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Cytogenetics is the study of chromosomes by light microscopy. The chromosomal constitution of a single cell or an entire individual is specified by a standardized notation. The total chromosome count is determined first, followed by the sex chromosome complement and then by any abnormalities. The autosomes are all designated by numbers from 1 to 22. A plus (+) or minus (–) sign indicates, respectively, a gain or loss of chromosomal material. For example, a normal male is 46,XY, whereas a girl with Down syndrome caused by trisomy 21 is 47,XX,+21; a boy with Down syndrome caused by translocation of chromosome 21 to chromosome 14 in a sperm or an egg is 46,XY,–14,+t(14;21).

Chromosomal analyses are done by growing human cells in tissue culture, chemically inhibiting mitosis, and then staining, observing, photographing, sorting, and counting the chromosomes. The display of all the chromosomes is termed the karyotype (eFigure 40–1) and is the end result of the technical aspect of cytogenetics.

Specimens for cytogenetic analysis can be obtained for routine analysis from the peripheral blood, in which case T lymphocytes are examined; from amniotic fluid for culture of amniocytes; from trophoblastic cells from the chorionic villus; from bone marrow; and from cultured fibroblasts, usually obtained from a skin biopsy. Enough cells must be examined so that the chance of missing a cytogenetically distinct cell line (a situation of mosaicism) is statistically low. For most clinical indications, 20 mitoses are examined and counted under direct microscopic visualization, and two are photographed and karyotypes prepared. Observation of aberrations usually prompts more extended scrutiny and, in many cases, further analysis of the original culture.

A variety of methods can be used to reveal banding patterns—unique to each pair of chromosomes—in the analysis of aberrations. The number of bands that can be visualized is a function of how “extended” the chromosomes are, which in turn depends primarily on how early in metaphase (or even in prophase for the most extensive banding) mitosis was arrested. The “standard” karyotype reveals about 400 bands per haploid set of chromosomes, whereas a prophase karyotype might reveal four times that number. As invaluable as extended karyotypes are in certain clinical circumstances, their interpretation is often difficult—in terms of the time and effort required and of ambiguity about what is abnormal, what is a normal variation, and what is a technical artifact. In situ hybridization with DNA probes for specific chromosomes or regions of chromosomes can be labeled and used to identify subtle aberrations. Given proper technique, fluorescent in situ hybridization (FISH) yields sensitivities and specificities of almost 100%. The tips of chromosomes are called telomers. An area of particular relevance is the use of FISH to detect small deletions in the regions of chromosomes just proximal to their tips (subtelomeric).

Increasingly, classic cytogenetics is being replaced by cytogenomics, in which a patient’s DNA is analyzed on an array platform (’chip’). The chips ...

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