What Genetic Testing is Available During My Fertility Care?

Preimplantation genetic testing (PGT) is the testing of a sample of cells from an embryo during IVF prior to transfer to the uterus. The embryo sample can be tested for various types of conditions, including single gene disorders and chromosomal abnormalities. If an embryo is found to be free of the disorder(s) in question, within the accuracy limitations of the test, the embryo is available for transfer. The goal of PGT, therefore, is to reduce the chance that the embryo has the disorder and/or a chromosomal abnormality that could lead to lack of implantation, pregnancy loss, or birth of a baby with a genetic disorder.

In order to test an embryo, a sample of cells must be obtained from the embryo. Currently in the United States, this removal of cells, known as a biopsy, is conducted on the embryo when it is a blastocyst. Most embryos reach the blastocyst stage at day 5 of development. At this stage, the embryo consists of 100s of cells and looks like a ball or sphere. The majority of cells make up the ball or shell. Collectively, these are known as the trophectoderm. This part of the embryo goes on to become support structures for the pregnancy, such as the placenta and amniotic sac. Attached inside the trophectoderm is a cluster of cells that goes on to make the fetus itself. In a trophectoderm biopsy, a small opening is made in the covering of the embryo allowing some cells of the trophectoderm to protrude. These cells are removed and are tested via PGT. The cluster of cells that goes on to make the fetus is not biopsied.

After biopsy, embryos are frozen while testing is performed. Any embryos that appear to be free of the single gene disorder or chromosomal abnormalities are available to be thawed and transferred at a later date. Most embryos survive both the biopsy and thaw; statistics on this vary per center. Patients may wish to discuss these statistics with their own IVF group. No test can detect all genetic or chromosomal disorders in an embryo. It is important for patients to discuss which PGT test is appropriate for their embryos with their genetic counselor and physician. Additionally, while testing of an embryo biopsy is a highly effective screening tool, no PGT test is 100% accurate. Patients should discuss follow up testing options that are available in pregnancy with their genetic counselor and physician.

The embryo testing landscape is constantly evolving. Currently, the main PGT tests are PGT-A (aneuploidy), PGT-SR (structural rearrangement) and PGT-M (monogenic disease).

PGT-A tests embryos for aneuploidy. Aneuploidy occurs when there is at least one extra or missing chromosome present. Typically, we have 46 chromosomes. Chromosomes come in pairs, and we receive one of each pair from our mother and one from our father. Having an extra or missing chromosome can result in an embryo not implanting in the uterus, a pregnancy ending in pregnancy loss or stillbirth, or a child born with physical and mental differences, such as Down syndrome. Aneuploidy is typically caused by a random error in the egg or sperm. While these errors can happen in sperm or eggs, they occur more frequently in eggs as women grow older. This is a reason that women in their 30s and 40s are offered aneuploidy testing in pregnancy and PGT-A during an IVF cycle. Aneuploidy screening is also available in all pregnancies. You may wish to speak to your provider about the types of aneuploidy screening available to you.

PGT-A may also detect partial aneuploidy: missing or extra pieces of a chromosome. If a piece is missing, it is called a deletion. If a piece is extra, it is known as a duplication. In some situations, partial aneuploidies can lead to a child born with malformations and intellectual disability.

Some PGT-A laboratories will report a situation known as mosaicism. Mosaicism is when the sample from the embryo has cells with different chromosome content. For example, some cells may have the typical number of chromosomes (euploidy) and some may have aneuploidy. Research is ongoing, but mosaicism can lead to an embryo not attaching to the uterus, a pregnancy ending in pregnancy loss or stillbirth, or a child born with physical and mental differences. However, there is some data showing that embryos with mosaicism can result in live births that appear to be healthy. Further long-term studies need to be conducted. Transfer of an embryo with mosaicism should be considered only after thorough consultation with your genetic counselor and physician. If transferred, thorough surveillance and testing of any resulting pregnancy should be performed.

Single gene disorders are those that are caused by a genetic mutation(s), or misspelling, of a specific gene, and are passed from parent to child in a particular pattern. The way in which these are passed on is known as an inheritance pattern. The main inheritance patterns are autosomal recessive, X-linked recessive, and autosomal dominant.

