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Pre-Implantation Genetic Testing (PGDT) And Its Role in IVF Babies

From a haploid cell to a multicellular complex organism; pregnancy, gestation, and birth are events that are nothing short of a biological miracle.

It was less than five decades ago that IVF infused a new hope in the lives of millions of couples who could not conceive naturally. However, the unperceived, intangible health and psychological strain that accompanies an IVF procedure because of the uncertainty factor, is best compensated only with a successful procedure and conception.

The best news is that in this world of consolidated global intelligence- medical science, embryology, and gynaecological genetics supplemented with unflagging innovations, have led to procedures, methods and treatments that were once unimaginable. This reliable path to identify and tweak the course of this ever so complex process has made life much easier for couples looking for a solution for infertility, thus leaving less to chance and peril.

WHAT IS PREIMPLANTATION GENETIC DIAGNOSIS?

Pre-implantation genetic diagnosis (PGD) is a genetic testing procedure that is used to identify genetic anomalies in embryos formed using IVF technique, before the embryo is placed in the uterus, to reduce the risk of passing on any genetic diseases.  

BRIEF HISTORY:

Pre-implantation Genetic diagnosis was first performed successfully in humans in 1988- it actually finds its theoretical roots in the first Prenatal diagnosis (amniocentesis), performed in 1956. Prenatal diagnosis is only but a precursor of PGD.

It involves developing and implementing cellular, genetic, and molecular methods as well as advanced ultrasonography to reliably identify and diagnose congenital conditions by chromosomal and genetic analysis of the fetal cells.

The outcome of these advances means that more information about the fetus’s anatomy, genetic make-up, and health is available today than ever before, at the initial stage in pregnancy.

WHAT IS PREIMPLANTATION GENETIC SCREENING OR PGS?

These two terms although analogous in terms of methods and techniques, differ in principle because in preimplantation genetic screening (PGS) there is no known genetic mutation in the parents, so it is more of caution than a definitive diminution.

The fertilized eggs are screened only for aneuploidy or chromosomal number defects. Aneuploidy is a common cause for genetic disorders. Most cases of aneuploidy result in miscarriages.

HOW IS PGD DIFFERENT FROM A REGULAR GENETIC SCREENING?

The nuance here is that Preimplantation genetic diagnosis (PGD) is indicated when there is known genetic abnormality in either of the parents such as cystic fibrosis or sickle cell anemia. In such cases it becomes mandatory to perform this test on the embryo to make sure that it does not carry the anomaly.

RATIONALE

As with any medical procedure it is pertinent to ask the ‘Why’ behind it since IVF already requires considerable financial investment and PGD is an elective procedure; therefore, it is only normal to question the rationale and the need for it.  

Preimplantation Genetic diagnosis and Preimplantation Genetic Screening are the only viable methods available to avert miscarriage, medical termination of pregnancy and also helps to significantly alleviate the likelihood of having a baby afflicted with a genetic condition.

WHO NEEDS IT?

PGD is not just for couples who are infertile, but is recommended for

1) Individuals who have a known family history of a genetic condition and want to diminish the risk of severe health issues or even early death of their offspring.

2) Previous multiple miscarriages for reasons that cannot be determined.

3) Have an offspring affected by a genetic condition while the parents exhibit no signs of the genetic condition.

CONDITIONS DIAGNOSED USING PGD:

PGD should be offered for three major groups of disease:

A)    Sex-Linked disorders: such as hemophilia, fragile X syndrome, over 900 neuromuscular dystrophies, Rett syndrome, incontinentia pigmenti, pseudo hyperparathyroidism, and vitamin D–resistant rickets.

If there is a genetic aberration on the X chromosome of the mother who does not manifest a disease but is a carrier, she has a 50% chance of passing on the gene and thus the associated manifestation to her son. Conversely the same aberration on the X chromosome of the father, will manifest the disease, will have a healthy son provided the mother is not a carrier, but their daughters will have a 50% risk of being carriers if the mother is healthy and 50% chances of daughters being affected by the genetic aberration if the mother is a carrier.

B)    Single gene defects: like Cystic fibrosis, Tay-Sachs disease, sickle-cell anemia, and Huntington disease. PGD can also be utilized to identify specific mutations such as BRCA-1, which might not cause any specific disease but increases the propensity to develop a set of diseases. C)   Chromosomal Disorders: a wide variety of chromosomal number permutations combinations anomalies resulting in trisomy, monosomy, rearrangements, translocations, inversions, and deletions have led to unviable pregnancies. PGD reduces the risk of first and second trimester miscarriages drastically.

