Polygenic Embryo Screening Singapore

[Angelica Cheng]

Polygenic Risk Scores: New Frontier in IVF or Just a Hype?

Experts said risk profiling of embryos for genetic anomalies is not ready for "prime time."

www.medscape.com

Genetic Testing for IVF Embryo Selection Deemed Unreliable Despite Continued Interest, Experts Warn​

Couples undergoing in vitro fertilization (IVF) are presented with a dizzying number of choices as they navigate the process — from selecting a retrieval method to selecting the sex of their fetus. Now, add one more choice: Using polygenic risk scores (PRS) to screen embryos for potential health risks like diabetes, cardiovascular disease, and certain cancers.

Choosing to undergo the genetic screening reflects growing interest among future parents interested in the possibility of giving their future child the healthiest start in life. Indeed, nearly three quarters of US adults support using PRS to screen embryos during IVF, according to a study published recently in JAMA Network Open.

However, mounting research suggests this test does not offer consistently accurate predictions, raising concerns about the clinical and ethical implications of the emerging reproductive technology.

Scientists calculate PRS by analyzing the number of risk increasing and decreasing variants in an embryo biopsy to measure the chance of developing a particular disease. The scores are presented as a percentile comparing the embryo to an average person's risk of developing conditions such as schizophrenia, asthma, and inflammatory bowel disease.

The technology has shown some predictive power for assessing risk for similar conditions among adults. Commercial labs in the United States have offered PRS since 2019.

But the screening has shown limited clinical benefit for preimplanted embryos, according to multiple studies, including research presented at the annual conference of the European Society of Human Genetics in Berlin.


Shinichi Namba, PhD, an assistant professor in the Department of Genomic Information at the University of Tokyo in Tokyo, and his colleagues used large-scale simulations and data to construct a screening tool for predicting adult height and the risk of developing type 2 diabetes.

"Our results were so conclusive that we can confidently say PRS scores in embryos are currently worthless," Namba told Medscape Medical News. "There is no point in further research until the technology improves significantly."

Many US-based physician groups recommend against the screening.

"At this time, there is insufficient evidence for the clinical utility of PRS testing for embryo selection," reads a February 2024 position statement from the American College of Medical Genetics (ACMG). "It should not be offered as a clinical service."

But companies that offer the screening say that the data acquired from the screenings can offer valuable and validated insights to help patients select healthy embryos.

In response to criticism of PRS, Jennifer Eccles, director of clinical genetics at LifeView, which offers genetic testing, said the technology is not designed to determine whether an embryo has a particular disease.

Instead, the screening tool measures which embryo has the lowest risk of developing a chronic condition relative to the other embryos and relative to the average risk for a person, Eccles said. LifeView partners with over 100 fertility clinics in the United States to provide PRS services.

"[Risk reduction is] a measurable number, and that is something we can calculate, validate, and publish," Eccles, who is also a genetic counselor, said. "This is a screening tool, not a diagnostic test. We're still exploring how it's used clinically, but we know mathematically this test works."

Still, a significant concern of using PRS is that parents might overlook healthy, viable embryos due to predicted risks, even if those risks are minimal, according to Jason Flanagan, a spokesperson for the National Society of Genetic Counselors (NSGC), which is not affiliated with LifeView.

"For example, if one embryo has a 0.5% increased risk for diabetes, is that a reason not to use the embryo?" he said.

Flanagan, who is also a genetic counselor at Sanford Fertility & Reproductive Medicine in Sioux Falls, South Dakota, said the technology "isn't ready for prime time; so until it becomes more standard and accessible, our clinic won't be offering it to patients."

NSGC maintains that the "evidence gaps" and "critical limitations of this technology" may not make it appropriate yet for widespread use, according to the group's practice resource guide.

Namba from the University of Japan said private companies that market embryo screenings to prospective parents "should clearly state the limitations and acknowledge the inaccuracy and inconsistency of the results. Even if the technology improves, a society-wide debate is needed before making it widely available."

Still a Niche Service​

Still, most IVF patients are focused on overcoming infertility and are not concerned with genetic predictions, Flanagan said. For instance, many patients do not want to conduct other, more reliable testing "for known genetic diseases that we can prevent," he said.

IVF patients also may not know about PRS.

"In my busy clinical practice, which includes a lot of patients undergoing IVF, I have not had one patient ask for PRS," said Susan D. Klugman, MD, president of the ACMG and director of Reproductive and Medical Genetics in the Department of Obstetrics & Gynecology and Women's Health at Albert Einstein College of Medicine in New York City. "Its use is limited in that it only accounts for the possible heritability of disease and not environmental or other lifestyle factors."

However, Nathan Treff, PhD, co-founder and chief science officer of Genomic Prediction, the parent company of LifeView, said patients may not know about the test because many clinicians are reluctant to introduce the option.

"It's a problem that many patients aren't aware of it," Treff said. "There is a risk with all of these negative opinions with patients who may benefit from the test not even being informed about the availability of testing."

Eccles said the scrutiny of PRS is similar to other genetic screenings during early iterations, such as Preimplantation Genetic Testing for Aneuploidy. This test, which is now routinely offered, looks at the number of chromosomes of an embryo to detect abnormalities in a fetus.

"These tests are always introduced before the medical community knows what to do about it," Eccles said. "We're in that period now with PRS."

If clinicians do offer the service, they should work with genetic counselors to communicate with patients the reliability and risks for the test, "given the absence of regulation and the recent commercial availability of the test," Namba and his colleagues wrote.

LifeView requires pretest genetic counseling for anyone considering screening, Eccles said. Genetic counselors discuss how the test works, its limitations, and how to understand the results, she said.

After undergoing the test, the clinician and patient ultimately decide how the results might influence their embryo choice, Eccles said. LifeView does not provide a genetic counselor to discuss results afterward.

