Genetic testing with IVF is becoming more common as the techniques become safer with improving technology and more people understand the benefits of having the good quality embryos implanted. However, pre-implantation genetic testing is not for everyone. So, what are the indications for PGD and should you get it?
If your doctor mentions PGT instead of PGD, don’t get all confused by the terminology. Back in 2018, the major reproductive health societies (including ASRM, ESHRE, and ICMART) came together to rename the genetic testing procedures, so as to represent what they do more accurately and bring about a standardization in terminology:
Pre-implantation genetic diagnosis is now referred to as:
- Pre-implantation genetic testing for monogenic (single-gene) defects (PGT-M): is performed to find specific inherited conditions controlled by a single gene such as autosomal recessive, autosomal dominant or X-linked disorders
- Pre-implantation genetic testing for chromosomal structural rearrangements (PGT-SR): is used to test for inherited chromosomal anomalies such as chromosomal inversions, reciprocal translocations, Robertsonian translocations, etc.
PGD looks for specific inherited anomalies in the embryo and it is used to detect either inherited genetic diseases or inherited chromosomal rearrangements.
The new terminology allows better distinction between the two kinds of PGT, which are applicable for different kinds of patients and employ different technology platforms.
For the purpose of this article, we will use PGD collectively for the two genetic testing techniques: PGT-M and PGT-SR.
Dr. Lam from Asia’s top IVF clinic for genetic testing, explains in the below video, the indications for PGD:
(Note: Pre-implantation genetic screening (PGS), which is now named as Preimplantation Genetic Testing for Aneuploidies (PGT-A) is a different technique, which has other applications, not covered here.)
What are the indications for PGD?
PGD is mainly indicated for couples, who have a significant risk of transferring an inherited condition to their offspring.
By testing the embryo before implantation, it helps avoid the selective termination of a pregnancy after discovering something untoward in a prenatal diagnosis.
Unexplained Infertility:
It is common practice to check the microscopic appearance of embryos to see if they are good to be transferred to the uterus. The ones that show adequate number of cells at specific times in their growth cycle, have uniformly-sized cells and no cellular fragments, are considered “high quality.”
However, even the embryos that are found perfectly healthy under simple microscopic evaluation may not be capable of producing a healthy pregnancy. Beyond the superficial appearance of an embryo, the genetic code of embryos determines their potential and it can be examined with the help of PGD.
In a lot of cases parents were unable to understand the reason for repeated miscarriages or IVF failure and they were simply given the frustrating diagnosis of unexplained infertility. However, with PGD it is now possible to examine the genetic composition of embryos and find their real potential.
Male Factor Infertility:
Almost half of all infertility cases are attributed to sperm problems and while a simple semen analysis can reveal morphologic and motility problems, it is not enough. You can get sperm DNA fragmentation analysis before IVF to check the genetic integrity of the sperm. However, if the father is a carrier of genetic diseases, PGD may be helpful in screening the embryos to identify the healthiest ones.
Genes linked to male infertility and spermatogenesis are present on the Y chromosome and while PGD cannot detect all Y-chromosome-related diseases, it can detect some like Retinitis Pigmentosa.
History of chromosomal problems in previous children:
If you have children with genetic diseases, PGD may help prevent them in future pregnancies. Genetic testing of embryos is a better alternative to Chorionic villus sampling (CVS) or Amniocentesis because it screens the embryos before the pregnancy thus avoiding the distress of pregnancy termination, if anomalies are found later.
Chromosomal translocations:
Reciprocal translocation is the exchange of two terminal segments of different chromosomes and it is seen in around one in 600 live births. It may result in physical and mental disability in the offspring or just be the reason for infertility.
Couples with high-risk translocations will benefit from PGD; but for couples with translocations, who have only a low risk of conceiving a chromosomally abnormal baby, natural conception may be advised.
According to a study in the European Journal of Human Genetics, with the use of PGD, miscarriage rate was reduced from 85% to 33% in 59 couples carrying reciprocal translocations.
