Concordance of whole-genome amplified embryonic DNA with the subsequently born child

Abstract

Before implantation subsequent to in vitro fertilization (IVF), the current options for Preimplantation Genetic Testing (PGT) are PGT for Aneuploidy (PGT-A) and, if clinically indicated, PGT for monogenic conditions (PGT-M). A more comprehensive approach involves PGT whole genome sequencing (PGT-WGS). PGT-WGS incorporates PGT-A, screens for hundreds of monogenic conditions, and can evaluate polygenic risk. Here for the first time, we compare PGT-WGS results against the genome of the subsequently born child. We demonstrated high levels of concordance (both in sensitivity and precision) in exome variant calls between amplified embryonic DNA and sequenced fetal cord blood. This concordance was higher when filtering against 1300 targeted monogenic conditions implicated in birth defects, neurodevelopmental disorders, and hereditary cancer. To evaluate PGT-WGS's ability to identify de novo variants we compared the child's genome to parental genomes and demonstrated that PGT-WGS successfully identified 5/5 confirmed de-novo variants. We further demonstrated concordance in polygenic risk scores calculated for both the embryo and the subsequently born child. This agreement extended to both traditional polygenic scores and oligogenic scores (Type 1 diabetes, Celiac disease, and Alzheimer's Disease), which heavily rely on accurate genotyping of HLA and APOE sites. To our knowledge, this is the first direct concordance study between a whole-genome sequencing of a trophectoderm biopsy and the DNA of the subsequently born child. By demonstrating a high degree of whole-exome concordance and adept detection of de novo variants, this approach showcases PGT-WGS's capability to identify genetic variants not explicitly targeted for monogenic screening.