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

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 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. ### Competing Interest Statement SL YX BP TG MK DC Nathan S and Noor S are members of Orchid Health, which performed this research and offers clinical preimplantation genetic testing. BB is a member of Orchid Health's scientific advisory board. ### Funding Statement Funding for this research was provided by Orchid Health. All authors performed this work as part of their employment or affiliation with Orchid Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: WCG Clinical Services gave ethical approval for this work under IRB 20222645. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes There are restrictions to the availability of the sequencing data analyzed in this study due to concerns for the privacy and confidentiality of the sequenced child and parents. Subsets of the data may be available from the corresponding authors on request.