GENETICS TESTING OPTIONS DURING YOUR JOURNEY TO PARENTHOOD


Whether you are just beginning your journey into the world of in vitro fertilization (IVF) or you are about to launch into your third IVF cycle, understanding the ins and outs of infertility treatments can be overwhelming. Add in a discussion about genetics and you can certainly be propelled into information overload. Your knowledge of genetics may be nonexistent or you may have loved biology and ended up working in a genetics-related field. If you are not in the latter group, do not fear, this overview will focus on the basics – what you need to know about your genetic testing options before, during, and after IVF.

Table of Contents

  • Genetics 101
  • Genetic Carrier Screening
  • Chromosome Abnormalities and Reproduction
  • Embryo Testing
    • Preimplantation Genetic Diagnosis
    • Preimplantation Genetic Screening
  • Screening and Diagnostic Testing Options During Pregnancy
  • Next Steps
  • Resources

Genetics 101

Chromosomes are the structures inside our cells that carry our genetic makeup, or DNA (deoxyribonucleic acid). Human cells typically have a total of 46 chromosomes – 23 chromosomes from the mother (egg) and 23 chromosomes from the father (sperm). The first 22 pairs of chromosomes are called “autosomes” and are the same whether you are a male or female. The last pair of chromosomes are called “sex chromosomes” and differ in males and females. Females typically have two ‘X’ chromosomes (XX) and males typically have one ‘X’ and one ‘Y’ chromosome (XY). The term “aneuploidy” (ahn-yu-ploy-d) refers to an incorrect number of chromosomes in a cell. An extra copy of a chromosome is referred to as a trisomy, such as trisomy 21 (Down syndrome), and a missing copy is referred to as a monosomy, such as monosomy X (Turner syndrome).

Genes are regions on our chromosomes. The building blocks of our genes consist of four DNA bases known by the letters A, T, G, and C. The order of these bases within a gene determines the instructions for how our bodies grow, develop, and function. 1 Changes to genes can affect their function and lead to genetic conditions. Changes may consist of a loss or gain of DNA or a misspelling (one letter replaces another letter). Genetic carriers are individuals who have a genetic change associated with a condition and may or may not display symptoms.2 Over 6,000 genetic conditions have been identified. 3 Some are inherited (passed on from one generation to the next) while others may be spontaneous (occur without any family history). The most common inheritance patterns, autosomal dominant, autosomal recessive, and X-linked recessive, are defined below. 2

  • Autosomal dominant: Only one copy of a gene change is needed for the condition to be present. Examples include Huntington’s disease and Neurofibromatosis. Each child of an affected individual each have a 50% or ½ chance of inheriting the condition.
  • Autosomal recessive: Two copies of a gene change (one from each parent) are needed for the condition to be present.Each child of two unaffected, carrier parents have a 25% chance of inheriting the condition. Examples include cystic fibrosis and sickle cell disease.
  • X-linked recessive: The gene for a condition is located on the X chromosome. Females have a 50% (1/2) chance of inheriting the gene change from their mother. Since they have two copies of the X chromosome, the effect of the change is masked given the presence of a second normal copy. As a result, the condition is typically mild or not present. Males also have a 50% (½) chance of inheriting the gene change from their mother; however, affected males generally show features of the condition since they have only one copy of the X chromosome. Examples include Fragile X syndrome and hemophilia.

Other less common patterns of inheritance exist. You can read more about inheritance patterns on the National Human Genome Research Institute.

GENETIC CARRIER SCREENING

Most individuals that are carriers of a genetic condition are not aware of their carrier status. Studies have shown that humans are carriers of one or two serious genetic conditions that their children are at risk of inheriting.4 Genetic carrier screening is a blood test that can identify whether you are a carrier for certain genetic conditions. If you are a carrier, your partner can also be tested to help determine whether your current or future children are at risk for inheriting that genetic condition. The American College of Obstetrics and Gynecologists (ACOG) recommends that all patients considering pregnancy or already pregnant should be offered screening for a minimum of cystic fibrosis, spinal muscular atrophy, and hemoglobin abnormalities such as sickle cell disease.5 Carrier screening can be performed for single conditions or for multiple conditions at the same time through expanded carrier screening. There may be additional recommendations based on your family history, medical history, and/or ethnic background. If you are considering IVF and there is a risk for a genetic condition in your children, preimplantation genetic diagnosis (PGD) may be available.

What if I am using a sperm or egg donor?

Medical guidelines recommend that genetic screening for inherited conditions be performed for all potential sperm and egg donors.6 The type of screening may vary depending on the donor’s family history. Ask your IVF provider to review what conditions your donor has been screened for.

