To the Editor:

Yang et al. recently published their work entitled “High-resolution structural variant profiling of myelodysplastic syndromes by optical genome mapping uncovers cryptic aberrations of prognostic and therapeutic significance” in leukemia [1]. The authors describe a high concordance in 96/99 cases of detected structural variants by routine diagnostics, most importantly chromosomal banding analysis (CBA), and optical genome mapping (OGM) as a whole genome method for structural variant profiling (SVP). More importantly, in 34% of the 101 patients included in the analysis, cryptic variants could be clarified and the risk score according to R-IPSS was changed by additional information obtained by OGM in 17% of patients.

These results and the approach chosen are well in line with the data published earlier this year by our group [2]. Although focusing on acute myeloid leukemia (AML), we also included a subgroup of six myelodysplastic syndrome (MDS) patients, three of them with excessive blasts I and three with excessive blasts II, or MDS/AML according to the recently updated international consensus classification [3]. Furthermore, 8 of 21 AML patients had myelodysplasia-related changes.

Currently, and updating our previous data, our cohort consists of 42 patients (35 AML and 7 MDS, Table 1). Of 42 patients, a conventional diagnostic approach by cytogenetics (CBA; fluorescence in situ hybridization (FISH) and Copy-number variation (CNV)-microarrays where indicated) was able to detect variants in 26 cases. All but three of these variants could also be seen by OGM, the latter below the applied threshold of 5% variant allele frequency (VAF) and in high-repetitive regions such as around telomers and centromeres [4]. In 27 cases (64%), we could clarify or add additional information by using OGM as a non-DNA dependent amplification based whole genome method. For MDS patients this number was similar with 4/7 cases, where the karyotype could be redefined by utilizing OGM (Table 2).

Table 1 Clinical characteristics of the study population.
Full size table
Table 2 Conventional diagnostics included karyotyping, RT-PCR Panel diagnostics, FISH, and CNV microarray, the latter two as indicated by the treating physician.
Full size table

Based on these data, we recently proposed a next-generation work up applying targeted sequencing and a cytogenomics or structural variant profiling approach [5]. This approach does not only identify single nucleotide variants addressable for risk stratification or for targeted therapy such as NPM1, IDH1, or IDH2. It gives a detailed picture of structural variants by OGM as a single method, allowing to further refine risk stratification and subsequently personalize treatment. Furthermore, this unbiased method with a limited need for time-consuming data interpretation helps discover so far unknown structural variants. In an exemplary case, we were able to identify a DDX3X::MLLT10 fusion which might play a causative role in the development of this AML. Additionally, the combination of methods uncovered a genetically biphenotypic disease, which was classified as AML with recurrent genetic aberrations by standard diagnostic procedures [5].

We want to thank Yang and colleagues for analyzing this remarkable single-center cohort and adding evidence to our previous work. We think optical genome mapping can be of relevant diagnostic importance not only in MDS and AML patients but also in a variety of hematological malignancies [6, 7].