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The ABCs of PGD, PGS and More
Are you new to an infertility diagnosis or just starting your research on in vitro fertilization (IVF)? Many clinics are offering an array of genetic testing options than can help you have a successful IVF that results in a healthy baby, but the alphabet soup of terms surrounding preimplantaton genetic diagnosis and other genetic testing on embryos can be confusing. PGD, PGS, CCS — what's the difference? Here's our best guide to genetic testing ...
Preimplantation Genetic Testing
Preimplantation genetic testing is the umbrella term for genetic testing on embryos. According to the Practice Committee of the Society for Assisted Reproductive Technology (SART) and the Practice Committee of the American Society for Reproductive Medicine (ASRM), this term describes procedures involving removing one or more nuclei from eggs (polar bodies) or embryos (blastomeres or trophoectoderm cells) to test for mutations in gene sequence or aneuploidy before transfer to the uterus.
PGD, Preimplantation Genetic Diagnosis
Preimplantation genetic diagnosis (PGD) is the most common genetic testing term that you are quite likely to hear as an umbrella term referring to any kind of genetic testing on embryos. "That term has been knocked around by both geneticists and reproductive endocrinologists and the lay press because it basically is related to testing embryos before they are transferred," says Houston fertility doctor Randall C. Dunn with Fertility Specialists of Houston.
Originally, PGD was developed in the late 1980s as an alternative for couples at risk of passing on serious genetic diseases to their children. Instead of a prenatal diagnosis of a genetic disorder with the possibility of terminating an affected fetus, the couple would use IVF to conceive, and the embryos would be tested before being transferred to the uterus for implantation.
Today, many fertility clinics use PGD as the term to describe testing for a specific genetic disease. It is a specific test offered to patients who are at a high risk of transmitting a known single-gene defect to their child, such as cystic fibrosis, hemophilia or Tay-Sachs disease. Single gene disorders are genetic conditions caused by the alteration or mutation of a specific gene in the affected person’s DNA. The SART/ASRM practice committee says the term applies when "one or both genetic parents carry a gene mutation or a balanced chromosomal rearrangement, and testing is performed to determine whether that specific mutation or an unbalanced chromosomal complement has been transmitted to the oocyte or embryo."
PGS, Preimplantation Genetic Screening
Preimplantation Genetic Screening (PGS) is a newer term used to describe the process of screening embryos to make sure they have the right number of chromosomes and to look for any structural abnormalities in the chromosomes. The process is also called aneuploidy screening. The SART/ASRM practice committee says the term PGS is to be used when "the genetic parents are known or presumed to be chromosomally normal and their embryos are screened for aneuploidy."
PGS is thought to increase success rates for IVF in women over 35, as well as those who have suffered repeated IVF failure or recurrent miscarriage. While the older technique of performing PGS uses FISH analysis on a single cell, which is limited to analysis of 5 to 10 chromosome pairs out of the 23 pairs of chromosomes, newer testing methods such as single nucleotide polymorphism (SNP) analysis or comparative genomic hybridization (CGH) allow testing of all 23 pairs of chromosomes.
CCS, Comprehensive Chromosomal Screening
Comprehensive Chromosomal Screening (CCS) is a term used to refer to a type of PGS/aneuploidy screening. The method allows for the evaluation of all 23 pairs of human chromosomes on a single cell with quantitative real-time polymerase chain reaction (qPCR), SNP or CGH.
With CCS, there are five to 10 cells retrieved from a Day 5 ot 6 embryo (blastocyst). The embryo has to be frozen while waiting for the result, and then in a separate cycle, the normal embryo is thawed and transferred. Biopsying a Day 5 embryo increases the accuracy of this testing and minimizes the potential damage that a biopsy can cause on an embryo because it has several hundred cells by then.
"The advantage to doing a biopsy on Day 5 is you don't just use a single cell as you do on Day 3, but now you have a few little cells, so you have a little more material to test with," says Dr. Dunn. "There is some controversy. Theoretically, the embryo might tolerate a Day 5 biopsy better than a Day 3 biopsy, but that is not for certain, and it's still one of those "go to medical meeting" conversations."
FISH, PCR, CGH and SNP are all methods of genetic analysis used for PGD, PGS and CCS.
FISH, Fluorescent In Situ Hybridization
Fluorescent In Situ Hybridization (FISH) is used for the determination of sex for X-linked diseases, chromosomal abnormalities and aneuploidy screening. However, this method of analysis does have its limitations. A human cell contains 23 pairs of chromosomes, but FISH analysis allows accurate assessment of only 10 to 12 chromosomes in each biopsied cell.
"The problem is, you're still only screening part of the chromosomes," Dr. Dunn says. "And so you're not screening for translocations and inversions, so it's not as effective a tool."
PCR, Polymerase Chain Reaction
PCR, sometimes called DNA amplification, is most often used for the diagnosis of single gene defects, including dominant and recessive disorders.
CGH, Comparative Genomic Hybridization
CGH allows genetic specialists to examine all 23 chromosomes and provides a more detailed picture of the entire length of the chromosome, which may detect imbalance of chromosomal segments. A newer advanced technique offered in some labs is called array CGH or microarray CGH (mCGH). This is an accelerated CGH protocol providing results in 24 hours for all chromosomes.
SNP, Single Nucleotide Polymorphism Analysis
SNP is another newer technique that can examine all 23 chromosome pairs. "Most genetics labs have gone to the technology of SNP analysis because of the fact that it can do both copy number changes and inversions and translocations," says Dr. Dunn.
Still confused? If you are considering PGD, PGS or CCS, ask your fertility clinic the following questions:
- Do you do the biopsy on a Day 3 or Day 5 embryo? Which do you consider safest and why?
- Will my embryo have to be frozen while we wait for the results?
- If my Day 3 embryo test comes back abnormal, but the embryo develops correctly to Day 5, will you re-biopsy the embryo for another screening?
- What method of genetic analysis are you using? Will it test all 23 chromosome pairs?
- Does this method of genetic analysis test for translocations and inversions? If not, do you think that is important?