Questions you may want to discuss with your IVF provider (if applicable):

  1. I/my partner do not have any information regarding our family history. What type of screening should we consider?
  2. For what genetic conditions has my sperm/egg donor been screened?
  3. I have a relative with a personal/family history of a genetic condition. How can I be sure I have the most appropriate screening based on this history?
  4. I/my partner have had a previous pregnancy. Should we have the screening again?

CHROMOSOMAL CONDITIONS AND REPRODUCTION

As discussed above, humans typically have a total of 46 chromosomes in their cells.When an embryo has a different number of chromosomes, it is referred to as a chromosomal condition or aneuploidy. The most common chromosomal condition in newborns is Down syndrome (an extra copy of chromosome 21).7

All embryos have a risk for a chromosomal condition to be present, regardless of whether they were created during an IVF cycle or not. These conditions are often seen without any family history; however, they are associated with increasing maternal age as well as other factors. 8 If an embryo with a chromosomal condition is transferred during an IVF cycle, several outcomes are possible. These potential outcomes include: implantation failure, miscarriage, or a baby born that may have intellectual disabilities and/or physical abnormalities. A common misconception is that if a woman and her partner do not have a family history of a chromosomal condition they are not at risk for having an affected child. All embryos are at risk regardless of family history of the donors. Studies have shown that approximately half of the embryos created in an IVF cycle have an incorrect number of chromosomes, although this number may increase with increasing age of the mother.8,9

This graph shows the approximate percentage of embryos that have chromosomal conditions (aneuploidy) based on the age of the mother.8

SCREENING EMBRYOS FOR GENETIC AND CHROMOSOMAL CONDITIONS

Preimplantation genetic diagnosis (PGD) enables screening of embryos for particular genetic conditions when there is a known risk. Preimplantation genetic screening (PGS) enables screening for chromosomal conditions. PGD and PGS are not a routine part of IVF, however, they can be performed if requested or indicated. Here’s how embryo screening works. After ovarian stimulation and fertilization, your embryos will undergo a biopsy where one or a few cells are removed from the embryo. DNA from these cells is then tested for the condition or conditions of interest. The embryos that are least likely to be affected can be considered for transfer into the uterus. Embryo biopsy can occur three days after fertilization when it consists of 8-cells (cleavage-stage) or five days after fertilization when it consists of approximately 100 cells (blastocyst-stage). The timing is typically determined by your IVF Provider.

PGD can significantly reduce the chances of passing on a known genetic condition

PGD was first performed in 1990 and can enable parents the opportunity to reduce the chances of having a child affected by a particular genetic condition. Once the risk of a genetic condition has been identified through either a review of the family history or through genetic carrier screening, PGD can be discussed as part of an IVF cycle. Embryos that are likely to be either unaffected or unaffected carriers, can then be considered for transfer. PGD is available for many genetic conditions.

How PGS can enhance your IVF journey

Some women who undergo IVF may choose to pursue PGS to increase the chances that only embryos with the correct number of chromosomes are considered for transfer. Here are a few reasons you may consider PGS during your IVF cycle. 10-12

  1. PGS reduces the chances of transferring a chromosomally abnormal embryo.
  2. Many individuals only wish to transfer one embryo to minimize the chance for twins or triplets.PGS can help your provider choose the embryo most likely to result in a healthy live birth.
  3. PGS has been shown to improve IVF outcomes (including live birth rates) in women 35 years of age or over.
  4. Some studies have found that PGS reduces the number of transfers necessary to achieve pregnancy, (shortens the time to pregnancy).

If you are interested in learning more about PGD or PGS, here are some questions you may want to ask your provider.

  1. Do you offer PGD/PGS to your patients?
  2. What day do you typically perform the embryo biopsy (day 3 or day 5/6)?
  3. After PGD or PGS is performed, do you typically transfer the embryos immediately or do you wait for a frozen cycle?

Screening for chromosomal abnormalities during pregnancy

Once you become pregnant, either with or without the help of IVF, testing options are available for those individuals interested in learning more about chromosomal or genetic conditions in their pregnancy. ACOG recommends that all women, regardless of age, be offered prenatal testing for chromosomal conditions.13 Two categories of prenatal tests exist:“screening tests” and “diagnostic tests”.

Screening tests can tell you if your pregnancy is more or less likely to be affected with a particular condition.Maternal serum screening and noninvasive prenatal testing (NIPT) provide information about certain chromosomal conditions in your developing baby. Screening tests do not provide definitive answers; however, they can tell you whether your risk is higher or lower than normal for your age. Most women will receive normal screening results that are reassuring. As will all screening tests, there is a chance that the results may not be correct.

