cancer diagnosis.
• Carriers of other mutations associated with genetic conditions, such as Huntington’s Disease or Marfan’s Syndrome.
• Couples who are both mutation carriers for the same recessive genetic condition, such as cystic fibrosis or Tay-Sachs disease.
• Individuals who have a personal or family history of a genetic disease, including a pregnancy or child with a genetic or chromosomal condition.

If you are considering pursuing PGT-M, we encourage you to speak with a fertility or reproductive specialist who will provide more information and guidance. Sharsheret may be able to connect you with a peer supporter who can share their experience.

PGT-M is a tool available to help build families but is not required.  It is important to remember:

• IVF and PGT-M do not have 100% success rates.
• Any mutations that are present in a parent – the ones you know about and the ones you don’t know about – can be passed along at a 50% rate.
• Having a child naturally does not mean that s/he will automatically be a carrier of any genetic mutations that the parents may carry.
• Couples should be aligned about whether they intend to pursue PGT and also about what to do if first attempts do not result in a successful pregnancy.

Each child of a BRCA mutation carrier has a 50% chance of inheriting the mutation. Most hereditary cancer mutations do not pose risks to children to develop cancer as children, meaning that they can be raised “normally.”  A parent may choose to share information about healthy lifestyles, family history, and cancer risks in developmentally appropriate ways.  Genetic testing is generally not recommended until the child is at least 18 years of age.

All types of PGT (M, A, and SR) are completed in the same manner using IVF. After the egg retrieval, the sperm and egg will be combined to form an embryo. Around day 5, the embryo is a mass of cells that resembles a ball composed of two parts: an outer layer and an inner layer. At this point, an embryo biopsy is performed, during which cells are removed from the outer layer of the embryo; these are the cells which will eventually develop into pregnancy structures, like the placenta and membranes.  It is thought to be safer to remove cells from the outer layer since pulling cells from the inner layer (which will become the fetus) might be damaging to normal development. The cells of the outer layer are generally expected to be representative of the entire embryo.

The embryo will stay in your reproductive center while the biopsy is sent to the laboratory of your choice for further testing. The laboratory will design a custom test for the embryos, called a probe, based on your personal and family medical history. This may require meeting with a reproductive specialist, genetic counselor, or laboratory technician; additional documentation or blood/saliva samples may be needed to design the probe.

The number of cells being tested is much smaller with PGT-M than when you have genetic testing done on a blood or saliva sample. The embryo biopsy is microscopic and made up of a very small number of cells, probably less than a dozen.  In order to test such a small number of cells, a special probe must be made just for you, which will test for the mutation that has already been identified in one or both parents.  This also allows for the highest accuracy possible; if the PGT-M test does not detect the mutation, you can be highly confident that it isn’t there.  Blood/saliva samples will be needed from the parents of the embryo and sometimes from other family members as well. The probe can take a few months to build.

The cells that are evaluated by the probe are destroyed in the process of testing. The biopsied cells can never be returned to the embryo.  If the egg or sperm were tested, they would not be able to be used.  Also, the egg and sperm each have only half the DNA (23 chromosomes) of a typical cell; the full amount is present after the egg and sperm merge (46 chromosomes).

A woman’s fertility begins to decrease with age and probably peaks before 30 years of age.  If you know you will want to use IVF, you may want to consider retrieving eggs at a younger age and freezing them.  Freezing eggs keeps them at the age they were when they were retrieved.  You may be older when you are ready to have children, but the quality of your eggs will be related to the time when they were harvested, not the time when they were thawed.

Freezing eggs requires a lab that has experience with freezing and thawing eggs.  When you freeze your eggs, there are no concerns about “custody,” which can arise when a couple who freeze embryos ends their relationship.

Women who are BRCA-mutation carriers may have a reduced ovarian reserve (fewer number of eggs responding to hormones), or they may experience menopause at an earlier than average age.  This might be more likely with BRCA1 than BRCA2, although the studies are not conclusive.

Once the pregnancy is well established, you will switch from the fertility practice to a “regular” obstetrician, generally between 8 and 12 weeks of pregnancy. This can feel like a big adjustment, since you will no longer have as many visits with the doctor. Your pregnancy will likely be treated as high risk, even if there is no indication that you are at high risk other than your having pursued PGT.

Some of the challenges cited most frequently include the following:

• As part of the IVF process, hormones are given to stimulate the development of egg follicles before the retrieval, and again after the implantation of the embryo. Often, these hormones are given by injection, which can be painful.  Also, some women report that taking hormones can make them feel like they are on an emotional roller coaster.
• IVF and PGT-M are processes that require significant time and funds, and they involve many physician appointments.

Pursuing IVF and PGT-M can strain a couple’s relationship. Some choose to explore mental health counseling, while others seek confidantes such as peer supporters with whom to discuss some of their experiences. Sharsheret may be able to connect you with a peer supporter who can share their experience.

