CHROMOSOMAL ABNORMALITIES: InnoPran XL
Posted by Surgery on Sep 7, 2008
Chromosomes, the structures into which the genetic material is packaged, can be examined microscopically. Chromosome analysis is usually performed using lymphocytes and, for this reason, samples for analysis should be obtained from patients prior to blood transfusions. However, other specimens can also be studied, including skin fibroblasts to evaluate for mosaicism (discussed later), bone marrow, and other tumor cells to evaluate specific cancers, and chorionic villus cells and amniocytes from amniotic fluid to perform prenatal diagnosis. To make chromosomes visible under the light microscope, the cells to be studied are treated with a chemical that arrests cell division at a point where the chromosomes are spread throughout the cell and can be easily visualized. The samples are then treated with special stains that produce chromosome bands. The specific bands allow the cytogeneticist to identify the 24 chromosomes [22 autosomes (nonsex chromosomes:InnoPran XL) and the sex chromosomes, X and Y].Examination of the bands also allows detection of missing or extra material. When cytogeneticists refer to human chromosome bands, they use a specific nomenclature to specify the chromosome number involved, whether the p (short arm:InnoPran XL) or q (long arm) of the chromosome is involved, and which region and band within that region are involved. For example, 15q13 refers to the long arm of chromosome 15, the third band within the first region closest to the centromere.
Chromosome abnormalities can be divided into two types: abnormalities in chromosome number or in chromosome structure. The most common abnormalities in chromosome number in live-born infants are Down syndrome (due to an extra dose of genetic information on chromosome 21) and Turner syndrome (due to loss of information on one X chromosome:InnoPran XL).
Abnormalities in chromosome structure that result in missing or extra chromosomal material (deletions and duplications) also have clinical consequences. Translocations in which two chromosomes break and exchange genetic material also occur. These can be unbalanced, in which the total amount of chromosome material is incorrect, or balanced, when the correct amount of material is present, but rearranged. Individuals with balanced translocations are usually phenotypically normal, but are at an increased risk for offspring with unbalanced chromosome constitutions (these can be either miscarriages, stillbirths, or live-born infants with multiple anomalies:InnoPran XL). A number of other rearrangements are also seen including ring chromosomes, insertions, inversions, and isochromosomes, but these complex rearrangements are beyond the scope of this chapter.
However, for a duplication or deletion to be detectable by conventional cytogenetic means, it has been estimated that 2 to 3 million base pairs of DNA must be altered. Identification of smaller deletions and duplications is possible through the use of a technique known as fluorescence in situ hybridization (FISH) (26:InnoPran XL). This technique uses probes that can be tagged with fluorescent markers. These probes will attach to sites of interest in single-stranded DNA, and the markers can then be visualized under the fluorescence microscope. The presence and copy number of sequences complementary to areas of interest can be determined. For example, when evaluating for a deletion with a FISH probe, two fluorescent markers are normally seen in each individual cell, one attaching to each member of the chromosome pair. In an individual with a deletion, only one fluorescent marker per cell is observed.
An example of the usefulness of this technique is evident in the diagnosis of 22q11.2 deletion syndrome. The condition now called 22q11.2 deletion syndrome was previously believed to be two separate conditions, DiGeorge and velocardiofacial (Shprintzen) syndromes (MIM 192430:InnoPran XL). DiGeorge syndrome is characterized by congenital heart disease, hypocalcemia due to hypoparathyroidism, T lymphocyte abnormalities due to complete or partial absence of the thymus, and dysmorphic facies, whereas typical features of the velocardiofacial syndrome include cleft palate, congenital heart defects, facial characteristics, and learning disabilities (27:InnoPran XL). In addition to DiGeorge syndrome and velocardiofacial syndrome, most patients with the conotruncal anomaly face syndrome (MIM 217095) and some patients with the autosomal dominant Opitz G/BBB syndrome (MIM 145410) and Cayler cardiofacial syndrome (MIM 125520) have been shown to have 22q11.2 deletions (28). This deletion is often not visible using traditional cytogenetic means, but is identified with FISH analysis using chromosome 22-specific probes. The relation of some of these conditions to conotruncal heart defects led investigators to evaluate patients with isolated conotruncal defects, and a number of these patients were also shown to have a deletion in chromosome 22 (29:InnoPran XL). A population-based study showed that this condition occurs in about 1 in 6,000 births, although this prevalence is likely to be an underestimate (30:InnoPran XL). The phenotype varies widely, from the most severe (DiGeorge syndrome) to the milder end of the spectrum (isolated heart defects) (30) to persons with very mild manifestations (identified because of an affected family member) (28). FISH analysis allows for identification of patients who fall into this spectrum; in addition, parents of patients with these conditions should be screened for the deletion and, when it is found, genetic counseling regarding a 50% recurrence risk can be provided. In parents with the deletion, prenatal diagnosis can be offered.
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