Long-read sequencing unmasks a cryptic three-way translocation resulting in an ETV6::PDGFRB fusion.

Abstract

Background: Myeloid/Lymphoid Neoplasms (MLN) with eosinophilia and PDGFRB rearrangements are rare but distinct hematologic malignancies driven by the constitutive activation of the PDGFRB tyrosine kinase through gene fusions. These neoplasms are sensitive to tyrosine kinase inhibitors (TKIs) such as imatinib, which often leads to rapid and durable molecular remissions. However, diagnostic challenges frequently arise from cryptic rearrangements, necessitating comprehensive molecular approaches.

Case presentation: A 37-year-old male patient initially presented with pancytopenia and a splenic infarct; subsequent bone marrow findings were suggestive of a myeloid/lymphoid neoplasm. Initial conventional cytogenetic analysis and fluorescence in situ hybridization (FISH) identified a PDGFRB gene rearrangement but were unable to fully resolve the structural complexity of the underlying genomic alteration. Long-read sequencing helped resolve a complex three-way translocation involving chromosomes 5, 12, and 20, precisely defining the ETV6::PDGFRB fusion with base pair resolution, and identified the partner gene (KAT14) on chromosome 20p. Following the diagnosis, the patient was started on imatinib therapy and has since achieved clinical and hematological improvement.

Conclusion: This case highlights the significant diagnostic utility of long-read sequencing in uncovering and characterizing cryptic and complex genomic rearrangements that are frequently missed by conventional methods. Accurate molecular characterization is critical for disease classification, guiding targeted therapeutic decisions, and ultimately improving patient outcomes in PDGFRB-rearranged neoplasms.