Optical genome mapping as a high-resolution tool for uncovering cytogenetic complex and cryptic alterations in a cohort of patients with MDS and AML.

Cytogenetic and molecular studies are the standard of care in the diagnosis of myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML), which are characterized by a highly heterogeneous genetic landscape. This complexity challenges accurate characterization, risk stratification, and treatment decision-making. Optical Genome Mapping (OGM) is emerging as a high-resolution technique capable of detecting cryptic structural variants (SVs) and copy number changes (CNVs). In this study, we analyzed 150 MDS and AML patients using standard diagnostic methods and complemented by OGM to assess its utility in resolving complex karyotypes and uncovering hidden genomic aberrations. The results revealed novel alterations and refined previous cytogenetic results (e.g., breakpoints, translocation partners) in 80% of cases, involving clinically relevant genes such as MECOM, KMT2A, and NUP98. Importantly, in complex karyotypes, undefined marker chromosomes and chromoanagenesis events were resolved by OGM, uncovering genomic aberrations with potential clinical relevance. Overall, our findings demonstrate that OGM enables a more comprehensive genomic characterization of patients, uncovering cryptic genomic alterations and resolving complex karyotypes in AML and MDS. The identified abnormalities have shown significant and potential clinical implications. Additionally, the discovery of novel alterations could offer insights into previously unknown pathogenic mechanisms, enhancing our understanding of AML and MDS pathogenesis.