Optical genome mapping improves clinical interpretation of constitutional copy number gains and reduces their VUS burden.

Abstract

Purpose: Genomic structure of copy number gains is critical for their clinical interpretation, but cannot be determined by chromosomal microarray (CMA) analysis, which does not provide information about chromosomal location and orientation of multiplied regions. We thus hypothesized that in CMA testing gains have higher probability than losses to be classified as VUS, and that structural information from Optical Genome Mapping (OGM) may improve their interpretation.

Methods: Using a chi-square test we assessed the association between classification of copy number variants as VUS and their type (gains vs. losses) in a cohort of 4,073 CMA cases. Thirty-three VUS gains involving disease-associated genes were characterized by OGM to evaluate if OGM data enables their more conclusive clinical interpretation.

Results: The proportion of variants reported as VUS compared to Likely-pathogenic/Pathogenic was significantly higher for gains than losses, confirming their increased VUS burden. OGM successfully determined genomic structure for all 33 copy number gains, showing that 26/33 were tandem duplications and 7/33 were complex rearrangements. Structural information facilitated clinical interpretation in majority of the cases; it supported benign nature for 27/33 gains and was inconclusive or supported pathogenic role for 6/33. An estimated 20% of reported VUS gains would not have been reportable if we had OGM data.

Conclusion: We illustrate a specific advantage of OGM compared to CMA: in addition to detecting both copy number variants and balanced rearrangements, OGM improves clinical interpretation of copy number gains by providing structural information, and is thus expected to significantly decrease their VUS burden.