Cryptic Fusion Due to Insertion into in a Patient with Acute Monoblastic Leukemia.

Background: rearrangements occur in ~10% of acute myeloid leukemia (AML) cases and are critical for classification, risk stratification, and use of targeted therapy. However, insertions involving the gene can evade detection using chromosomal analysis and/or fluorescence in situ hybridization (FISH).

Methods: We present a case of a 22-year-old woman with acute monoblastic leukemia harboring a cryptic fusion identified by RNA sequencing. Initial FISH showed a 3' deletion, while conventional karyotyping and the automated bioinformatic pipeline for optical genome mapping (OGM) did not identify the canonical translocation.

Results: To resolve these discrepancies, metaphase FISH (break-apart fusion probe) was performed to assess whether was translocated to another chromosome. However, the results did not support this possibility. As the fusion signal remained on the normal chromosome 11, with the 5' signal localized to the derivative chromosome 11. A subsequent manual review of the OGM data revealed a cryptic ~300 kb insertion of into the 3' region of , reconciling the discrepancies between chromosomal analysis, FISH, and RNA fusion results.

Conclusions: This case highlights the importance of integrating multiple testing modalities with expert review when there is a discrepancy. Our findings emphasize the need for a comprehensive approach to genomic assessment to enhance diagnostic accuracy and guide therapeutic decision-making.