Integrative approach for delineating structural variants using optical genome mapping and long-read genome sequencing

Area of Science:

• Genomics
• Human Genetics

Background:

• Structural variants (SVs) are significant contributors to human genetic disorders.
• Traditional cytogenetic and short-read sequencing methods often fail to fully resolve complex SVs.
• Long-read sequencing (LRS) and optical genome mapping (OGM) offer advanced capabilities for SV detection.

Purpose of the Study:

• To evaluate the combined utility of OGM and LRS for precise characterization of clinically relevant chromosomal rearrangements.
• To assess the diagnostic yield of an integrated OGM and LRS approach for complex SVs.

Main Methods:

• Investigated five patients with suspected chromosomal abnormalities using standard methods (karyotyping, FISH, CMA, TP-PCR).
• Applied integrative analysis with OGM and LRS for comprehensive SV detection.
• Compared the resolution capabilities of OGM and LRS for various types of structural variants.

Main Results:

• OGM identified genome-wide structural insights, while LRS provided nucleotide-level breakpoint resolution.
• The combined approach successfully delineated complex SVs, including insertions, translocations, inversions, microdeletions, and fusions, in five patients.
• Novel rearrangements were identified in four out of five cases, demonstrating the power of this integrated strategy.

Conclusions:

• The combined application of OGM and LRS enables comprehensive characterization of complex SVs.
• This integrative approach significantly improves diagnostic yield for patients with genetic disorders.
• The findings support the implementation of OGM and LRS in clinical settings for SV detection and genotype-phenotype correlation.