  • Maternal serum screening may involve one or two maternal blood draws with or without an ultrasound measurement called a nuchal translucency, a measurement of thickness of the back of the baby’s neck. Results in the form of a risk are provided for Down syndrome, trisomy 18 and in some cases trisomy 13. Your result may also include information about open neural tube defects as well.
  • NIPT analyzes fragments of DNA circulating in the mother’s blood. NIPT can provide information about many chromosomal conditions. Exact conditions may vary depending on which laboratory is used.

Diagnostic tests: Chorionic villus sampling (CVS) and amniocentesis provide the most accurate information about the presence of chromosomal and genetic conditions in your pregnancy. Both procedures are associated with a small risk of pregnancy loss. Both procedures allow the analysis of cells directly from the baby. In addition to chromosomal analysis, testing for many other genetic conditions may be available.

  • CVS involves a sampling of the placenta obtained through either the cervix or the abdomen.
  • Amniocentesis involves a sampling of a small amount of amniotic fluid through the abdomen.

The following factors are important when considering which test, if any, is right for you.

  • Sensitivity is the portion of individuals with a condition that have a positive test.
  • False positive occurs when you receive a positive result and the condition is not present.
  • False negative occurs when you receive a negative result, yet the condition is present.


Next Steps

All of the tests discussed above are optional. While they can provide valuable information about the health of your embryo during IVF or your baby during pregnancy, false positive and false negative results can occur. In addition, not all birth defects or genetic conditions can be identified before or during pregnancy. Speak with your healthcare provider about which testing option(s) may be right for you.

References

  1. Gardner RJM, Sutherland GR, Schaffer LG. Chromosome Abnormalities and Genetic Counseling. 4th ed. New York, NY: Oxford University Press; 2012.
  2. National Human Genome Research Institute. Talking Glossary of Genetic Terms. https://www.genome.gov/glossary/index.cfm?textonly=&search=carrier. Updated April 14, 2014. Accessed July 21, 2017.
  3. Gene Tests™. Disorders. https://www.genetests.org/disorders/. Accessed July 21, 2017.
  4. Gao Z, Waggoner D, Stephens M, Ober C, Przeworski M. An estimate of the average number of recessive lethal mutations carried by humans. Genetics, 2015; 199:1243–54.
  5. Carrier screening for genetic conditions. Committee Opinion No. 691. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2017;129:e41-55.
  6. Practice Committee of the American Society of Reproductive Medicine. Recommendations for gamete and embryo donation: a committee opinion.Fertil Steril.2013 Jan;99(1):47-62.
  7. Jones KL, Jones MC, del Campo M. Smith’s Recognizable Patterns of Human Malformation. 7th ed. Philadelphia: Elsevier Saunders; 2013.
  8. Harton GL, Munn S, Surrey M, et al. Diminished effect of maternal age on implantation after preimplantation genetic diagnosis with array comparative genomic hybridization. Fertil Steril. 2013;100(6):1695-1703. doi:10.1016/j.fertnstert.2013.07.2002.
  9. Fragouli E, Wells D. Aneuploidy in the human blastocyst. Cytogenet Genome Res. 2011;133(2-4):149-159.
  10. Grifo JA, Hodes-Wertz B, Lee HL, Amperloquio E, Clarke-Williams M, Adler A. Single thawed euploid embryo transfer improves IVF pregnancy, miscarriage, and multiple gestation outcomes and has similar implantation rates as egg donation. J Assist Reprod Genet. 2013;30(2):259-264. doi:10.1007/s10815-012-9929-1.
  11. Forman EJ, Hong KH, Ferry KM, et al. In vitro fertilization with single euploid blastocyst transfer: A randomized controlled trial. Fertil Steril. 2013;100(1):100-107.e1. doi:10.1016/j.fertnstert.2013.02.056.
  12. Rubio C, Bellver J, Rodrigo L, et al. In vitro fertilization with preimplantation genetic diagnosis for aneuploidies in advanced maternal age : a randomized controlled study. Fertil Steril. 2017;107(5):0-7.
  13. American College of Obstetricians and Gynecologists. Screening for fetal aneuploidy. Practice Bulletin No. 163. Obstet Gynecol. 2016; 127(5):e123-137.

GENETIC RESOURCES

American College of Obstetricians and Gynecologists: www.acog.org

American Society of Reproductive Medicine: www.asrm.org

Genetic Alliance: http://www.geneticalliance.org/publications/understandinggenetics

National Human Genome Research Institute: https://www.genome.gov/19016903/



This educational material was made possible through a generous contribution from

Illumina