Optical Genome Mapping for Chromosomal Aberrations Detection-False-Negative Results and Contributing Factors

Area of Science:

• Genomics
• Clinical Genetics
• Molecular Diagnostics

Background:

• Optical genome mapping (OGM) is a comprehensive technology for detecting chromosomal aberrations.
• Limitations exist in OGM's detection range for certain genetic variations.

Purpose of the Study:

• To identify and analyze chromosomal aberrations missed by OGM.
• To investigate factors contributing to OGM's false-negative results.

Main Methods:

• OGM was performed on 123 samples with 154 reported variations, using both GRCh37 and GRCh38 reference genomes.
• Results were compared to standard assays, with analysis of QC metrics, sample types, reference genome, coverage, and aberration characteristics.
• False-negative cases were examined for breakpoint locations and repetitive sequences.

Main Results:

• OGM missed 6.5% of aberrations with GRCh37, including copy number variations (CNVs), translocations, and inversions.
• Using GRCh38 reduced the false-negative rate to 4.5%.
• Missed aberrations had breakpoints in segmental duplication (SD) regions or areas lacking DLE-1 labels.

Conclusions:

• Structural variations (SVs) with breakpoints in large repetitive sequences or centromeric regions may be missed by OGM.
• GRCh38 is the recommended reference genome for OGM to enhance accuracy.
• Understanding OGM's limitations is crucial for effective clinical application.