Genetic Disorders

Chromosome Abnormalities

Standard cytogenetic testing uses light microscopy to identify loss or gain of visible segments of chromosomes, including whole chromosomes and smaller segments. Although this technique readily detects abnormalities of large segments of chromosomal material, the smallest deletions or duplications are beyond the resolution of microscopic analysis. Over the past two decades, new techniques for diagnosis of smaller and smaller chromosome abnormalities have had a great impact on the practice of medical genetics. With the advent of fluorescence in situ hybridization (FISH) technology, it has become possible to detect deletions or duplication not visible through the microscope. FISH uses fluorescent molecules to bind to genes, chromosome regions, or whole chromosomes and detects missing or extrachromosomal material. More recently, fluorescence technology has been used to construct chromosome microarrays, which can detect literally thousands of abnormalities in a single reaction. Among patients who are evaluated for a chromosome abnormality and who have already had a normal cytogenetic analysis, 5% to 7% have a chromosome deletion or duplication when analyzed by chromosome microarray. Such technical advances will increasingly be used to improve genetic diagnosis and to identify mechanisms by which chromosome imbalance leads to human disease.

Although chromosome abnormalities may be found in all age groups, they are particularly common in spontaneous abortions. Among recognized pregnancies, between 10% to 20% are spontaneously aborted; and of these, chromosome abnormalities are present in about half. The great majority, more than 95%, of these abnormalities, involve an entire missing or extra chromosome, which is referred to as aneuploidy. [Page 414]Aneuploidy is the result of nondisjunction, which is failure of homologous chromosome pairs to disjoin and assort to different germ cells during the first phase of meiosis. The only well-characterized risk factor for chromosome abnormalities is advanced maternal age, which is associated with aneuploidy. Environmental factors such as parental drug use, cancer chemotherapy, and radiation exposures have been investigated, and none of these appears to increase the relative risk for having an affected child. Although chromosome abnormalities may be present in between 5% and 10% of conceptions, they are found in about 0.5% of newborns. The most common abnormalities in liveborn infants are trisomies for chromosomes 21, 18, and 13, while other trisomies such as trisomy 16 and trisomy 22 are rarely, if ever, encountered at birth. The decreased viability of fetuses with these chromosome abnormalities is believed to result from an increased amount of genetic imbalance, as compared with those with viable chromosomal abnormalities. Clinically, those conditions with the greatest quantity of missing or extrachromosomal material also have the most severe phenotypic manifestations. As a general rule, abnormalities of the autosomal chromosomes (the chromosomes not involved with sex determination) are characterized by significant developmental disabilities and birth defects, and sex chromosome abnormalities (involving the X and Y chromosomes) are characterized by abnormalities in sexual differentiation, maturation, and fertility.

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