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5. Comparative benchmarking of optical genome mapping to chromosomal microarray reveals high technological concordance in CNV identification and additional structural variant refinement

      Children with developmental delays and/or congenital anomalies with suspected genetic etiology are often tested for structural variation (SVs) by chromosomal microarray (CMA). Because copy number variants (CNVs) are often found to be causative, CMA is recommended as a first-tier testing for many indications. Optical genome mapping (OGM) is an accurate technique for enabling the detection of CNVs similar to a CMA, but with added benefit of detecting balanced rearrangements and repeat array analysis. This study compares OGM to CMA for genomic variants, some of which have additional validation and positional information by fluorescence in situ hybridization (FISH).  OGM was performed on samples from 55 subjects with CNVs and regions of absence of heterozygosity (AOH) previously identified by CMA. SVs identified by OGM were filtered by a control sample SV database (N=297) to remove most polymorphic variants and then by a gene list to prioritize relevant findings before comparison with CMA results. We evaluated the performance of OGM in comparison with CMA for 61 reported abnormalities from the 55 subjects with variable phenotypes. OGM successfully identified CNVs SVs, and AOH in samples previously tested with CMA. OGM results showed 98% concordance with CMA while also characterizing the genomic structure for CNVs such as unbalanced translocations and duplications (location and orientation defined). The structures were consistent with FISH results.  OGM has sufficient analytical validity to detect variants identified by CMA. OGM can also identify rearrangements (otherwise requiring FISH) within a single assay on a genome wide scale providing added utility compared to CMA.
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