PREIMPLANTATION GENETIC TESTING: Preimplantation genetic testing for polygenic disease risk

Abstract

<jats:p>Since its introduction to clinical practice, preimplantation genetic testing (PGT) has become a standard of care for couples at risk of having children with monogenic disease, and for chromosomal aneuploidy to improve outcomes for patients with infertility. The primary objective of PGT is to reduce the risk of miscarriage and genetic disease and to improve the success of infertility treatment with the delivery of a healthy child. Until recently, the application of PGT to more common but complex polygenic disease was not possible, as the genetic contribution to polygenic disease has been difficult to determine, and the concept of embryo selection across multiple genetic loci has been difficult to comprehend. Several achievements, including the ability to obtain accurate, genome-wide genotypes of the human embryo, and the development of population level biobanks have now made PGT for polygenic disease risk applicable in clinical practice. With the rapid advances in embryonic polygenic risk scoring, diverse considerations beyond technical capability have been introduced.</jats:p>

Reproductive Embryo Editing: Attending to Justice

“…Fertility clinics also use PGT to identify chromosomal abnormalities. PGT could also be employed to identify complex (polygenic) conditions, such as congenital diabetes or cardiomyopathies, although fertility societies have not yet accepted the clinical utility of these procedures 23 …”

Three models for the regulation of polygenic scores in reproduction

“…13 The idea is that through aggregating the relative PS for multiple conditions, weighted based on population prevalence and quality-adjusted life years, we can generate one singular score to correlate with predicted health. 13 Someone with a lower genomic index score theoretically has a lower overall risk of developing a polygenic disease compared with someone with a higher score. When applied to a cohort of over 11 000 matched sibling pairs, a risk reduction was detected for all 11 conditions included in the genomic index score i when one sibling was selected via genomic index testing compared with random selection.…”

“…A series of papers with authors working at, or otherwise related to, the company Genomic Prediction argue and present data that ‘[s]everal achievements, including the ability to obtain accurate, genome-wide genotypes of the human embryo and the development of population-level biobanks, have now made PGT [preimplantation genetic testing] for polygenic disease risk applicable in clinical practice.’ 13 The idea is that through aggregating the relative PS for multiple conditions, weighted based on population prevalence and quality-adjusted life years, we can generate one singular score to correlate with predicted health. 13 Someone with a lower genomic index score theoretically has a lower overall risk of developing a polygenic disease compared with someone with a higher score. When applied to a cohort of over 11 000 matched sibling pairs, a risk reduction was detected for all 11 conditions included in the genomic index score i when one sibling was selected via genomic index testing compared with random selection.…”

Evolution and utility of preimplantation genetic testing for monogenic disorders in assisted reproduction - A narrative review

“…An emerging field now is PGT for polygenic disease risk. [ 91 92 93 ] Efforts are on linking the genetic constitution of the embryo to its morphology, implantation potential and transcriptome using single-cell RNA sequencing. [ 94 ]…”