Family history of structural chromosomal condition:
Even if the parents do not have a certain disease, they may give it to their offspring if they are carriers. That’s why it is important to know the family history of genetic disorders to see what problems were present in the family tree and may be passed to the new babies.
PGD is recommended for couples who have a certain risk of passing genetic defects to the next generation. This way the embryos can all be screened and only the ones with no genetic defect are chosen for implantation. The most commonly diagnosed conditions with PGD include:
- Cystic fibrosis
- Hemophilia A
- Sickle cell anemia
- Spinal muscular atrophy
- Duchenne muscular atrophy
- Fragile X syndrome
- Myotonic dystrophy
- BRAC 1 & BRAC 2 genetic mutations
- Huntington’s disease
- Tay-Sachs disease
Family history of X-linked disease:
Monogenic diseases that are passed through an X-linked inheritance are usually discovered while taking family history or at the birth of a child who is affected.
X-linked recessive diseases usually only affect males as they have only one X chromosome and any mutation to the genes on that will cause the disorder. That’s why conditions like Hemophilia, Fragile X syndrome, etc. are more common in men.
If a woman has the affected gene on one X chromosome, its effect is masked by the normal X chromosome. However, they will still be carriers and may pass it to their children. If the child is a boy, the disease will likely show and if it is a girl, she might be a carrier too.
- Late on-set disorders:
Some genetic diseases are present at birth while others develop later during your childhood or adult life. These include cardiomyopathies, predisposition to cancer, neurodegenerative conditions such as Alzheimer’s and Huntington’s.
The usage of PGD is now being extended to check for gene mutations that may cause late-onset disorders. While it may be beneficial, experts urge to exercise caution against the overuse of PGD, which may get people to invest in unnecessary procedures to detect a problem that may or may not occur later in life.
Inherited predisposition to cancer:
Genes that raise the risk of developing breast and ovarian cancer in women can be identified with PGD but women who don’t have any fertility issues or the need for expensive reproductive methods, are not encouraged to do it. Patients are urged to undergo extensive counseling so they understand the risks and benefits of these procedures before undertaking them.
Human leukocyte antigen (HLA) typing:
PGD combined with HLA typing is used as a method for creating a baby that can serve as a hematopoietic stem cell (HSC) donor to its sibling, who is in need of a stem cell transplant. PGD is used to ensure the HLA of the new-born matches that of their affected sibling.
The process of creating a donor child is obviously somewhat controversial but considering there is no harm to the baby by donating cord blood or bone marrow to it’s sick sibling, it is being practiced. However, experts have urged the need for clear guidelines as to what should and should not be allowed in PGD-HLA procedure to assuage the ethical concerns.
The indications for PGD are expanding slowly as the technology becomes more refined and its usage becomes applicable to more situations.
PGD testing has been established as a safe and effective technique to check the embryos for genetic problems and prevent the transference of faulty genes to the next generation. It is a sophisticated technology that must be performed carefully at a well-equipped lab so the integrity of the embryos is protected and the results are accurate.
One you understand the indications for PGD, you can consult with our top providers of genetic testing services at various locations in Europe, Asia, and North America. For more information on PGD testing with IVF, get in touch via the form on this page.
With contributions from Dr. Lam Wei Kian, IVF and fertility specialist.
Resources:
Scriven, P., Flinter, F., Khalaf, Y. et al. Benefits and drawbacks of preimplantation genetic diagnosis (PGD) for reciprocal translocations: lessons from a prospective cohort study. Eur J Hum Genet 21, 1035–1041 (2013). https://doi.org/10.1038/ejhg.2013.9
Noble, R., Bahadur, G., Iqbal, M., & Sanyal, A. (2008). Pandora’s box: ethics of PGD for inherited risk of late-onset disorders. Reproductive biomedicine online, 17 Suppl 3, 55–60. https://doi.org/10.1016/s1472-6483(10)60332-x
Devolder K. Preimplantation HLA typing: having children to save our loved ones. Journal of Medical Ethics 2005; 31:582-586. http://dx.doi.org/10.1136/jme.2004.010348