Optical genome mapping enables constitutional chromosomal aberration detection.

Area of Science:

• Genetics
• Genomics
• Molecular Biology

Background:

• Chromosomal aberrations and structural variations (SVs) are key drivers of human genetic diseases.
• Current detection methods like karyotyping and CNV microarrays have limitations in resolution and detecting balanced SVs.

Purpose of the Study:

• To evaluate the efficacy of optical genome mapping (OGM) in detecting constitutional chromosomal aberrations.
• To compare OGM's performance against standard cytogenetic tests.

Main Methods:

• Ultra-high-molecular-weight DNA was isolated from 85 samples and analyzed using OGM.
• De novo genome assembly was performed, followed by SV and copy number variant (CNV) calling and annotation.
• Results were benchmarked against standard-of-care tests (karyotype, FISH, CNV microarray).

Main Results:

• OGM analyzed 99 chromosomal aberrations, including aneuploidies, deletions, duplications, translocations, inversions, and complex rearrangements.
• High-resolution OGM achieved 100% concordance with standard assays for aberrations with non-centromeric breakpoints.
• The study identified variants in complex genomic regions associated with microdeletion/microduplication syndromes.

Conclusions:

• OGM demonstrates significant potential for comprehensive detection of diverse chromosomal aberrations and SVs.
• OGM offers a cost-effective and user-friendly alternative, paving the way for "next-generation cytogenetics."
• Filtering strategies are proposed to prioritize clinically relevant findings, with future improvements discussed.