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New Tech Helps At-Risk Couples Ensure Their Kids Don’t Inherit Their Illnesses

New Tech Helps At-Risk Couples Ensure Their Kids Don’t Inherit Their Illnesses

pre-implantation genetic diagnosis, pre-implantation genetic screening, thalassemia, in-vitro fertilisation, IVF, embryos, mosaicism, uterus, genetic defects, chromosomal defects, next gen sequencing, American Society for Reproductive Medicine, assisted reproductive therapy, aneuploidy, sex determination,

To be born with the right genes used to be a blessing. But thanks to technological advances, it is possible today for at-risk couples undergoing in-vitro fertilisation (IVF) to have their embryos subjected to genetic screening before being implanted in the womb. This way, the couple will know the child doesn’t have any genetic or chromosomal defects.1

Dr Nandita Palshetkar, president of the Federation of Obstetric and Gynaecological Societies of India, shared a case study with The Wire. Two partners – both carrying the genes for thalassemia, a life-limiting blood disorder – had tried to have a baby thrice but failed. The first two pregnancies had to be medically terminated after doctors diagnosed the foetuses with thalassemia and the third was a miscarriage.

Doctors then advised the couple to undergo IVF followed by pre-implantation genetic diagnosis (PGD). Two IVF cycles later, they had six embryos at the day-5 stage. An embryologist performed biopsies and sent the cell samples to a genetic lab to be analysed; the embryos were kept frozen. When the results arrived, they showed three embryos were ‘normal’ and three had inherited the genes for thalassemia. So doctors transferred the ‘normal’ embryos to the womb. Later, an amniocentesis 2 confirmed that the child did not have thalassemia, and the mother delivered a healthy baby.

A diagram illustrating how IVF works: After ovulation, the egg is collected from the woman's reproductive organs, fused with sperm and the resulting fertilised ovum is reinserted into the uterus. Image: Manu5/Wikimedia Commons, CC BY-SA 4.0
A diagram illustrating how IVF works: After ovulation, the egg is collected from the woman’s reproductive organs, fused with sperm and the resulting fertilised ovum is reinserted into the uterus. Image: Manu5/Wikimedia Commons, CC BY-SA 4.0

“Any additional embryos that are free of genetic problems are kept frozen for possible use later while embryos with problematic genes are destroyed,” Dr Palshetkar said.

“PGD enables identification of genetic defects in the early embryo before the embryo is transferred to the uterus in an IVF program,” Dr N. Pandiyan, the head of the department of reproductive medicine at the Chettinad Super Speciality Hospital and Research Institute, Chennai, explained.

Dr Sasikala Natarajamani, founder and scientific director of Crea Conceptions, an assisted reproduction centre in Chennai, said that, “according to the Human Fertilisation and Embryology Authority, UK, PGD has been approved for testing over 600 genetic conditions.”

Also read: After U-Turn on Rare Disease Policy, Health Ministry Assures New One in 9 Months

There are “numerous tests,” in Dr Pandiyan’s words, that enable PGD. For example, scientists developed PGT-M – pre-implantation genetic testing for monogenic defects – to prevent the birth of a baby with genetic defects “when the previous baby was affected” or when the parents have “a history of inheritable disease in the family.”

Another kind is PGT-A, where the ‘A’ stands for aneuploidy, a condition where the body’s cells don’t have the normal number of chromosomes, 46. This gives rise to chromosomal disorders like Down syndrome. In PGT-A, embryos from parents presumed to be ‘chromosomally normal’ are screened to check whether the cells in each embryo contain 46 chromosomes. Such screening is called pre-genetic screening (PGS).

“At present, PGS and PGD are the only options available to parents trying to avoid the risk of having a child affected with a genetic disease, prior to implantation,” Dr Natarajamani added.

PGD has been gaining traction of late. “Screening the embryo for possible life-threatening and debilitating genetic diseases before transfer changes reproductive options for families at risk,” Dr Palshetkar told The Wire. “In some cases, further testing is needed during pregnancy to ascertain if a genetic factor is still possible.”