However, Flanagan said PRS information should be accompanied by thorough genetic counseling before and after receiving the results to help couples make informed decisions.

"Information by itself isn't harmful; it is how we interpret or respond to it that can cause harm or anxiety," he said. "With appropriate counseling, this information could inform a couple in such a way that they transfer the embryo with the healthiest potential."

 

[Angelica Cheng]

Polygenic testing for IVF embryo selection in Singapore: Proceed with caution - Journal of Medical Ethics blog

By Alexis Heng Boon Chin, Lee Wei Lim, and Sayyed Mohamed Muhsin Singapore, like most affluent East Asian countries, has seen a drastic decline in total fertility rates (TFR) in recent years. In 2022 and 2023, the TFR hit new lows of 1.04 and 0.97 children per woman, respectively. This has...

blogs.bmj.com

Regulatory safeguards needed if preimplantation genetic testing for polygenic risk scores (PGT-P) is permitted in Singapore - PubMed

Singapore, a highly affluent island city-state located in Southeast Asia, has increasingly leveraged new assisted reproductive technologies (ART) to overcome its dismal fertility rates in recent years. A new frontier in ART is preimplantation genetic testing (PGT) for polygenic risk scores (PRS)...

pubmed.ncbi.nlm.nih.gov

Polygenic testing for IVF embryo selection in Singapore: Proceed with caution​

Singapore, like most affluent East Asian countries, has seen a drastic decline in total fertility rates (TFR) in recent years. In 2022 and 2023, the TFR hit new lows of 1.04 and 0.97 children per woman, respectively. This has dire implications for the country’s future economic growth, as well as national security due to the projected shortfall in conscripted military manpower.

In typical Singaporean fashion to seek high-tech solutions to any outstanding problem, Government policymakers have increasingly leveraged new assisted reproductive technologies (ART) to overcome the country’s demographic challenges, with generous subsidies for IVF treatment at public hospitals. Nevertheless, in its eagerness to embrace new ART to boost its dismal birthrates, Singapore should beware that the unregulated and wanton misuse of some new technologies could instead backfire and result in the opposite effect of further lowering fertility rates.

The example discussed here is highly complex predictive genetic testing for optimizing the health and intelligence of IVF embryos, technically referred to as preimplantation genetic testing for polygenic risk scores (PGT-P). Currently, PGT-P has not yet been approved for clinical application in Singapore, so it is timely to propose safeguards for future clinical trials.

Complex traits such as good health, intelligence, skin complexion and height, are determined by the combined interactions of several genes with the environment. Polygenic risk scores (PRS) can estimate an individual IVF embryo’s likelihood of developing such complex multi-factorial traits by analyzing the combination of specific genetic variants within its genome. There are minimal risks with PGT-P, unlike human germline editing, due to the absence of permanent genetic modifications that can be transmitted to future generations.

In an era of ultra-low fertility rates, prospective parents inevitably invest more money, time and effort on their fewer children, very often resulting in unrealistic and unreasonable parental expectations, with the phenomenon of “tiger parenting” being commonplace in Singapore. Nevertheless, the major confounding challenge to every parent’s great expectations and best-laid plans is the unpredictability and randomness of the natural fertilization process, which involves mixing and recombining genes from the egg and sperm to produce new genetic variants. This often results in siblings born from the same pair of parents differing so much in looks, health and academic performance.

Hence, there is no guarantee that the offspring of high-achieving parents may necessarily be high-achievers, with the risk that all the money, time, and effort invested in an “inherently mediocre” child will ultimately go to waste. The PGT-P technique thus attempts to overcome the randomness and unpredictability of the natural human fertilization process to yield the best possible outcome.

The PGT-P technique will likely be expensive. Besides the high costs of the technique itself, additional medical fees for IVF are also required. Healthy and fertile couples might deliberately and unnecessarily choose to conceive via IVF to avail themselves of embryo selection by PGT-P for optimizing the health and intelligence of their offspring. Social pressure may make resisting such predictive genetic testing difficult if it becomes trendy. Prospective parents might feel guilty for not utilizing PGT-P to give their offspring the best start in life. As a result, many prospective parents desiring two or more children may ultimately decide to have just one superior “genetically optimized” child due to the high costs involved.

However, the efficacy of PGT-P is severely reduced by the small number and limited genetic variability of IVF embryos produced by the same pair of parents. When selecting specific polygenic traits within such a small sample size with limited genetic variability, the number of possible outcomes is very much limited.

Additionally, there are also other very obvious technical limitations. For example, the statistical probability of two dark-skinned parents conceiving a child with fair complexion by predictive genetic testing will always be low because most genes predisposing to fair skin are simply absent in those parents. The same can be said of two short parents attempting to beget a tall offspring.

Nevertheless, the actual effectiveness of PGT-P may not really matter. Because prospective parents naturally and instinctively desire the best future for their offspring, these thus represent particularly lucrative business opportunities for fertility clinics, which may deceive and exploit patients with their aggressive sales pitches and slick marketing gimmicks.

Hence, the following stringent regulatory safeguards are thus proposed. These include (i) Restricting the application of PGT-P only for the prevention of clinically relevant polygenic disease traits, (ii) Securely blocking patients’ access to the raw genomic DNA sequencing data of their IVF embryos, (iii) Validating diagnosis of polygenic disease traits in the prospective parents/grandparents of IVF embryos, and restricting PGT-P only for preventing specifically-diagnosed polygenic disease traits, and (iv) Mandating rigorous and comprehensive genetic counseling for IVF patients considering PGT-P.

There is a dire need to prevent abuse of the PGT-P technique and protect the interests and welfare of patients if its clinical application is to be permitted in Singapore.