Three Expert Opinions on “The alarming rise of complex genetic testing in human embryo selection”
Reporter: Aviva Lev-Ari, PhD, RN
Based on this articles three expert opinions where formed by the following domain knowledge experts and are presented, below.
Expert Opinions on rise of complex genetic testing in human embryo selection
ttps://www.nature.com/articles/d41586-022-00787-z
Domain Knowledge Experts:
Prof. Marc Feldman, Genetics, Stanford University
Dr. Shraga Rottem, MD, D.Sc., Fetal OB
Prof. Steven J. Williams, Biological Sciences, Temple University
The recent publication in Nature Medicine on genetic risk prediction in pre-implementation embryos(1) has already engendered heated discussion.(2,3) Kumar et al.(1) advocate the integration of polygenic risk scores (PRS) derived from pre-implantation genetic testing (PGT) with standard monogenic prediction. The paper focuses primarily on BRCA1 (and breast cancer) and APC (and colon cancer). Genetic tests for inherited disorders such as Tay-Sachs disease and breast cancers caused by BRCA1 and BRCA2 have been approved, but these are potentially devastating conditions with relatively simple inheritance; in most counseling situations the risks are straightforward to calculate.
The limitation on the amount and quality of DNA available from early embryo biopsies has made it difficult to produce genomic profiles of embryos in the IVF situation. Kumar et al. genotyped more than one-hundred embryos at hundreds of thousands of nucleotide sites and combined these genotype data with whole genome sequences of the prospective parents to produce reconstructed embryo genomes. These genomes were compared with those of ten born siblings and polygenic risk scores (PRS) were calculated for twelve conditions related to diseases. The PRS were claimed to be 97–99 percent accurate.
The primary market for this procedure would be couples seeking IVF, and Kumar and his colleagues, most of whom are employees of biotech companies, show that it is feasible to calculate a PRS for an embryo. The authors do present several caveats for the use of their procedure for PGT. For example, if a couple has a family history of a disease, they “may unintentionally prioritize” a mutant embryo for PGT-based only on PRS. They also acknowledge that results from research cohorts may not generalize to sibling embryos in IVF, which could limit the clinical utility of their approach. Kumar et al. also acknowledge the “portability” problem, namely PRSs have limited predictive accuracy in people with non-European ancestry(2,3) or of different ages or socioeconomic status.(4,5) They also mention the issue of unequal access to IVF technology in general.(2)
It is also important, However, to stress the limited predictive utility of PRS for common traits, not only diseases. There is increasing use of PRS among social scientists for characteristics such as years of education, which have heritabilities in the 10–15 percent range. Such studies, and potentially this one by Kumar et al., can lead to reduced emphasis on environmental and social associations with diseases or other traits. For omnigenic traits, such as height or body mass index (BMI), that have hundreds or thousands of associated nucleotide polymorphisms, and high heritability, the public might receive the mistaken impression that PGT or other genomic interventions can allow parents to choose their offspring’s phenotype.
For example, a recent study(6) of BMI in 881 subjects from Quebec found that PRS could explain only between 1.2 percent and 7.5 percent of the variance in BMI of these participants. Even when PRSs are statistically significant, their predictive value is too weak to be applied. The use of polygenic risk scores to select embryos, abbreviated ESPS for embryo selection based on polygenic scores, has been criticized before.(7) One of the important points raised by Turley et al.(7) concerns the environmental context of the children of IVG customers, which may be quite different from that of the sample of people from which the PRS was calculated. Because of gene-environment interactions, the predictive power of PRS for any complex trait is limited. As pointed out by Turley et al. (p. 79), “the predictive power of a polygenic score is maximized when the person is from the same environment as the research participants from whom the polygenic scores were derived. But this will never be the case in ESPS.”
