Copy-Neutral Loss of Heterozygosity in Myelofibrosis

Myelofibrosis (MF) is a hematologic malignancy with a highly heterogeneous clinical course. Copy-neutral loss of heterozygosity (CN-LOH) may contribute to disease progression by promoting mutation homozygosity. Although single-nucleotide polymorphism (SNP) arrays are the gold standard for CN-LOH detection, optical genome mapping (OGM) has emerged as a promising alternative. In this multicenter study, the capability of OGM to detect CN-LOH in 78 patients with MF was assessed. OGM data were analyzed using both de novo (DN) and guided assembly pipelines (GA), followed by re-analysis of CN-LOH-positive cases with the Variant Intelligence Applications (VIA) software. Results were validated with SNP arrays. Compared with 45% for GA and 37% for DN, VIA demonstrated the highest concordance, confirming 90% (46/51) of CN-LOH events found by SNP arrays. Although VIA maintained a high concordance (90%) for all event sizes, GA (70%) and DN (61%) showed improved concordance for larger events (≥25 Mb). VIA also identified six CN-LOH events in 9p involving the JAK2 gene that were missed by DN and GA. Among 19 CN-LOH events detected by all three pipelines, 89% were confirmed by SNP arrays. Events ≥25 Mb exhibited greater concordance across platforms. These findings demonstrate that OGM, particularly when analyzed with VIA, is a sensitive and reliable method for CN-LOH detection in MF. However, in the absence of broader validation, confirmation with orthogonal methods remains necessary.