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Clinical Application of Microarray-Based Molecular Cytogenetics: An Emerging New Era of Genomic Medicine

2009; Elsevier BV; Volume: 155; Issue: 3 Linguagem: Inglês

10.1016/j.jpeds.2009.04.001

1097-6833

Marilyn M. Li, Hans C. Andersson,

Prenatal Screening and Diagnostics

Geneticists have long recognized the role of genomic imbalances (eg, deletions or duplications of chromosomal material) in the pathogenesis of human disorders. Numerous methods have been developed to detect genomic alterations since the discovery of the correct chromosome number in human cells in 1956. In 1959, Lejeune et al 1 Lejeune J. Turpin R. Chromosomal aberrations in man. Am J Hum Genet. 1961; 13: 175-184 PubMed Google Scholar discovered that an extra copy of chromosome 21 (trisomy 21) caused Down syndrome, the first evidence linking genomic imbalances with human disease. Soon after, new clinical syndromes were delineated on the basis of the identification of multiple patients with the same cytogenetic abnormality, such as trisomy 13 in Patau syndrome and trisomy 18 in Edwards syndrome. The identification of the Philadelphia chromosome, which was later showed to be caused by a translocation between chromosomes 9 and 22, and its association with chronic myelocytic leukemia in 1960 marked the beginning of cancer cytogenetics. 2 Nowell P.C. Hungerford D.A. A minute chromosome in human chronic granulocytic leukemia. Science. 1960; 132: 1488-1501 Crossref PubMed Google Scholar The invention of chromosome banding techniques in 1970 led to the discovery of numerous structural chromosome aberrations and their association with human diseases. 3 Caspersson T. Zech L. Johansson C. Modest E.J. Identification of human chromosomes by DNA-binding fluorescent agents. Chromosoma. 1970; 30: 215-227 Crossref PubMed Scopus (808) Google Scholar By optimizing culture conditions to arrest cellular division at prometaphase, high-resolution banding could detect chromosomal changes to a resolution of 3 to 5 Mb. The next breakthrough in cytogenetics was the development of fluorescent in situ hybridization (FISH) technology, which laid the foundation for molecular cytogenetics. 4 Lichter P. Ward D.C. Is non-isotopic in-situ hybridization finally coming of age?. Nature. 1990; 338: 348-350 Google Scholar The technology not only allows the detection of small genomic alterations of 50 Kb to 100 Kb, but also permits the direct visualization of these alterations in uncultured cells. These features made FISH testing ideal not only in detecting microdeletion/microduplication syndromes, but also for prenatal aneuploidy screens, where a fast turnaround time is highly desirable, and for cancer genetics studies, where metaphase chromosomes may not be obtainable. Although FISH allows the detection of genomic imbalances with great accuracy, it can only probe specific sequences that are known and suspected to be associated with known syndromes.