Nathan R. Treff

Polygenic risk scores (PRSs) can reduce lifetime disease risk by guiding embryo selection during in vitro fertilization (IVF). We performed genome-wide association meta-analyses totaling ∼1.5 million individuals to construct state-of-the-art PRSs for nine diseases: Alzheimer’s disease, breast cancer, coronary artery disease, endometriosis, hypertension, prostate cancer, rheumatoid arthritis, type 1 diabetes, and type 2 diabetes. The resulting predictors achieved liability-scale R ² values of up to 22.9% for type 2 diabetes, matching or exceeding previously published benchmarks across all scores. Three PRS - Alzheimer’s disease, prostate cancer, and type 2 diabetes - explained over 75% of the common-SNP heritability. Within-family validation in 40,872 siblings across 18,840 families showed that, for eight of nine diseases, predictive performance was comparable to population-level results, confirming substantial direct genetic effects. Modeling of embryo selection suggests that couples with five euploid embryos could achieve 27-67% relative risk reduction across diseases. While the limitations of genetic data availability meant that these estimates were performed in European ancestry samples, we performed validation in the multi-ancestry US-based All of Us Biobank, demonstrating significant statistical power across ancestries. These findings support the clinical applicability of PRS-guided embryo selection to reduce the burden of common diseases.

Cas9 provides a powerful tool to interrogate DNA repair and to introduce targeted genetic modifications. However, a major challenge of Cas9-based editing in human embryos is the occurrence of chromosomal abnormalities caused by Cas9 cleavage. Furthermore, mosaicism - different genetic outcomes in different cells, prevent accurate genotyping using a single embryo biopsy. Through timed analysis of editing outcomes during the first cell cycle and timed inhibition of Cas9 using AcrIIA4, we show that most edits occur at least 12 hours post Cas9 injection and therefore after the first S-phase. This timing limits the ability to achieve uniform editing across cells. We found that segmental chromosomal abnormalities and the consequential loss of heterozygosity are common at Cas9 cleavage sites throughout the genome, including at MYBPC3 and at CCR5 loci, for which this has not previously been reported. Surprisingly, inhibiting Cas9 activity 8-12 hours before mitosis does not eliminate chromosomal aneuploidies. This suggests that double-strand break (DSB) repair in human embryos is exceedingly slow, with breaks remaining unrepaired for many hours. Thus, the timing of DSB induction and repair relative to the first S-phase and the first mitosis is intrinsically limiting to preventing mosaicism and maintaining genome stability in embryonic gene editing.

Purpose: This study aimed to evaluate whether a high-throughput high-resolution PGT-A method can detect copy number variants (CNVs) that could have clinical implications for patients and their embryos. Methods: A prospective analysis of PGT-A cases was conducted using a high-resolution SNP microarray platform with over 820,000 probes. Cases where multiple embryos possessed the same segmental imbalance were identified, and preliminary PGT-A reports were issued recommending either parental microarray or conventional karyotyping to identify CNVs or translocations. Results: Analysis of 6080 sequential PGT-A cases led to identification of 41 cases in which incidental findings were observed (0.7%) and parental testing was recommended. All cases, in which parental studies were completed, confirmed the original PGT-A incidental findings. In 2 of the cases, parental studies indicated a pathogenic variant with clinical implications for the associated embryos. In one of these cases, the patient was identified as a carrier of a duplication in chromosome 15q11.2:q11.2 (SNRPN + +), which is associated with autism spectrum disorder. In the second case, the patient was heterozygous positive for an interstitial deletion of 3p26.1:p26.3, which is associated with 3p deletion syndrome and had clinical implications for the patient and associated embryos. In each case, parental studies were concordant with PGT-A findings and revealed the presence of an otherwise unknown CNV. Conclusion: High-throughput high-resolution SNP array–based PGT-A has the ability to detect previously unknown and clinically significant parental deletions, duplications, and translocations. The use of cost-effective SNP array–based PGT-A methods may improve the effectiveness of PGT by identifying and preventing previously unknown pathogenic CNVs in children born to patients seeking in vitro fertilization.

Machine learning methods applied to large genomic datasets (such as those used in GWAS) have led to the creation of polygenic risk scores (PRSs) that can be used identify individuals who are at highly elevated risk for important disease conditions, such as coronary artery disease (CAD), diabetes, hypertension, breast cancer, and many more. PRSs have been validated in large population groups across multiple continents and are under evaluation for widespread clinical use in adult health. It has been shown that PRSs can be used to identify which of two individuals is at a lower disease risk, even when these two individuals are siblings from a shared family environment. The relative risk reduction (RRR) from choosing an embryo with a lower PRS (with respect to one chosen at random) can be quantified by using these sibling results. New technology for precise embryo genotyping allows more sophisticated preimplantation ranking with better results than the current method of selection that is based on morphology. We review the advances described above and discuss related ethical considerations.