First clinical validation of whole genome screening on standard trophectoderm biopsies of preimplantation embryos

Abstract

Whole Genome Sequencing (WGS) is used in healthcare and in the clinic, with the notable exception of preimplantation genetic testing (PGT). In PGT, only a few cells are available for sequencing, requiring DNA amplification which reduces data quality, sequence fidelity and sharply limits subsequent clinical impact. Here we demonstrate the first clinical validation of WGS on embryo biopsies using our lab development protocol, opening the door to broad use of WGS in fertility. We find that amplified DNA with comparable sensitivity and specificity to genomic DNA when performing whole genome sequencing assays. DNA amplification on cell lines and donated human embryos had an amplification success rate of >99.9% and 98.2% respectively and accuracy on both was >99.9% on aneuploidy status. GIAB samples (Genome in the Bottle reference NA12878) showed that our amplified DNA was broadly comparable to genomic DNA (99.99% accuracy, 99.99% specificity, 98.0% sensitivity and 98.1% precision). Using our assay, we were able to call variants, detect mitochondrial heteroplasmy, perform high precision screening without access to parental genomes, detect compound heterozygous variants, and score microdups/dels and uniparental disomies (to reduce risk of diseases such as DiGeorge syndrome and Prader-Willi syndrome). Our clinical study suggests that the full spectrum of traditional clinical genome bioinformatics, so far reserved to large samples, can now be performed on embryos before implantation.