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.

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Whole genome screening is currently not available in preimplantation genetic testing (PGT) due to poor performance of whole genome amplification methods. Here, we present the first validation study using our latest whole genome amplification (WGA) protocol, which yields amplified DNA with comparable quality to genomic DNA when perfoming whole genome sequencing assays. We started by validating PGT for aneuploidy (PGT-A) using our WGA protocol on cell lines and donated human embryos, where amplification success rates were >99.9% and 96.2% respectively. Accuracy on both was >99.9% on aneuploidy status. We next validated whole genome sequencing using amplified and genomic DNA from the Genome in the Bottle reference sample NA12878 to demonstrate accuracy, specificity, sensitivity, and precision of our WGA methods. Amplified DNA and genomic DNA are comparable in this case, with 99.99% accuracy, 99.99% specificity, 98.0% sensitivity and 98.1% precision with our WGA protocol. We additionally examined variant calls between biopsies and the remaining embryos from which they were derived. Again, 99.99% accuracy, 99.99% specificity, 98.1% sensitivity and 98.0% precision were observed. Mitochondrial heteroplasmy between biopsies and embryos was validated, and 99.9% accuracy, 100% specificity, 99.1% sensitivity and 100% precision were observed. Finally, we demonstrated the ability to improve the accuracy of certain types of mendelian variants in our data to close to 100% by leveraging parental and a born child’s genome to perform linkage analysis.

hormone concentration-time curve, and MVT-602 PK parameters were determined. RESULTS: The median (minimum, maximum) change from baseline for peak serum LH response were 3.5 (1.1, 25.5), 10.0 (2.9, 75.4), and 8.1 (3.1, 11.9) IU/L for the three escalating MVT-602 doses (0.3, 1, or 3 mg, respectively) with little change observed in the placebo group, 3.6 (0.0, 6.1) IU/L. The peak LH response generally occurred 24 hours postdose and returned to baseline approximately 72 hours postdose. An area-under the serum LH curve also showed a plateauing, albeit less variable, doseresponse relationship. The day of dosing relative to menstrual start and baseline LH concentration appeared to positively correlate with response. Increases in serum E2 appeared to correlate with LH response. Little dosedependent changes in FSH or P were observed. The peak plasma MVT-602 concentration was observed $30 minutes post-dose, suggesting rapid absorption from the injection site; the plasma half-life was <3 hours. MVT-602 was well tolerated; no serious adverse events (AEs) or severe AEs were reported. The most frequent treatment-emergent AE was headache (placebo n¼3; 0.3 mg n¼3; 1 mg n¼3; 3 mg n¼4). No dose response was observed for any AE. CONCLUSIONS: MVT-602 stimulated the release of LH and was welltolerated when administered to healthy premenopausal women in the follicular phase. The dose-dependent changes in serum LH suggest MVT-602 is a promising agent to stimulate the hypothalamic-gonadotropin axis and trigger oocyte maturation and ovulation. Supported by: Sponsored by Myovant Sciences GmbH.

Whole-genome sequencing of preimplantation human embryos (PGT-WGS) is not currently performed due to the insufficient quality of amplified DNA from embryo biopsies. Here we present a PGT-WGS approach that takes advantage of the improved genome coverage and uniformity of primary template-directed amplification (PTA) to call almost all early embryo genetic variants accurately and reproducibly from a preimplantation biopsy. In a research sibling cohort, we identified clonal and mosaic chromosomal aneuploidy, de novo mitochondrial variants, and variants predicted to cause mendelian and non-mendelian diseases. In addition, we utilized the genome-wide data to compute polygenic risk scores for common diseases. Finally, we performed a clinical study on the parents and 8 sibling embryos of an infant with neonatal-onset seizures and severe developmental delay. We first used low-pass whole genome sequencing to identify embryos most likely to successfully implant based on aneuploidy. We then performed PGT-WGS and evenly covered a mean of 99.1% of the embryo genomes at least 10X, resulting in the detection of 99.5% of parental variants and enabling us to screen genome-wide for inherited and de novo genetic variants in each embryo using ACMG rules. Although numerous computational, interpretive, and ethical challenges remain for widespread implementation, this study establishes the technical feasibility of screening for and preventing numerous debilitating genetic diseases with PGT-WGS.