7. Optical genome mapping for prenatal diagnostic testing

Abstract

The current standard-of-care (SOC) for diagnostic prenatal testing incorporates a combination of cytogenetic technologies that include karyotyping, FISH, and chromosomal microarray (CMA) using cultured amniocytes or chorionic villi sampling (CVS). However, each technology has certain limitations viz. karyotyping has low resolution (>5Mb), FISH is targeted, and CMA does not detect balanced SVs or decipher complex rearrangements in the genome. The result of these limitations is the requirement to use multiple technologies to reach a genetic diagnosis. The current diagnostic prenatal testing workflow demonstrates the need for an alternative technology that can provide results in a cost and time-effective manner. Optical genome mapping (OGM) is an emerging technology that has demonstrated its ability to detect all classes of structural variants (SVs), including copy number variations (CNVs) and balanced aberrations in a single assay, but has not been evaluated in prenatal setting. Herein, we evaluated 80 prenatal amniocyte cases using OGM that were previously characterized by SOC technologies (Karyotype and FISH/CMA). Three samples were run in triplicate to evaluate inter-run, intra-run and inter-instrument reproducibility. Clinically relevant SVs and CNVs were reported using built-in filtration criteria and phenotype-specific analysis. OGM data was found to be 100% concordant with conventional cytogenetic analyses. In addition to identifying previously characterized SVs, OGM identified additional aberrations and demonstrated a higher resolution and sensitivity to accurately define SVs w.r.t size and location. Furthermore, OGM demonstrated 100% technical and analytical reproducibility across runs and instruments. This study demonstrated that OGM has the potential to identify all classes of SVs, including complex structural rearrangements. OGM has a standardized laboratory workflow and reporting solution that can be easily adopted in routine clinical laboratories. In conclusion, OGM has the potential to replace the current SOC methods for prenatal diagnostic testing and can be used as first-tier genetic test in prenatal setting.