PGT and ESPS raise ethical issues beyond IVG that more generally concern designer babies.(7,8) PRSs have been calculated for non-disease related traits such as educational attainment, income, or IQ, and it is conceivable that some prospective parents might regard these as important enough for intervention. There are also traits related to social constructs of race including skin pigmentation or facial features, and parental choice based on these phenotypes could enhance racial prejudices.
References
- Kumar, A., K. Im, M. Banjevic, P.C. Ng, T. Tunstall, G. Garcia, L. Galhardo, J. Sun,O.N. Schaedel, B. Levy, D. Hongo, D. Kijacic, M. Kiehl, N.D. Tran, P.C. Klatsky, and M. Rabinowitz. 2022. Whole-genome risk prediction of common diseases in human preimplantation embryos. Nature Medicine 28: 514–516. doi: 10.1038/s41591-022-01735-0.
- Johnston, J., and L.J. Matthews. 2022. Polygenic embryo testing: understated ethics, unclear utility. Nature Medicine 28: 445–451. doi: 10.1038/s41591-022-01743-0.
- Nature editorial. 2022. The alarming rise of complex genetic testing in human embryo testing. Nature 603: 549–550. doi: 10.1038/d41586-022-00787-z.
- Rosenberg, N., M. Edge, J. Pritchard, and M. Feldman. 2019. Interpreting polygenic scores, polygenic adaptation, and human phenotypic differences. Evol. Med. Public Health 2019: 26–34. doi: 10.1093/emph/eoy036.
- Duncan, L.E., H. Shen, B. Gelaye, J. Meijsen, K.J. Ressler, M.W. Feldman, R.E. Peterson, and B.W. Domingue. 2019. Analysis of polygenic score usage and performance in diverse human populations. Nat. Comm. 10: 3328. doi: 10.1038/s41467-019-11112-0.
- De Toro-Martin, J.E., F. Guenard, C. Bouchard, A. Tremblay, L. Perusse, and M.-C. Vohl. 2019. The challenge of stratifying obesity: attempts in the Quebec family study. Front. Genet. 10:994. doi: 10.3389/fgene.2019.00994.
- Turley, P., M.N. Meyer, N. Wang, D. Cesarini, E. Hammonds, A.R. Martin, B.M. Neale, H.L. Rehm, L. Wilkins-Haug, D.J. Benjamin, S. Hyman, D. Laibson, and P.M. Visscher. 2021. Problems with using polygenic scores to select embryos. N. Engl. J. Med 385(1): 78–86.
- Forzano, F., O. Antonova, A. Clarke, G. de Wert, S. Hentze, Y. Jamshidi, Y. Moreau, M. Perola, I. Prokopenko, A. Read, A. Reymond, V. Stefansdottir, C. van El, and M. Genuardi. 2021. The use of polygenic risk scores in pre-implantation genetic testing: an unproven, unethical practice. European Journal of Human Genetics. doi: 10.1038/s41431-021-01000-x.
PENDING
Third expert opinion by Prof. Steven J. Williams, Biological Sciences, Temple University
There has been much opinion, either as commentary in literature, meeting proceedings, or communiques from professional societies warning that this type of “high-impact” genetic information should not be given directly to the consumer as consumers will not fully understand the information presented to them, be unable to make proper risk-based decisions, results could cause panic and inappropriate action such as prophylactic oophorectomy or unwarranted risk-reduction mastectomy, or false reassurance in case of negative result and reduced future cancer screening measures taken by the consumer. However, there have been few studies to investigate these concerns.
The article by Kumar The alarming rise of complex genetic testing in human embryo selection
discusses the common trend of DTC (direct to consumer) and other genetic consutancy groups to offer disease risk assesment based on genetic predispostion genetic information in preimplantation embryos upon in vitro fertilization. Although this editorial discusses some caveats and potential ethical issues the opinion of this reviewer feels a certain number of key issues points have not been addressed (which will be discussed below) including:
- the underlying risk of disclosure of all parties involved in decision making based on genetic testing including other family members
- complicating ethical issues not addressed through proper guideline establishment and regulation as seen in countries that allow such advances to go without proper review board
- a lack of discussion of the health disparities which may result of this type of genetic information or “selection” where groups of people would be shut out of such services due to socioeconomic status
Although the editorial highlights the issue that most genome wide association studies, on which most of the genetic counseling is based upon is from cohorts of European descent (and misses a large cohort which is Asian or African descent), there is little attention given to the issue that most panels of these agreed upon risk associated variants have not been validated in larger GWAS studies or that these panels only focus on the most common variants. An example of this would be BRCA1/2 and assumed future breast cancer risk.
