Chromosomal aberrations are abnormalities in the structure or number of chromosomes and are often responsible for genetic disorders. For more than a century, scientists have been fascinated by the study of human chromosomes. It was not until 1956, however, that it was determined that the actual diploid number of chromosomes in a human cell was forty-six (22 pairs of autosomes and two sex chromosomes make up the human genome). In 1959 two discoveries opened a new era of genetics. Jerome Lejeune, Marthe Gautier, and M. Raymond Turpin discovered the presence of an extra chromosome in Down syndrome patients. And C. E. Ford and his colleagues, P. A. Jacobs and J. A. Strong first observed sex chromosome anomalies in patients with sexual development disorders.
Advances in Chromosomal Analysis
Identification of individual chromosomes remained difficult until advances in staining techniques such as Q-banding revealed the structural organization of chromosomes. The patterns of bands were found to be specific for individual chromosomes and hence allowed scientists to distinguish the different chromosomes. Also, such banding patterns made it possible to recognize that structural abnormalities or aberrations were associated with specific genetic syndromes. Chromosome disorders, or abnormalities of even a minute segment (or band) are now known to be the basis for a large number of genetic diseases.
Chromosomal disorders and their relationship to health and disease are studied using the methods of cytogenetics . Cytogenetic analysis is now an integral diagnostic procedure in prenatal diagnosis. It is also utilized in the evaluation of patients with mental retardation, multiple birth defects, and abnormal sexual development, and in some cases of infertility or multiple miscarriages. Cytogenetic analysis is also useful in the study and treatment of cancer patients and individuals with hematologic disorders. The types of chromosomal abnormalities that can be detected by cytogenetics are numerical aberrations, translocations, duplications, deletions, and inversions.
Chromosomal abnormalities can result from either a variation in the chromosome number or from structural changes. These events may occur spontaneously or can be induced by environmental agents such as chemicals, radiation, and ultraviolet light. However, mutations are most likely due to mistakes that occur when the genes are copied as the cells are dividing to produce new cells. These abnormalities may involve the autosomes, sex chromosomes, or both. The disruption of the DNA sequence or an excess or deficiency of the genes carried on the affected chromosomes results in a mutation. Such a change may or may not alter the protein coded by a gene. Often, however, a mutation results in the disruption of gene functionality. The resulting altered or missing protein can disrupt the way a gene is meant to function and can lead to clinical disease. Only mutations occurring to the DNA in the gametes will potentially pass on to the offspring.
Mutations appear in gametes in one of two ways. A mutation may be inherited from one of an individual's parents. However, a mutation may also occur for the first time in a single gamete, or during the process of fertilization between an egg cell and a sperm cell. In this case the mutation or change is often called a de novo mutation. The parents are not affected by the condition and are not "carriers" of the mutation. The affected individual will have this mutation in all of his or her cells and may be able to pass the mutation on to any offspring. Some common abnormalities and their resulting phenotypes are discussed below.
Aneuploidy is the gain or loss of individual chromosomes from the normal diploid set of forty-six chromosomes. As in structural anomalies, the error may be present in all cells of a person or in a percentage of cells. Changes in chromosome number generally have an even greater effect upon survival than changes in chromosome structure. Considered the most common type of clinically significant chromosome abnormality, it is always associated with physical and/or mental developmental problems. Most aneuploid patients have a trisomy of a particular chromosome. Monosomy , or the loss of a chromosome, is rarely seen in live births. The vast majority of monosomic embryos and fetuses are probably lost to spontaneous abortion during the very early stages of pregnancy. An exception is the loss of an X chromosome, which produces Turner's syndrome. Trisomy may exist for any chromosome, but is rarely compatible with life.
Aneuploidy is believed to arise from a process called nondisjunction. Nondisjunction occurs when chromosomes do not separate correctly during meiosis. The direct result is that one gamete will have an extra chromosome and the other will be lacking a chromosome. When these gametes are fertilized by a normal gamete, they have either an extra chromosome (trisomy) or are missing a chromosome (monosomy).
Disorders Associated with Aneuploidy
Three well-known autosomal chromosome disorders associated with trisomies of entire autosomes are sometimes found in live births. These are trisomy 21 (Down syndrome), trisomy 13, and trisomy 18. Growth retardation, mental retardation, and multiple congenital anomalies are associated with all three trisomies. However, each has distinctive morphological characteristics, which are presumably determined by the extra dosage of the specific genes on the additional chromosome.
Down syndrome (chromosome 21) is the most frequent trisomy found in humans, and one of the most common conditions encountered in genetic counseling. General characteristics are mental retardation, distinctive palm prints, and a common facial appearance. The average life expectancy is now much greater thanks to improvements in medical care. Generally, individuals with Down syndrome have affable personalities and are able to be partially independent. The incidence of Down syndrome is about 1 in 800 children and is often associated with later maternal age (as may also be the case with other aneuploids).
Down syndrome appears to be related to the difference in gamete formation (gametogenesis) between males and females. In females, oocytes are formed before birth and held in a static state until ovulation. In the case of older mothers, an oocyte may be in this stage for more than forty years, during which time environmental factors may affect the genetic material. In trisomy 13 and trisomy 18 patients, congenital abnormalities are much more severe. These individuals generally do not live much beyond birth. Both trisomy 13 and trisomy 18 result in syndromes characterized by specific dysmorphic features and severe organ malformations.
