O-088 Whole transcriptome and genome sequencing of standard embryo biopsies can potentially reduce failed euploid transfers

Abstract Study question Can whole transcriptome sequencing (WTS) of embryos and whole genome sequencing (WGS) of parents and embryos identify variants associated with embryo viability? Summary answer WGS/WTS can identify variants from conventional biopsies that are potentially associated with embryo viability, likely reducing failed euploid transfers. What is known already Since 45% of euploid transfers fail, and up to 95% of patients will achieve a pregnancy and live birth if enough euploid embryos are transferred, euploid failures are likely embryonic in origin. Further, they are likely due to the genetics of the embryo (beyond ploidy) since WGS studies of pregnancy loss, stillbirth and perinatal death demonstrate that 50% of euploid cases are due to single nucleotide variants (SNVs). WGS/WTS of parents and embryos has the potential to reduce failed euploid transfers by identifying SNVs that may be associated with reduced embryo viability and deprioritizing those embryos. Study design, size, duration The study was conducted on donated embryos, regardless of ploidy status. Variants were evaluated independently of ploidy, as they are expected to segregate independently. Parents who did not use donor gametes and had completed their fertility treatment were offered participation in the study. Parents were consented to the study by their treating physician and blood samples were provided for WGS. The study included 30 donated embryos from seven families (2-7 embryos/family). Participants/materials, setting, methods WGS/WTS (50x depth) was performed on at least two samples per donated embryo, including the remainder. WGS (30x depth) was performed for each parental blood sample. Genes were considered essential to embryo viability based on product of conception (PoC) and CRISPR-Cas9 knockout studies. Variants were annotated based on in vivo, in vitro, and computational evidence available in human data resources and published scientific work. Main results and the role of chance Twelve of 30 embryos (40%) were found to have predicted pathogenic, likely pathogenic or pathogenic SNVs associated with reduced embryo viability. Variants segregated independent of chromosome abnormalities, as expected. Among the 12 embryos with variants, 7 embryos had compound heterozygous SNVs in genes associated with autosomal recessive inheritance, 6 male embryos had hemizygous SNVs in genes associated with X-linked recessive inheritance (variants were confirmed to be maternally inherited) and 2 embryos had de-novo SNVs, believed to be de-novo because they were not inherited from either parent and not observed in any population databases (note the sum is greater than 12, as some embryos had multiple variants detected). Since sequencing was performed on multiple samples, the likelihood of a false positive variant call is less than 1%. Given the rate of detectable SNVs in this study is consistent with the 50% reported in the literature, we estimate that prioritizing euploid embryos without SNVs associated with reduced embryo viability could reduce failed euploid transfers by up to 50%. Further reductions could likely be achieved by including additional genetic variation, such as structural variants and copy number variants. Limitations, reasons for caution The reduction in failed euploid transfers can only be estimated at this time. Observational studies of pregnancy and live birth rates, based on transfers using WGS results are currently under way. Wider implications of the findings Reducing failed euploid transfers by prioritizing euploid embryos without SNVs that may be associated with reduced embryo viability could further improve live birth rates per embryo transfer and thereby save aspiring parents time, expense and anxiety in their IVF journeys. Trial registration number No

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