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Genetic testing of embryos - a potential game changer in fertility sector

Dr. Varsha Samson Roy
Wednesday, May 31, 2017, 08:00 Hrs  [IST]

Preimplantation Genetic Screening (PGS) for aneuploidy is a powerful genetic test that may be performed on embryos during IVF treatment to screen for numerical chromosomal abnormalities. This technique is performed as an embryo biopsy prior to transfer such as to identify chromosomal abnormalities.

PGS offers comprehensive analysis of all 23 sets of chromosomes: one set of sex chromosomes (X & Y) and the 22 other non-sex chromosomes (autosomes). Normally there are 23 pairs of chromosomes in each human cell. A numerical change in the number of chromosomes is called aneuploidy. Aneuploidy is responsible for the vast majority of spontaneous miscarriages and can result in birth defects and intellectual disability in live born babies. The most common syndromes caused by non-sex chromosome aneuploidies are Down syndrome, Edward’s syndrome and Patau syndrome. Aneuploidy is usually not inherited and can involve any chromosome.

Next Generation Sequencing (NGS) as an effective technique for the analysis of copy number variation in single cells. This technology is specially developed for analysis of only a few cells or even a single cell as is required for preimplantation genetic testing. Validation studies with cell lines of known karyotype have been performed in laboratories to optimize library preparation, timing and diagnosis accuracy. PGS testing with NGS is 99% accurate.

Benefits of PGS

  • Increase in implantation rate: Some embryos that are chromosomally abnormal will fail to implant into a woman’s uterus. Therefore, by transferring chromosomally normal embryos through PGS by NGS can increase the implantation rate.
  • Reduction in miscarriage rate: In general, 20% of all clinical pregnancies miscarry and about half are chromosomally abnormal. Since PGS evaluates numerical changes in chromosome numbers and large chromosome imbalances, embryos with chromosome abnormalities will not be transferred. Therefore, especially, in high-risk groups, PGS reduces the risk of miscarriage.
  • Increase in chances of delivering a healthy baby: PGS can increase the chance of delivering a healthy baby by assisting physicians in identifying chromosomally healthy embryos for transfer. These conditions can also be detected by chorionic villus sampling (CVS) or amniocentesis later during the pregnancy.
Who should use PGS testing?
Those couples who are at an increased risk of aneuploidy in their embryos should consider PGS.

These are advanced maternal age (women > 35 yrs), those with history of repeated abortions (naturally conceived or through treatment cycles), those failing to conceive through IVF cycles in spite of having good embryos (Repeated implantation failure) and those with severe male factor infertility (poor semen parameters)

In the case of advanced maternal age/delayed maternity a woman is born with a certain number of eggs, and her ability to have children decreases over her lifetime, in part because the chance of chromosome abnormalities also increases as she ages. The decline in fertility is gradual, but many medical providers consider the risks of chromosome abnormalities to be significant at the age 35 or older.

For those with repeated/multiple miscarriages, it is observed that approximately 50% of spontaneous miscarriages occur in the first trimester because of random chromosome abnormalities. PGS studies in these couples have revealed that 65% of embryos are chromosomally abnormal, and in 15% of couples, all embryos are chromosomally abnormal.

The reason for repeated implantation failure occurs because of abnormalities of either the uterus or the embryo itself. If chromosomal abnormalities are impacting embryo viability, the selection of chromosomally normal embryos will improve the chances of implantation and ongoing pregnancy.

Another cause is male infertility. low sperm count increases the percentage of chromosomally abnormal sperm and therefore increases the risk of producing aneuploid embryos. For couples who experience male-factor infertility, approximately 55-65% of embryos may be chromosomally abnormal depending on the severity of the male factor.

PGD for single gene disorders is a powerful genetic test that may be performed during IVF treatment to screen embryos that are at risk to develop a serious genetic disease. PGD is performed on a small embryo biopsy and identifies which embryos are not at increased risk of developing the disease. It is done before the pregnancy is established and helps avoid difficult decisions and situations.

DNA is organized into small segments called genes. There are about 25,000 genes in humans all of which influence our growth and development. Just like chromosomes come in pairs, most genes also come in pairs, one copy inherited from the egg and the other from the sperm. When the function of a gene is altered by a change (called a mutation) in the DNA sequence, a genetic disease results. These mutations can be transmitted in families from generation to generation, or can be a new change in an individual. Common examples of conditions caused by mutations in single genes (monogenic diseases) include beta thalassaemia, sickle cell anaemia, duchenne muscular dystrophy, spinal muscular atrophy (SMA), cystic fibrosis, and fragile X disease.

During the IVF process, PGD can be used to screen embryos for these conditions. Embryos that are not at increased risk for developing the single gene disorder are identified and preferentially transferred for the pregnancy. The goal of PGD testing is to help couples build healthy families.

Mr and Mrs 'X' came with a history of having a male child diagnosed with Sandhoff disease. Sandhoff disease is a rare, genetic, lipid storage disorder resulting in the progressive deterioration of the central nervous system. There is no specific treatment for the disease and death usually occurs by age 3. Having lost their first child, the couple had a desire to conceive and have a healthy second child.

A gentist confirmed that the husband was carrier of mutation for Sandhoffs disease. Pre-PGD work up of the couple included blood tests to confirm the mutation. PCR gene sequencing was done for both the parents. Once this was done an assay was developed which would then identify that mutation in the couple’s embryos by the process of NGS (next generation Sequencing).

The couple went through the procedure of IVF-ICSI. Ovarian stimulation with Antagonist protocol was used, 8 oocytes (eggs) were retrieved out of which 7 were mature. The following day out of 7 oocytes, 6 of the oocytes had accepted the sperm DNA (fertilized eggs or zygotes).These zygotes were then cultured in the laboratory till day5/6 (Blastocyst stage). Out of the 6 fertilized eggs (zygotes) 4 of them grew to the blastocyst stage.

Of the 4 blastocysts that were biopsied and underwent PGD & PGS by NGS, only a single blastocyst was found to be healthy without the disease causing gene. Till the NGS reports were made available the blastocysts were frozen independently. The subsequent month the single normal blastocyst was warmed & transferred in a Frozen Embryo Transfer Cycle. The patient underwent embryo transfer with this single genetically normal embryo. 6 weeks later she was confirmed to be pregnant with a single baby by ultrasonography and later went to deliver a healthy baby.

PGD scenario in India

Due to significant growth in Indian medical tourism and exaggerated infertile domestic population, many renowned healthcare providers, and hospitals are looking at adding these services.As a result, many IVF and PGD centers can be seen growing even in Tier II and Tier III cities in the country. The medical advancements to taking the edge off health related risks have fueled rapid acceptance of IVF and PGD technology to deal with reproduction problems in the country. In lieu of these factors put altogether, the Indian IVF as well as PGD market is bound to witness a rapid inflation in its growth rate in the coming year.

India consists of ethnically, geographically and genetically diverse population. The tradition of consanguineous marriage in certain Indian communities puts them at a higher risk. The most common genetic disorders in Indian ethnicity are Beta-Thalassemia, Cystic Fibrosis, Sickle Cell Anaemia, Spinal Muscular Atrophy and Haemophilia A.

This procedure of PGD will specifically benefit these patients to have healthy children devoid of the inherited disease that runs into families from generations. PGD can be offered to couples where one or both the parents have a known genetic abnormality or an affected child or relative in the family.

(Author is chief embryologist & scientific director,  Manipal Fertility)


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