Improvements in chromosome banding allowed detection of small deletions and duplications, beginning with missing small bands on chromosome 13 in certain children with retinoblastoma and on chromosome 15 in certain children with Prader–Willi syndrome. These subtle deletions, called microdeletions, were sometimes not reproducible because banding techniques could vary according to the specimen and laboratory conditions. Fluorescent in situ hybridization (FISH) and chromosome painting technologies, using fluorescent DNA probes to highlight specific chromosome regions, improved the characterization of microdeletions and complex rearrangements, revealing a new class of submicroscopic deletions that were not visible by the best-banding techniques. If targeted DNA segment is deleted, then the probe will not yield a fluorescent signal on that chromosome. Chromosome microscopic and submicroscopic deletions cause half (haploid) dosage of autosomal genes within the deleted area, or complete deficiency of genes within deleted regions of the X chromosome in males. The phenotypes of submicroscopic deletions are more easily explained by their haploid or missing genes than are aneuploidies of larger chromosome segments described in Chapters 7 and 8.

Schmickel (1986) coined the term “contiguous gene deletion” to denote composite phenotypes that result when neighboring deleted genes are associated with standard Mendelian diseases. Several examples of these aggregate phenotypes are found with small X chromosome deletions like that causing Duchenne muscular dystrophy, glycerol kinase, and adrenal hypoplasia. Each of these disorders had been described as a separate X-linked-recessive disease, so their concurrence in one patient is caused by deletion of the contiguous genes.