Structural Variant Analysis of Complex Karyotype Myelodysplastic Neoplasia Through Optical Genome Mapping

ABSTRACT Myelodysplastic neoplasia with complex karyotype (CK‐MDS) poses significant clinical challenges and is associated with poor survival. Detection of structural variants (SVs) is crucial for diagnosis, prognostication, and treatment decision‐making in MDS. However, the current standard‐of‐care (SOC) cytogenetic testing, relying on karyotyping, often yields ambiguous results in cases with CK. Here, SV detection by novel optical genome mapping (OGM) technique was explored in 15 CK‐MDS cases, which collectively harbored 85 chromosomes with abnormalities reported by SOC. Additionally, OGM was utilized in the discovery of novel SVs. Altogether, OGM detected corresponding > 5 Mbp alterations for 73 out of 85 SOC reported abnormalities, resulting in an 86% concordance rate. OGM provided further specification of these abnormalities, revealing that 64% of the altered chromosomes were affected by multiple SVs or chromoanagenesis. Prominently, only 5% of missing chromosomes reported by SOC were true monosomies. In addition, OGM detected alterations in chromosomes not reported as abnormal by karyotyping in 93% of cases and provided clinically relevant gene‐level information, such as SVs in TP53, MECOM, NUP98, IKZF1, and ETV6. Analysis of novel SVs revealed two previously unreported gene‐fusions (SCFD1::ZNF592 and VPS8::LRBA), both confirmed by transcriptome sequencing. Furthermore, the repositioning of CCDC26 (8q24.21) was identified as a potential cause of inappropriate gene activation in two cases, affecting MECOM and SOX7, respectively. This study shows that OGM can significantly enhance the diagnostic analysis of SVs in CK‐MDS and highlights the utility of OGM identifying novel SVs in complex cancer genomes.