But “overall, PGD has been able to diagnose genetic defects with approximately 98% accuracy,” she added.

This is the result of major advancements in the last three decades, such as being able to visualise specific chromosomes using fluorescence in situ hybridisation, to produce thousands of copies of a DNA fragment using the polymerase chain reaction, and to profile genomes rapidly using next-gen sequencing (NGS).

This isn’t to say the procedure is entirely free of issues. For example, according to a review published by the American Society for Reproductive Medicine (ASRM) in 2017, IVF embryos sometimes have a condition called mosaicism – where all cells in the embryos don’t have identical sets of chromosomes. When these abnormal cells proliferate, it could result in a miscarriage or severe birth defects.

However, Dr Natarajamani said, “Techniques like NGS have allowed for very high-fold coverage,” allowing scientists to detect “even low levels of mosaic mutations” and ensure only the healthiest embryos are transferred. In general, according to the review, NGS can eliminate mosaic cells when they make up fewer than a fifth of all cells in the embryo but fail when the extent of mosaicism crosses 50%. In the latter case, the embryo is deemed aneuploid and discarded.

According to Dr Palshetkar, the most frequently diagnosed disorders include those of blood and muscles, and other rare conditions such as cystic fibrosis, beta thalassemia, sickle-cell disease, spinal muscular atrophy, myotonic dystrophy, haemophilia A and Duchenne muscular dystrophy.

Since the requisite testing facilities aren’t widely available in India, results can take up to three weeks to arrive. But this hasn’t put people off from opting for it, especially since the procedure seems safe. According to the Centre for Advanced Reproductive Services, Connecticut, there has thus far been no increase in the rate of congenital abnormalities or pregnancy complications due to embryo biopsies.

Nonetheless, Dr Natarajamani hopes that non-invasive techniques will replace biopsies soon, given the inescapable risk the latter procedure carries in some cases.

Also read: Widely-Available Genetic Risk Tests Aren’t Always Useful – and Could Even be Harmful

Then there are the potential ethical issues. However, Dr Pandiyan is quick to defend PGD and draws a line between PGD and PGS as well as other, more morally fraught practices.

“PGD is clearly and absolutely indicated in certain circumstances, like in couples with a previous child with abnormalities, with a family history of abnormalities, etc.,” he said. “The debate is only about routine screening of all embryos, as in PGS, before embryo transfer or when [the technique] is used to identify the sex of the embryo.”

In his telling, the doctors’ decisions aren’t arbitrary but are guided by the recommendations of bodies like the ethics committee of the ASRM. For example, in an opinion published last year, entitled ‘Disclosure of sex when incidentally revealed as part of … PGT’, this committee reached the following conclusion:

“When patients undergo [assisted reproductive therapy] and PGT for medical reasons, embryo sex could be a common secondary finding. Patients should be informed of this possibility before undergoing PGT. Patients have the right to information about an embryo’s sex, as well as the right to request not to be given this information. Clinics may have policies not to take an embryo’s sex into account in making transfer decisions. Clinics must have nondiscrimination policies regarding embryo transfer when the sex of the embryo is known. Patients should be informed about these policies.”

Indeed, all genetic labs in India are required to follow guidelines set by the Pre-Conception and Pre-Natal Diagnostic Techniques (Prohibition Of Sex Selection) Act 2003.

Dr Palshetkar, like Dr Pandiyan, has no doubts: “PGD is an amazing technology and the application of next-gen sequencing [has been] a game-changer. It will reduce the incidence of genetic diseases and complications [associated with] multiple births.” She added that many IVF centres around the world have also been able to achieve “fantastic birth rates” after transferring “only one genetically normal embryo” into the womb.

Sudha Umashanker is a Chennai-based freelance journalist, author and award-winning storyteller.

  1. Each chromosome consists of a DNA molecule + the material that packages and holds it in place inside a cell.

  2. testing the amniotic fluid surrounding the foetus in the uterus

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