In addition to trisomies involving the autosomal chromosomes, aneuploidy may also involve the sex chromosomes. Two examples are Turner's syndrome and Klinefelter's syndrome. As mentioned previously, Turner's syndrome is a monosomy involving the X chromosomes. Turner's syndrome females possess forty-five chromosomes (45, X) as compared to clinically normal forty-six (46, XX). They are usually sterile and short in stature with some neck webbing. Klinefelter's syndrome patients have a trisomy involving the sex chromosomes and thus have forty-seven chromosomes (47, XXY). Klinefelter's syndrome individuals are sterile males possessing some female characteristics. These chromosome abnormalities are of interest especially for their implications in infertility and abnormal development.
Abnormalities of Chromosomal Structure
Four types of structural changes may occur in chromosomes: duplications, deletions, translocations, and inversions. All may result when there is breakage of the chromosomes and a rejoining or loss of chromosome fragments. If the same broken ends rejoin, the chromosome becomes intact once again. The resulting effects of such events depend on how large they are and where they occur on the chromosome. Rearrangements may occur in many forms and are less common than abnormalities of chromosome number.
The most common type of rearrangement is called a balanced translocation because the amount of genetic information within that cell is normal even though it is repositioned. Therefore the individual with a balanced translocation may appear normal. However, there will be a risk to the children of a carrier of a balanced translocation since that person is likely to produce unbalanced gametes (bearing too little or too much genetic information), and therefore the risk of having abnormal offspring is increased. Rearrangements such as aneuploidy may be found in all cells of an individual, or they may occur only in a percentage of an individual's cells. This latter condition is known as mosaicism. In general, mosaic individuals show a less severe expression of their syndrome than those with chromosome abnormalities in all their cells.
Unbalanced Chromosome Rearrangements
A rearrangement is considered unbalanced if it results in extra or missing information. Structural rearrangements may be caused by a number of factors including chemicals, some viral infections, and ionizing radiation. Because the complement of DNA or genetic material in the chromosomes is greater or less than the complement of DNA in a normal set of chromosomes, there is likely to be abnormal development.
A deletion is the loss of a segment of a chromosome. The amount of deleted material may be any length from a single base to a large piece of the chromosome. The result is a chromosomal imbalance, with the individual being monosomic or possessing half of the required genes present in a normal individual for the segment of DNA missing. Only small deletions are tolerated, and the effect on the individual will depend upon the size of the deleted segment and the number and functionality of the genes that are contained within it. Larger deletions and the deletion of an entire chromosome always result in nonviable embryos. Cri du Chat's ("cat's cry") syndrome individuals have a deletion of the short arm of chromosome 5. Although they possess the usual signs of chromosomal anomalies, such as mental retardation and low birth weight, their appearance is not extraordinarily different from normal individuals. One peculiarity is that affected infants make an unusual cry resembling that of a cat, hence the name of the syndrome. Two other interesting diseases are Prader-Willi's syndrome and Angelman's syndrome. In both cases, patients with these diseases possess a deletion in the long arm of chromosome 15. Interestingly, the deletion is in the same location, but the resulting syndrome depends on whether the deletion was in the maternal or paternal chromosome.
Duplications also result from the reuniting of broken pieces of homologous chromosomes. In some cases the chromosome pieces rejoin in such a way that there is a doubling, or redundancy, of a portion of the chromosome. This changes the number of genes present and may result in a problem with health, development, or growth.
Large insertions and deletions prevent the production of useful proteins. The effect of smaller insertions or deletions depends upon how many bases are involved. Sometimes an entire gene can be inserted (in duplications) or deleted. The effect depends upon where in the genome the changes occur and how many base pairs are involved.
An inversion is the rotation of a broken chromosome segment in such a way that it rejoins the chromosome in a reversed state, or is flipped, end to end. Inversions are usually characterized by whether the centromere is included in the inverted segment. Inversions containing the centromere are called pericentric. Those not containing the centromere are called paracentric. Although an inversion does not change the overall content of cellular DNA and can be considered a balanced translocation, it can affect a gene at many levels because it alters the normal DNA sequence. The gene may not produce its corresponding protein at all, or a nonfunctioning protein may result. There is a common inversion seen in human chromosomes involving chromosome 9. A small pericentric inversion is present in approximately 1 percent of tested individuals. There appears to be no detrimental effect on the carrier, and it does not appear to cause miscarriage or unbalanced off-spring.
Chromosomal aberrations may be inherited from a parent, and because of this many families seek genetic counseling in order to determine if a genetic disorder will recur in another member of the same generation or in generations that will follow. The family needs to know the genetic risk, also known as the recurrence risk, and any means by which transmission may be prevented. A recurrence risk will be calculated based on the accuracy of the diagnosis, the pedigree of the family, and the known genetic mechanisms of the disorder in question.
see also Birth Defects; Chromosome Banding; Crossing Over; Down Syndrome; Meiosis; Mutation; Nondisjunction; Prenatal Diagnosis.
Jacqueline Bebout Rimmler
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