In the related article The uncertain science of preimplantation and prenatal genetic testing
Gleicher al state
PGS and PGT-A
diagnoses have been built on biologically
incorrect assumptions and on unvalidated
guidelines dating back to 2016. These
guidelines, which remain influential to this
day, were published without a description
of methods, without peer review, with no
author identification, and without any
references1
. The guidelines changed the
binary diagnosis of euploid and aneuploid
to normal, mosaic and aneuploid.
In fact most family risk assesment programs are more effective upon counseling of young women, not at the embryonic stage where genetic risk factors may not be evident or resulting from epigenetic changes or accumulated somatic mutation.
- Lack of communication to all related and involved parties
Many times it is women, who having undergone these testings, have problems in communicating these risk findings to their children and family members, resulting in familial strains.
For instance, some women who discover they have the BRCA gene mutation, which puts them at higher risk for breast cancer, choose to tell their children about it before the children are old enough to understand the significance or deal with it, a new study found.
“Parents with the BRCA mutation are discussing their genetic test results with their offspring often many years before the offspring would need to do anything,” said study author Dr. Angela Bradbury, director of the Fox Chase Cancer Center’s Family Risk Assessment Program, in Philadelphia.
According to Bradbury, more than half of parents she surveyed told their children about genetic test results. Some parents reported that their children didn’t seem to understand the significance of the information, and some had initial negative reactions to the news.
“A lot of genetic information is being shared within families and there hasn’t been a lot of guidance from health-care professionals,” Bradbury said. “While this genetic risk may be shared accurately, there is risk of inaccurate sharing.”
In the study, Bradbury’s team interviewed 42 women who had the BRCA mutation. The researchers found that 55 percent of parents discussed the finding and the risk of breast cancer with at least one of their children who was under 25.
Also, most of the women didn’t avail themselves of the services of a doctor or genetic counselor in helping to tell their children, Bradbury’s group found.
The identification of familial risk factors can have very stressful impacts on the affected and their family however an IVF selection might even augment that familial stress. More research is needed on the psychological impact of such testing and a patient’s choice.
2. Lack of health disparity considerations in IVF selection research or guidelines
Another major concern, which has been highlighted in multiple articles on this site, is the growing health disparities between those who can obtain access to quality health care and those who are left out in the void of the medical system, either for economic or sociological reasons. This has been very apparent in the cancer treatment and personalized medicine world (for example the disparities of health care access for cancer treatment in the southern poorer rural parts of the US versus metropolitan areas and the gaping disparities seen between rich and poor countries in Africa). These health disparities have been also apparant in the genetic testing market, and although the DTC market meant to make genetic testing more affordable, interestingly these disparities still exist in this niche market.
3. Lack of proper establishment of Institutional Review Board oversight in countries allowing this technique have been problematic with regard to addressing bioethical concerns
The third concern is, of course, a bioethical concern on the use of advanced genetic technologies in the human and clinical setting. It has come to many people’s attention at the speed at which countries that do not seem to have strong bioethical review boards readily allow this type of research to be carried out without regulatory oversight or consequence. A prime example of this included the shunned Chinese research carried out to produce cloned humans, which was rapidly condemmed in the biomedical world however this research was conducted nonetheless. This lack of attention is addressed in Kumar’s article yet little guidance is given as to best practices to establish review boards overseeing such work and or research.
SOURCE
https://www.nature.com/articles/d41586-022-00787-z
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