Chromosomal Abnormalities

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Chromosomal Abnormalities

Normal number and structure of human chromosomes

Normal cell division

Alterations in chromosome number

Alterations in chromosome structure

Genetic counseling


Chromosome abnormalities describe alterations in the normal number of chromosomes or structural problems within the chromosomes themselves. Both kinds of chromosome abnormalities may result from an egg (ovum) or sperm cell with the incorrect number of chromosomes or from a structurally faulty chromosome uniting with a normal egg or sperm during conception.

Some chromosome abnormalities may occur shortly after conception. In this case, the zygote, the cell formed during conception that eventually develops into an embryo, divides incorrectly. Other abnormalities may lead to the embryos death. Zygotes that receive a full extra set of chromosomes, a condition called polyploidy, usually do not survive inside the uterus, and are spontaneously aborted (a process sometimes called a miscarriage).

Chromosomal abnormalities can cause serious mental or physical disabilities. Down syndrome, for instance, is caused by an extra chromosome 21 (trisomy 21). People with Down syndrome are usually mentally retarded and have a host of physical defects, including heart disorders. Other individuals, called Down syndrome mosaics, have a mixture of normal cells and cells with three copies of chromosome 21, resulting in a mild form of the disorder.

Normal number and structure of human chromosomes

A chromosome consists of the bodys genetic material, deoxyribonucleic acid (DNA) along with many kinds of protein. Within the chromosomes, the DNA is tightly coiled around these proteins (called histones), allowing huge DNA molecules to occupy a small space within the cell nucleus. When a cell is not dividing, the chromosomes are invisible within the cells nucleus. Just prior to cell division, the chromosomes uncoil and begin to replicate. As they uncoil, the individual chromosomes look somewhat like a fuzzy X. Chromosomes contain the genes, or segments of DNA that encode for proteins, of an individual. When a chromosome is structurally faulty, or if a cell contains an abnormal number of chromosomes, the types and amounts of proteins encoded by the genes are changed. When proteins are altered in the human body, the result can be serious mental and physical defects and disease.

Humans have twenty-two pairs of autosomal chromosomes and one pair of sex chromosomes, for a total of fortysix. These can be studied by constructing a karyotype, or organized depiction, of the chromosomes. To construct a karyotype, a technician stops cell division, using a chemical such as colchicines, just after the chromosomes have replicated; the chromosomes are visible within the nucleus at this point. The chromosomes are photographed, and the technician cuts up the photograph and matches the chromosome pairs according to size, shape, and characteristic stripe patterns (called banding).

Normal cell division

In most animals, two types of cell division exist. In mitosis, cells divide to produce two identical daughter cells. Each daughter cell has exactly the same number of chromosomes. This preservation of chromosome number is accomplished through the replication of the entire set of chromosomes just prior to mitosis.

Sex cells, such as eggs and sperm, undergo a different type of cell division called meiosis. Because sex cells each contribute half of a zygotes genetic material, sex cells must carry only half the full complement of chromosomes. This reduction in the number of chromosomes within sex cells is accomplished during two rounds of cell division, called meiosis I and meiosis II. Prior to meiosis I, the chromosomes replicate and chromosome pairs are distributed to daughter cells. During meiosis II, however, these daughter cells divide without a prior replication of chromosomes. Mistakes can occur during either phase. Chromosome pairs can be separated during meiosis I, for instance, or fail to separate during meiosis II.

Meiosis produces four daughter cells, each with half of the normal number of chromosomes. These sex cells are called haploid cells (haploid means half the number). Nonsex cells in humans are called diploid (meaning double the number) since they contain the full number of normal chromosomes.

Alterations in chromosome number

Two kinds of chromosome number defects can occur in humans: aneuploidy, an abnormal number of chromosomes, and polyploidy, more than two complete sets of chromosomes.


Most alterations in chromosome number occur during meiosis. During normal meiosis, chromosomes are distributed evenly among the four daughter cells. Sometimes, however, an uneven number of chromosomes are distributed. Chromosome pairs may not move apart in meiosis I, or may not separate in meiosis II. The result of both kinds of mistakes (called non-disjunction of the chromosomes) is that one daughter cell receives an extra chromosome, and another daughter cell does not receive any chromosome.

