Abstract
For over 2 decades preimplantation genetic testing (PGT) has been in clinical use to reduce the risk of miscarriage and genetic disease in patients with advanced maternal age and risk of transmitting disease. Recently developed methods of genome-wide genotyping and machine learning algorithms now offer the ability to genotype embryos for polygenic disease risk with accuracy equivalent to adults. In addition, contemporary studies on adults indicate the ability to predict polygenic disorders with risk equivalent to monogenic disorders. Existing biobanks provide opportunities to model the clinical utility of polygenic disease risk reduction among sibling adults. Here, we provide a mathematical model for the use of embryo screening to reduce the risk of type 1 diabetes. Results indicate a 45–72% reduced risk with blinded genetic selection of one sibling. The first clinical case of polygenic risk scoring in human preimplantation embryos from patients with a family history of complex disease is reported. In addition to these data, several common and accepted practices place PGT for polygenic disease risk in the applicable context of contemporary reproductive medicine. In addition, prediction of risk for PCOS, endometriosis, and aneuploidy are of particular interest and relevance to patients with infertility and represent an important focus of future research on polygenic risk scoring in embryos.
Highlights
Contemporary preimplantation genetic testing (PGT) is a well-established method for reducing the risk of adverse outcomes in in vitro fertilization (IVF)
In the first application of PGT for polygenic disease risk, 6 embryos were tested for aneuploidy and for lifetime risk of type 1 diabetes, type two diabetes, breast cancer, testicular cancer, prostate cancer, basal cell carcinoma, malignant melanoma, heart attack, atrial fibrillation, coronary artery disease, hypertension, high cholesterol
This study demonstrates the clinical utility of PGT for type 1 diabetes risk reduction, ranging from 45 to 72% in families with an affected individual
Summary
Contemporary preimplantation genetic testing (PGT) is a well-established method for reducing the risk of adverse outcomes in in vitro fertilization (IVF). PGT-A (aneuploidy screening) reduces the risk of miscarriage, implantation failure, and multiples without compromising success rates [1, 2]. Given the maternal age-related increase in aneuploidy, PGT-A has been shown to be important in older women [3]. PGT-SR (structural rearrangements) is widely used by couples which carry a balanced translocation or other structural rearrangement, in order to reduce the risk of miscarriage and to prevent disease associated with an unbalanced karyotype [4]. PGT-M (monogenic disease) has helped prevent many serious conditions in children born to at risk parents [5]. As with any new application in reproductive medicine, PGT for Polygenic Disease the recent introduction of PGT-P (for polygenic disease risk reduction) has been met with both criticism and enthusiasm
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