Medical cytogenetics is the study of human chromosomes under the light microscope and the relationship of chromosomal abnormalities to human diseases, disability, and dysmor-phology. As a discipline, human cytogenetics developed slowly at first throughout the 20th centuary. In the early 1900s, the human chromosome number was believed to be 48 for females with an XX sex chromosome complement, and 47 for males with a single X chromosome. In 1928, Painter suggested that both sexes had 48 chromosomes, but that males had two sex chromosomes, an X and a Y (1).
In 1952, Hsu discovered that use of a hypotonic solution swelled cells and separated the chromosomes, making their study much easier (2). This was the first of several technical advances that opened the doors to the clinical evaluation of human chromosomes. Four years later, in 1956, Tijo and Levan, aided by the discovery of hypotonic solution and improved cytogenetic technique, established that the chromosome number in humans was actually 46, not 48 (3).
The first chromosomal abnormality was described by Lejeune in 1959. He discovered that there was an extra copy of chromosome 21 in Down syndrome (4). Later that same year, other researchers reported that Turner syndrome had a 45,X chromosome complement (5) and that Klinefelter syndrome had an 47,XXY chromosome complement (6). A woman with 47,XXX was also described (7). The following year, the other common autosomal trisomies (trisomy 13 and 18) were described (8,9). Also in 1960, Nowell and Hungerford described the first consistent chromosomal change seen in cancer. They noticed that in chronic myelogenous leukemia (CML), one chromosome 22 was always unusually small. They dubbed this small chromosome the Philadelphia (Ph) chromosome after the city in which it was discovered. Lejeune described the first deletion syndrome in 1963 and 1964 when he reported that deletion of the short arm of chromosome 5 (cri du chat syndrome) was seen in patients with a catlike cry and phenotypic anomalies (10,11).
Throughout this time, human chromosomes were solid stained using nuclear stains with an affinity for DNA. The classification of individual chromosomes was based on their overall length, the position of the centromere, and the ratio of short to long arms, but the individual chromosomes could not be positively identified and structural rearrangements were difficult, and sometimes impossible, to characterize. In 1970, Caspersson applied to human chromosomes fluorescent techniques that were being used to study plant chromosomes (12). He found that each human chromosome had a unique banding pattern that allowed for the definitive identification of each chromosome pair and made the detection and characterization of structural rearrangements much easier. Over the next several years, a variety of different banding techniques were developed, including ones using Giemsa, introduced by Sumner in 1971 (13), that became fundamental to most cytogenetics laboratories in the United States.
In 1972, Rowley determined that the Ph chromosome seen in CML was actually the result of a reciprocal translocation between a chromosome 22 and a chromosome 9 (14). Prior to banding, the derivative chromosome 9 was not appreciated. In the mid-1970's, Yunis developed techniques of chromosome elongation that allowed chromosomes to be studied earlier in the cell cycle, when they were longer than the typical metaphase preparations that were the mainstay of cytogenetic laboratories (15). Longer prophase and prometaphase chromosomes exhibit more bands than their shorter metaphase counterparts, and this allowed for the detection of smaller structural rearrangements. Pinkel and Gray introduced fluorescence in situ hybridization (FISH) in 1986 (16). FISH is a marriage of classical cytogenetics and newer molecular technologies and has extended the range of the former. FISH is dealt with in a chapter of its own elsewhere in this volume.
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