Evaluating concordance of preimplantation genetic testing-whole-genome sequencing with genetic findings in live-born children.

OBJECTIVE

To clinically assess concordance between preimplantation genetic testing-whole-genome sequencing (PGT-WGS) and whole-genome sequencing results from corresponding live-born children, including evaluation of genome-wide variants, targeted gene panels, de novo variants, and genetic risk scores.

DESIGN

Patients underwent a standard in vitro fertilization workflow with PGT-WGS. After pregnancy or live birth, patients were contacted for consent to participate in this study. This small study included 10 biopsy-child pairs. Deoxyribonucleic acid (DNA) samples were collected from children, and whole-genome sequencing was performed accordingly. Genetic findings from PGT-WGS were compared with the child's whole-genome sequencing results. For de novo variant assessment (3 biopsy-child pairs), parental samples were also requested.

SUBJECTS: Clinical trophectoderm biopsy samples, corresponding live-born children, and parental DNA samples.

EXPOSURE: No applicable.

MAIN OUTCOME MEASURES: Variant concordance across the whole genome and within designated gene panels; concordance of clinically relevant variants and de novo variants; concordance of functionally significant single-nucleotide polymorphisms (SNPs), including HLA and APOE; and resulting genetic risk scores.

RESULTS

Analysis of single-nucleotide variants (SNVs) and insertions/deletions (indels) identified an average of 3,562,534 variants genome-wide and 2,656 variants within the 1,200-gene panel per embryo-child pair, yielding a sensitivity of 97.6% and a precision of 98.4% on genome and 98.4% and 98.7% respectively, on monogenic panels.Traditional PGT approaches do not enable prospective screening for de novo variants. In this study, all 42 confirmed de novo variants detected in live-born children were also identified in the corresponding PGT-WGS results. High concordance (>99%) was observed on HLA, APOE, as well as SNPs used for genetic risk scores.

CONCLUSION

This study provides a small clinical study comparing PGT-WGS results with whole-genome sequencing findings in live-born children. Preimplantation genetic testing-whole-genome sequencing, offered using an opt-in panel of approximately 1,200 genes, demonstrated high sensitivity and precision and enabled direct interrogation of the trophectoderm genome. It has the feasibility to identify de novo variants.