The detection of structural DNA variation has long played a role in the diagnosis of cancer and Mendelian disorders, predating the advent of modern DNA sequencing (1,2). Structural DNA variation is generally defined as variation in a DNA region larger than 1 kb and includes several classes such as translocations, inversions, insertions/deletions (indels) and copy number variations (CNVs) (3). In the clinical laboratory, the detection of structural variation is performed by a diverse group of methods. Among the oldest and most basic methods for structural variation detection is routine cytogenetics, in which metaphase chromosomes are stained and morphologically evaluated by light microscopy. Conventional cytogenetics represents an unbiased approach for the detection of translocations, inversions, and large deletions or insertions; however, most clinical cytogenetic as-says are performed at the 350–500 band level and are of limited resolution and sensitivity. For example, clinically relevant events such as the FIP1L1-PDGFRA deletion on chromosome 4q12 in myeloid neoplasms, unusual or multi-partner rearrangements, and variants present in less than 5% of cells are generally not identified by conventional cytogenetics (4–6). Another major limitation of conventional
