Preimplantation Genetic Testing – The Next Generation of ART

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What is Next Generation Sequencing and can it improve IVF success?

IVF technology revolutionized the field of reproductive medicine and helped millions around the world struggling with infertility become parents. More than 400,000 babies from 1.6 million ART cycles are born around the world every year. To date, it is reported that over 8 million babies were born through IVF.

However, IVF success depends greatly on the quality of the embryo. So far, the embryologists had to rely solely on morphology to choose a healthy embryo with the most chances to end up in a live birth. However, Embryos that look good under the microscope don’t always have what it takes to produce a viable pregnancy. Chromosomal Aneuploidy in embryos, embryos with an abnormal number of chromosomes will fail to develop normally and in most cases will result in spontaneous miscarriages. Aneuploidy cannot be detected by a microscope and requires genetic testing.  

Genetic testing on live embryos was a challenge for many years. However, with scientific and technological advancements, the concept of genetic testing of embryos was first successfully performed in 1989 when scientists reported the screening for Y chromosome in embryos to reduce the chances of X-linked recessive disease. The technology further developed and now Preimplantation Genetic Testing (PGT)  is available in many fertility clinics as an additional screening tool that allows embryologist to select the embryo with the most chances to implant and result in a viable pregnancy.

What is Preimplantation Genetic Screening (PGS)?

PGS (also known as PGT-A)  is a highly specialized genetic testing for screening chromosomal abnormalities in embryos. On day five or six after fertilization, the embryologist will remove a few cells from the developing embryo that will be used to verify the presence of all 23 chromosomes. The cells are taken from the part of the embryo that will later form the placenta.  The results will allow selection of embryo/s with a normal number of chromosomes. These embryos are more likely to result in an ongoing pregnancy with a lower risk of miscarriages. The process of PGS is illustrated in this great animated video.

Historically, this test was performed on day 3 when the embryo has just eight cells. These methods were not sensitive enough and prone to misdiagnosis. In addition, these test only identify aneuploidy in up to 12 chromosomes. With scientific advancements, PGS is now available to simultaneously evaluate the ploidy status of all 23 chromosomes pairs. Further developments allowed embryologists to perform the biopsy in blastocyst stage (day 5-6 after fertilization) and on the extra-embryonic (Trophectoderm) tissue, which increased accuracy and reduced the risks for the embryo development.

PGS is a powerful new tool in the optimization of assisted reproductive technologies. Studies show PGS improve IVF results by increasing pregnancy and birth rates and decreasing miscarriage rates. There are several methods available for PGS. All genetic technologies will equally identify “whole chromosome” aneuploidy. However, some genetic technologies are more sensitive and will identify large segmental chromosome duplications or deletions.

Over the years several methods were developed to define the number of copies of each of the chromosomes. These methods differ in the mechanism that reports on the presence of a chromosome and the extent that each of the chromosomes is covered by the reporting mechanism. These methods include:

  • Microarray Comparative Genomic Hybridization (Array CGH) –  aCGH was one of the first techniques used to provide comprehensive PGS of all 23 pairs of chromosomes, and is a technique that is still widely used in clinical practice. By comparing the fluorescence intensity of the embryonic sample with that of a control sample it is possible to determine the copy number of each chromosome in the biopsied cell.
  • SNP Microarray – Capable of detecting the widest range of chromosomal abnormalities in all 23 chromosome pairs. By measuring the intensity of red-to-green fluorescence at each SNP (single DNA base substitutions that are unique to each chromosome)  site on the array, it is possible to simultaneously genotype more than 300,000 SNPs in each sample.
  • qPCR or Real-Time PCR –  is very effective in the assessment of known single gene defects, and has traditionally been used for preimplantation genetic diagnosis rather than PGS. In most recent years this technique has been adapted to provide a rapid method of PGS which is able to be completed in just 4 hours. However, only a few loci are assessed for each chromosome, resulting in a significantly lower resolution.
  • Next-generation sequencing (NGS) – NGS is the latest technological breakthrough in pre-implantation genetic testing. NGS is well accepted in the prenatal testing arena and recently applied to PGS. It allows us to study all 23 pairs of chromosomes at a more comprehensive level, and with deeper resolution. Studies demonstrated that NGS is able to detect embryos with unbalanced chromosomal translocations that were not identified by SNP array. This method provides much better coverage of the chromosomes and a higher resolution. The barrier to earlier implementation was a need for technological advancement in sequencing technology to make it faster and more affordable which is now available through NGS.

Juno Fertility is proudly offering PGT-A through Access Genomics which is utilizing Next Generation Sequencing (NGS) platform (VeriSeq™ by Illumina), the best available method in the market.  

It is important to note that while the accuracy of these tests improved significantly over the years, prenatal genetic testing is still recommended once clinical pregnancy is achieved.

Who should consider PGS?

  • Women over 35
  • Women experiencing recurrent miscarriages
  • Clinical aneuploidy (Downs’ Syndrome) risk
  • Sex-linked genetic illness risk

The fertility specialist may recommend additional PGS testing, but it is an elective test. It’s the parent’s choice to include it or not. While this looks like an additional upfront expense, it might save you time and money down the road by avoiding embryo transfers that have no chance to implant.  

Do you have more questions about PGS, our team of experts is here for you! Call us to learn more about your options.

 

References:

  1. Preimplantation genetic testing for Aneuploidy: what technology should you use and what are the differences? P. R. Brezina et al.J Assist Reprod Genet. 2016 Jul;33(7):823-32
  2. Pre-Implantation Genetic Screening Techniques: Implications for Clinical Prenatal Diagnosis; S. C. Kane et Al. Fetal Diagn Ther. 2016;40:241–254
  3. Chromosomal analysis in IVF: just how useful is it? Reproduction. 2018 Jul;156(1):F29-F50

 

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