Completely resolved structural variants by optical genome mapping with adaptive sampling from CNV discovery

Structural variants (SVs), including duplications, deletions, inversions, translocations, and insertions, contribute to human phenotypic diversity but are often challenging to identify due to their size variability and complex configurations. Optical genome mapping (OGM) uses ultra-high molecular weight DNA (> 150 kb) fluorescently labeled at a specific six-nucleotide sequence, enabling comprehensive SVs detection by analyzing labeling patterns along long DNA molecules. This study aimed to fully characterize SVs using OGM.OGM was applied to 30 cases with exome sequencing-based copy number variants (16 deletions, seven duplications, and seven deletions and duplications). Additionally, targeted Oxford Nanopore long-read sequencing with adaptive sampling was used to determine breakpoints of SVs. This approach revealed undetected SVs in 14 cases (46.7%), and disclosed gene disruptions or copy number alterations explaining clinical features in eight cases (26.7%).Even complex SVs involving numerous chromosomal segments and breakpoints were resolved efficiently, highlighting the power of combining OGM and long-read sequencing.