When an egg or sperm that has undergone faulty meiosis and has an abnormal number of chromosomes unites with a normal egg or sperm during conception, the zygote formed will have an abnormal number of chromosomes, a condition called aneuploidy, which has several types of expression: If the zygote has an extra chromosome, the condition is called trisomy. If the zygote is missing a chromosome, the condition is called monosomy. If the zygote survives and develops into a fetus, the chromosomal abnormality is transmitted to all of its cells. The child that is born will have symptoms related to the presence of an extra chromosome or absence of a chromosome.

Examples of aneuploidy include trisomy 21, also known as Down syndrome, that occurs approximately 1 in 700 newborns; trisomy 18, also called Edwards syndrome (1:3500); and trisomy 13, also called Patau syndrome (1:5, 000). Trisomy 18 and 13 are more severe than of Down syndrome. Prenatal ultrasound anomalies of fetuses affected by Down syndrome include nuchal thickening, duodenal stenosis, short femur, and many other defects. Children with trisomy 21 have the characteristic face with a flat nasal bridge, epicanthic folds, protruding tongue and small ears. Among possible malformations, cleft palates, hare lips, and cardiac malformations (atrial and ventricular septal, and atriventricular canal defects). Mental retardation is always present in various degrees. The life span once the individual has survived one year ranges between 50 and 60 years. Trisomy 18, known as Edwards syndrome, results in severe multisystem

defects. Most trisomy 18 occurrences result in spontaneous abortion. Affected infants have a small faces, small ears, overlapping fingers and rocker-bottom heels. Cardiac and other internal malformations are frequent. Newborns with trisomy 13 have midline anomalies as well as scalp cutis aplasia, brain malformations, cleft lip and or palate, omphalocele and many others. Polydactyly (having extra fingers or toes) is also frequent. Children with trisomy 13 and trisomy 18 usually survive less than a year after birth and are more likely to be females (Figure 1).

Aneuploidy of sex chromosomes

Sometimes nondisjunction occurs in the sex chromosomes. Humans have one set of sex chromosomes. These sex chromosomes are called X and Y after their approximate shapes in a karyotype. Males have both an X and a Y chromosome, while females have two X chromosomes. Remarkably, abnormal numbers of sex chromosomes usually result in less severe defects than those that result from abnormal numbers of the other 22 pairs of chromosomes. The lessened severity may be due to the fact that the Y chromosome carries few genes, and any extra X chromosomes become inactivated shortly after conception. Nevertheless, aneuploidy in sex chromosomes causes changes in physical appearance and in fertility (Figure 2).

In Klinefelter syndrome, for instance, a male has two X chromosomes (XXY). This condition occurs in 1 out of every 2, 000 births (approximately 1:800 males). Men with Klinefelter syndrome have small testes and are usually sterile. They also have female sex characteristics, such as enlarged breasts (gynecomastia). Males who are XXY are of normal intelligence or affected by a mild delay or behavioral immaturity. However, males with more than two X chromosomes, such as XXXY, XXXXY, or XXXXXY are mentally retarded.

Males with an extra Y chromosome (XYY) have no physical defects, although they may be taller than average. XYY males occur in 1 out of every 2, 000 births (approximately 1:800 males). This condition is not associated with increased aggressive and criminal behavior as initially thought.

Females with an extra X chromosome (XXX) are called metafemales. This defect occurs in 1 out of every 800 females. Metafemales have lowered fertility (oligomenorrhea and premature menopause), but their physical appearance is normal.

Females with only one X chromosome (XO) have Turner syndrome. Turner syndrome is also called monosomy X and occurs in 1 out of every 5, 000 births (1:2, 500 females). People with Turner syndrome have sex organs that do not mature at puberty; they are usually sterile. They are of short stature and have no mental deficiencies.