An autosomal recessive condition is one that is equally likely to affect both men and women and is caused by having a mutation in both copies of a particular gene. A person with the condition typically inherits a mutation from each of their parents. Having one copy of a gene with a mutation and one normally working copy is known as being a carrier. Carriers usually have no symptoms of the disease. Carrier status is usually detected through a test called carrier screening, or through birth of a child affected with the disorder. If both parents are carriers, they have a 1 in 4, or 25%, chance to both pass the mutation and therefore have a child with the disease. Cystic fibrosis is an example of an autosomal recessive condition. When both members of a couple are carriers for the same autosomal recessive condition, PGT-M may be available.

An X-linked recessive genetic condition is one in which the disease-causing gene is on the X chromosome, one of our sex-related chromosomes. Women have two X chromosomes and men have an X and a Y chromosome. A woman with a mutation in a gene on one X chromosome is known as being a carrier. She typically has no symptoms of the disease, or milder symptoms, as she has a working copy of the gene on her other X chromosome. Men with a mutation in a gene on their X chromosome will have the disease.

Carrier testing for X-linked conditions is therefore typically offered only to women. A woman that is a carrier has a 50% chance to pass the mutation. Sons with the mutation will have the disease, whereas daughters will be carriers like their mother. When a man with an X-linked condition has children and his partner is NOT a carrier for the same, all of his sons are expected to be unaffected while all of his daughters will be carriers. Fragile X syndrome and hemophilia A are examples of X-linked recessive conditions. When a female is a carrier for or a male has certain X-linked recessive conditions, PGT-M may be an option.

An autosomal dominant genetic condition is one that is equally likely to affect both men and women and is caused by having a mutation in only one copy of a particular gene. A person with the condition has a 50% chance to pass the mutation, and therefore the disease, to a child. Huntington disease and neurofibromatosis are examples of autosomal dominant conditions. When an individual has an autosomal dominant condition, PGT-M may be available.

PGT-M (M = monogenic disease) tests for known single gene disorders in the family. Single gene disorders are also known as monogenic (mono=one, genic=gene) diseases. A PGT-M test is created for the specific disease in the individual/couple, and is custom built based on genetic information from that specific family. This test creation process requires DNA samples from the couple, and possibly from some family members.

For convenience, most laboratories request a cheek swab sample, though some may need blood samples. You will likely work with a genetic counselor through this process, whether at your physician’s office, at the testing laboratory, or both. Your genetic counselor will review the test creation process, and assist with collection and shipment of any necessary samples for test preparation.

PGT-M test creation can take a few weeks. The genetic counselor will keep you updated as to the progress of the test creation. In most cases, an IVF cycle is not started until the PGT-M test is complete. Once the PGT-M test is ready, the IVF cycle and embryo testing can begin. Most PGT laboratories in the United States are able to add aneuploidy testing (PGT-A) to the PGT-M test. The embryos will therefore be tested for the genetic disease in the family as well as any sporadic extra or missing chromosomes. Your genetic counselor will be able to discuss how your PGT-M test will be done and if aneuploidy testing can be added.

Patients with a personal or family history of infertility, pregnancy loss, or a chromosomal disorder, may undergo a chromosome test known as a karyotype. This test is performed on a sample of blood and looks at the number and structure of chromosomes. If an individual is found to have a change in the structure of their chromosomes, PGT-SR may be available.

PGT-SR (SR = structural rearrangement) tests embryos for known changes in the structure of the patient’s chromosomes. The most common of these structural rearrangements are translocations and inversions.

A reciprocal translocation occurs when 2 pieces of chromosomes break off and switch places. If no chromosome material is lost, the translocation is known as being balanced and the person is healthy. Think of this like having a red pen and a blue pen and switching their caps. You still have all the same pieces, just structured in a different way. A Robertsonian translocation occurs when certain chromosomes lose their tops and the bottoms fuse. The tops of these specific chromosomes have little necessary information so their loss is of no consequence. Again, if no necessary chromosome material is lost, the Robertsonian translocation is balanced and the person is healthy.

An inversion is when a piece of material within a chromosome flips on itself. For example, if a chromosome is typically spelled ABCDEFG, an inversion would be spelled ABEDCFG. Again, if all the chromosome material is present, the inversion is balanced and the individual with such is healthy. When an individual has a balanced chromosomal structural rearrangement, it is known as being a carrier for such.

