ABSTRACTStructural chromosomal variants [copy number variants (CNVs): losses/ gains and structural variants (SVs): inversions, balanced and unbalanced fusions/translocations] are important for diagnosis and risk-stratification of myelodysplastic syndromes (MDS). Optical genome mapping (OGM) is a novel single-platform cytogenomic technique that enables high-throughput, accurate and genome-wide detection of all types of clinically important chromosomal variants (CNVs and SVs) at a high resolution, hence superior to current standard-of-care cytogenetic techniques that include conventional karyotyping, FISH and chromosomal microarrays. In this proof-of-principle study, we evaluated the performance of OGM in a series of 12 previously well-characterized MDS cases using clinical BM samples. OGM successfully facilitated detection and detailed characterization of twenty-six of the 28 clonal chromosomal variants (concordance rate: 93% with conventional karyotyping; 100% with chromosomal microarray). These included copy number gains/losses, inversions, inter and intra-chromosomal translocations, dicentric and complex derivative chromosomes; the degree of complexity in latter aberrations was not apparent using standard technologies. The 2 missed aberrations were from a single patient within a composite karyotype, below the limit of detection. Further, OGM uncovered 6 additional clinically relevant sub-microscopic aberrations in 4 (33%) patients that were cryptic by standard-of-care technologies, all of which were subsequently confirmed by alternate platforms. OGM permitted precise gene-level mapping of clinically informative genes such as TP53, TET2 and KMT2A, voiding the need for multiple confirmatory assays. OGM is a potent single-platform assay for high-throughput and accurate identification of clinically important chromosomal variants.
Chromosomal microarray analysis, or comparative genomic hybridization: A high throughput approach