Use of mate-pair sequencing to characterize a complex cryptic BCR/ABL1 rearrangement observed in a newly diagnosed case of chronic myeloid leukemia.

Chronic myeloid leukemia is characterized by a t(9;22)(q34;q11.2) resulting in BCR/ABL1 fusion located on the derivative chromosome 22, also known as the Philadelphia chromosome. We present the first case, to our knowledge, of chronic myeloid leukemia with 2 cryptic insertional events resulting in BCR/ABL1 fusion on the derivative chromosome 9 and FNBP1/BCR fusion on the derivative chromosome 22. These insertional events were misinterpreted as a typical balanced BCR/ABL1 translocation by interphase fluorescence in situ hybridization studies and were cryptic by conventional chromosome analysis, resulting in a "normal" karyotype. Mate-pair sequencing, a novel next-generation sequencing technology that can detect and characterize structural variants with significantly higher resolution and precision compared with traditional cytogenetic methodologies, identified 2 insertional events and resolved the seemingly discrepant chromosome and fluorescence in situ hybridization results. This case demonstrates the complexities of genetic abnormalities unappreciable by traditional cytogenetic methodologies and highlights the clinical utility of mate-pair sequencing.