How is PGS Testing done?

BIOPSY METHODS:

Conventionally three approaches can be utilized for PGD. Although the procedure is the same, the stage at which the cells are retrieved is what sets them apart.

When the genetic screening is done on the polar body to establish the status of the oocyte or egg it is:

Method 1: Polar Body Assay

Each oocyte is associated with a ‘Polar body’, or a sister cell formed at the time of oogenesis or primitive egg formation. So, each Polar body consists of the other half of the chromosomes of its sister oocyte. This polar body is removed and put under the microscope, in the event a polar body has the mutated gene its associated oocyte is inferred to be “normal,” and therefore fit for fertilization since the resultant embryo will be unaffected by the genetic condition of concern.

This technique is infrequently used because

●      It only works to identify female chromosomal disorders.

●      Chromosomal abnormalities of the sperm cannot be studied in this procedure therefore the chromosomal architecture of the subsequent embryo is not known

Method 2: Cleavage-stage embryo biopsy OR Blastomere biopsy.

Method 3: Blastocyst stage

After initiation of an IVF cycle, multiple eggs are matured and retrieved. Each oocyte aka primitive egg cell is then inseminated by injecting a single sperm directly into the cytoplasm of the egg also known as the intracytoplasmic sperm injection. Biopsy of the cells from the resultant embryos are then done by either method two or method three.

Cleavage-stage embryo biopsy:

This is by far the most used method of the three methods. The embryo on day three is a six to ten celled structure called the blastocyst. After incubating the embryos in Calcium and Magnesium free medium to prevent cells adhering to each other, one cell is accessed and retrieved through a process called assisted hatching and studied for the genetic anomaly. Those that are cleared by the embryologist of the genetic variant are then transferred to the uterus for implantation.

The only limitation of this biopsy is that the blastomere retrieved for genetic testing may not completely represent the entire embryo due to the fact the embryo might be composed of different lines of cells aka Mosaic embryo.

Blastocyst Stage:

On the fifth day of the IVF, the embryo is the mass of more than one hundred cells, consisting of an inner cellular corpus enveloped by an outer cell mass. The outer cell mass is also known as the trophectoderm which later develops into the placenta. The cells of this trophectoderm are accessed by assisted hatching and carefully retrieved using a fine biopsy pipette, while leaving the inner cell untouched. Transferred to be studied and analysed and any embryo carrying the genetic aberration is then removed from potentially viable embryos.

Drawbacks of the blastocyst biopsy are:

●      Incorrect representation as the cells of the outer cell mass or trophectoderm might not be precise depiction of the mosaic embryo.

●      After egg retrieval the embryos are viable in the laboratory for less than six days and this biopsy is performed out on day five. Chromosomal analysis and aneuploidy testing require 24- 48 hours therefore the blastocysts need to be cryopreserved right after biopsy.

All three approaches though are highly technique sensitive and time dependent, appear to be safe. Studies have shown no increased chances of genetic or birth or growth disorders in infants born after PGD when compared to infants born after other assisted reproductive technologies.

GENETIC TESTING METHODS:

Polymerase chain reaction or DNA     amplification: A single DNA     sequence, known to carry the gene under consideration, is multiplied in an     enzymatic medium, therefore leading to rapid replication and creating     billions of the same molecule which facilitates its analysis.

It helps to identify:

●      Genetic aberrations on the autosomal chromosomes

●      Genetic aberrations in male infertility.

●      Genetic aberrations in X-linked diseases.

Fluorescence in situ hybridization or FISH: Specific chromosomes being analysed are     exposed to complementary sequences of DNA called “probes.” Each probe is     colour marked with a fluorescent dye. After introducing the biopsied cells     to these “probes,” it is then observed under a specialised microscope and     anomalies are then identified by studying and counting the colour coded     probes and their bindings. FISH is often the preferred method of genetic     analysis as it rules out any instances of contamination (paternal and     maternal). It helps to identify:

●       Trisomy or monosomy screening in women of advanced maternal age

●       Trisomy or monosomy screening for male infertility

●       Identification of sex in recessive or X-linked diseases

Recurrent miscarriages caused by parental translocations

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