The concern for balanced translocation or inversion carriers is not about day-to-day health, but rather reproduction. When balanced carriers go to have children, these changes make it difficult for the chromosome pairs to align and separate correctly, so extra and missing pieces of the chromosomes involved in the translocation or inversion can be passed in the sperm or egg. This can lead to an embryo not attaching to the uterus, a pregnancy ending in pregnancy loss or stillbirth, or a child born with physical and mental differences.

The PGT-SR test will test the embryo for the specific chromosomal rearrangement in the patient. Most PGT-SR tests performed in the US will also be able to look at all the chromosomes for aneuploidy. Please discuss the PGT test options with your genetic counselor and physician to determine the best test for your particular situation.

Preconception carrier screening is a very common genetic test offered to both women and men who are planning a pregnancy. Carrier screening can determine whether you carry a genetic condition. Carriers of a genetic condition have one working and one non-working copy of a particular gene. Carriers are expected to be healthy. They typically have no symptoms of the condition they carry. Being a carrier of one or more genetic conditions is normal. Some would even say it is part of being human.

Most genetic conditions included on carrier screening are autosomal recessive (see above for explanation of recessive inheritance), while some conditions on carrier screening are inherited in an X-linked manner (see above for explanation of X-linked inheritance). Both males and females are screened for autosomal recessive conditions. X-linked conditions are caused by genes on the X chromosome. Females have two X chromosomes, while males have one X chromosome and one Y chromosome. Typically only females are screened for X-linked disorders because only females can be apparently unaffected carriers.

The type of carrier screening you are offered may vary based on your ancestry and ethnicity, as certain conditions are more common in certain ethnic backgrounds. Your family health history may also influence what conditions you could be screened for. Alternatively, expanded carrier screening tests for 300+ conditions regardless of ethnicity. Most expanded carrier screening panels only include conditions that significantly impact health in childhood. A normal result on carrier screening reduces, but does not eliminate, your chance to be a carrier of the genetic conditions tested.

You can learn more about carrier screening here. If you and your reproductive partner are both identified to carry the same autosomal recessive condition, or if you are identified to carry an X-linked condition, your physician will discuss your reproductive planning options, including the option of IVF with PGT-M testing to reduce your chance of having an affected child. While some patients at risk to have a child with a disorder identified through carrier screening may choose PGT-M, others may elect to use an egg or sperm donor, pursue diagnostic testing during pregnancy or after birth of their child, consider adoption to complete their family, or choose not to change their reproductive plans at all.

Your physician may offer you additional genetic testing to help determine the best course of treatment for you. There are several genetic tests that can be considered depending on your individual concerns.

Chromosome analysis:

Chromosome analysis is another group of genetic testing options for specific individuals or couples. Chromosomes are tightly-packed units of genetic information in our cells. Humans typically have 46 chromosomes organized into 23 pairs. Changes to the number or structure of chromosomes can impact health or fertility.

A karyotype is a genetic test that assesses the number and structure of your chromosomes. Karyotyping is recommended for couples who have experienced two or more pregnancy losses, as 2-5% of these cases can be explained by a structural chromosome rearrangement, such as a translocation, in one of the partners. If karyotyping identifies a chromosome rearrangement in you or your partner, your physician will discuss the option of IVF with PGT-SR to improve your chance of achieving a successful pregnancy. Some providers may call a karyotype a chromosome analysis (a detailed explanation of chromosome rearrangements and PGT-SR can be found above).

Y chromosome microdeletions:

Y-chromosome microdeletion analysis is a blood chromosome test available to men with a very low sperm count. The Y chromosome contains many genes critical for male fertility. If a small portion of the Y chromosome is missing, this can impact a man’s sperm production. Y-microdeletion analysis assesses the Y chromosome for these small missing pieces. A finding on Y-microdeletion analysis can explain why a couple is having difficulty conceiving, and that knowledge can inform future reproductive options.

Other Genetic Tests:

This list is not intended to be comprehensive, rather to suggest a few common types of genetic testing you may encounter during your fertility journey. Your doctor or genetic counselor may suggest other types of genetic tests to address a particular personal or family history concern.