• PGT-M can be a very controversial subject, and sometimes partners or their family members don’t agree about it.
• PGT-M can be cost-prohibitive.
• No matter the reason, whether or not to pursue PGT-M is a very personal decision that should be made thoughtfully and carefully.

It’s important to have realistic expectations when using IVF and PGT-M. This process does not prevent all birth defects, unknown genetic mutations, or health problems in your children. There is always a 3-5% risk that a child will be born with another health condition or birth defect (e.g., autism) that cannot be predicted prior to birth. Also, if you haven’t yet tried to have children naturally, you won’t know if you have fertility issues that are yet to be discovered.

Because of their fragile state, some embryos do not survive to the biopsy stage or the thawing process (if they were frozen) prior to being transferred. Also, for reasons that can’t always be explained, some embryos stop growing and cannot be used for transfer.

It is possible that some or all of the embryos that are biopsied will be found to have a genetic condition; in fact, there can be a big drop-off from the number of eggs retrieved to the number of embryos that are found to be genetically healthy and developing normally. Multiple cycles may be required to yield the desired number of embryos, and it may be best to overestimate the number of eggs that are needed.

The cost of PGT varies depending on various factors, including insurance coverage, personal and family medical history, and laboratory costs.  IVF, which is a necessary component of the PGT process, can cost between $25,000-50,000 without grants or insurance coverage.

Pursuing IVF and PGT-M does not guarantee that a healthy child will be born; in fact, it may require multiple cycles to have enough healthy embryos to attain a healthy pregnancy.  Miscarriages may occur, usually for unexplained reasons.

In efforts to make PGT more affordable, women with insurance coverage often choose to complete as many costly procedures as possible during one insurance calendar year – these procedures could include egg retrievals, IVF, and (bilateral) mastectomy and reconstruction – in order to maximize benefits.  Also, select fertility clinics have unused, donated medications, and some communities advertise informal networks of women who share their unused and leftover medications.

Sharsheret has information about organizations that offer grants to individuals pursuing PGT, many of which are local to specific states or metropolitan areas.  It is probably helpful to search fertility resources in your local area – please let us know if you find any that we could include in our information bank.

Some genes included on hereditary cancer testing panels can also be linked to childhood genetic conditions when both parents carry a mutation in the same gene. While carriers are typically healthy aside from an increased cancer risk, understanding autosomal recessive inheritance is important for family planning. Examples include Fanconi anemia (FA), Ataxia-Telangiectasia (AT)  and Constitutional mismatch repair deficiency (CMMRD). 

FA is a rare inherited genetic condition that affects the body’s ability to repair damaged DNA. Over time, this can lead to bone marrow failure and an increased risk of developing certain cancers, often at a young age.

More than 20 genes are associated with FA. Some of these genes are also included on hereditary cancer testing panels because carrying a single mutation may increase cancer risk. 80 to 90 percent of FA cases are caused by  variants in one of three genes: FANCA, FANCC and FANCG. Some of the other genes associated with FA include: BRCA1, BRCA2, BRIP1, PALB2, RAD51C, RAD51D.

AT is a rare inherited condition that affects the nervous system, the immune system, and other parts of the body.. It is caused by mutations in the ATM gene. One of the most common symptoms is difficulty with coordination of body movement.

CMMRD is a childhood cancer predisposition syndrome. It occurs when a person has two mutations in a mismatch repair gene (MLH1, MSH2, MSH6, PMS2 and EPCAM) . This increases the risk for developing cancers in childhood, including blood cancers, , brain and central nervous system (CNS) tumors, colorectal tumors,and other malignancies.

FA, AT, and CMMRD are typically inherited in an autosomal recessive pattern. This means that a child must inherit two non-working copies of the same gene—one from each parent—to develop the condition. 

When both parents carry a mutation in the same gene:

• There is a 25% chance that a child will have the genetic condition
• A 50% chance the child will be a carrier like the parents
• A 25% chance the child will inherit two working copies of the gene

Carriers typically do not have FA, AT, or CMMRD, but may still have important health considerations, such as an increased risk for certain cancers.

For individuals or couples who both carry a mutation in the same gene associated with an autosomal recessive condition, preimplantation genetic testing for their specific mutation (PGT-M) may be an option when using IVF. PGT-M can help identify embryos that do not have two non-working copies of the gene.

Not everyone who carries a mutation will choose PGT-M, but understanding this option can help families make informed decisions.

When you both carry the same genetic mutation:

When you and your partner both carry a mutation in the same gene, there is a 25% chance with each pregnancy that a child could be born with that genetic condition. A child must inherit two copies of the same mutated gene (one from each parent) to be affected. 

When you and your partner carry mutations in different genes

If you and your partner carry mutations in different genes associated with autosomal recessive conditions, your child would not be expected to develop that condition. However, the child may still be a carrier of one of the mutations without having the condition.

To learn more about PGT, including personalized medical, technical, and financial considerations, please reach out to a reproductive specialist or medical provider near you.

Sharsheret can often find a peer supporter who is willing to discuss their own experience with you.  Please reach out to Sharsheret for more information.

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