Uniparental disomy is a condition in which both chromosomes of a given pair in a diploid cell line come

from only one of the two parents. Possible consequences of uniparental disomy include imprinting of single genes (abnormal levels of gene product) and homozygosity for mutant alleles. Microdeletion syndromes associated to a disomy of chromosome 15 include Prader-Willi (maternal disomy) and Angelman syndrome (patermal disomy).


Polyploidy is lethal in humans. Normally, humans have two complete sets of 23 chromosomes. Normal human cells, other than sex cells, are thus described as diploid. Two polyploid conditions occur in humans. Triploidy is a condition in which there are three sets of chromosomes, resulting in 69 chromosomes with XXX, XXY or XYY sex chromosomes. Tetrapolidy results in 92 chromosomes and either XXXX or XXYY sex chromosomes. Triploidy could result from the fertilization of an abnormal diploid sex cell with a normal sex cell. Tetraploidy could result from the failure of the zygote to divide after it replicates its chromosomes. Human zygotes with either of these conditions usually die before birth, or soon after. Interestingly, polyploidy is common in plants and is essential for the proper development of certain stages of the plant life cycle. Also, some kinds of cancerous cells have been shown to exhibit polyploidy. Rather than die, the polyploid cells have the abnormally accelerated cell division and growth characteristic of cancer.

Alterations in chromosome structure

Another kind of chromosomal abnormality is alteration of chromosome structure. Structural defects arise during replication of the chromosomes just prior to a meiotic cell division. Meiosis is a complex process that often involves the chromosomes exchanging segments with each other in a process called crossing-over. If the process is faulty, the structure of the chromosomes changes. Sometimes these structural changes are harmless; other structural changes, however, can be lethal.

Five types of general structural alterations occur during chromosome replication (Figure 3). All four types begin with the breakage of a chromosome during replication. In a deletion, the broken segment of the chromosome is lost. Deletion can be terminal (arising from one break) or interstitial (arising from two breaks). A particular case is the ring chromosome in which two points of breakdown are present and then fused. Segments distal to the breaks are lost, and such a loss involves both arms of the chromosome. In isochromosomes, one of the chromosome arms (p or q) is duplicated, and all material from the other arm is lost. The arm of one side of the centromere is a mirror image of the other. In a duplication, the segment joins to the other chromosome of the pair. In an inversion, the segment attaches to the original chromosome, but in a reverse position. It can be pericentric (break and rearrangements of both sides of the centromere) or paracentric (break and rearrangement on the same side of the centromere) In a translocation, the segment attaches to an entirely different chromosome. Translocaton can be Robertsonian (involves chromosomes 13-15, 21 and 22), in which the whole arms of the chromosomes named acrocentric are fused and reciprocal. Reciprocal translocation results from breakage and exchange of segments between chromosomes.

Because chromosomal alterations in structure cause the loss or misplacement of genes, the effects of these defects can be quite severe. Deletions are usually fatal to a zygote. Duplications, inversions, and translocations can cause serious defects, as the expression of the gene changes due to its changed position on the chromosomes.

Examples of structural chromosomal abnormalities include cri du chat (cat cry in French) syndrome. Children with this syndrome have an abnormally developed larynx that makes their cry sound like the mewing of a cat in distress. They also have small heads, misshapen ears, and rounded faces, as well as other systemic defects. These children usually die in infancy. Cri du chat is caused by a deletion of a segment of DNA in chromosome 5.

A structural abnormality in chromosome 21 occurs in about 4% of people with Down syndrome. In this translocation abnormality, a piece of chromosome 21 breaks off during meiosis of the egg or sperm cell and attaches to chromosome 13, 14, or 22.

Some structural chromosomal abnormalities have been implicated in certain cancers. For instance, myelogenous leukemia is a cancer of the white blood cells. Researchers have found that the cancerous cells contain a translocation of chromosome 22, in which a broken segment switches places with the tip of chromosome 9.

Some unusual chromosomal abnormalities include Prader-Willi syndrome, Angelmans syndrome, and fragile-X syndrome. These structural defects are unusual because the severity or type of symptoms associated with the defect depend on whether the child receives the defect from the mother or the father.

Both Prader-Willi syndrome and Angelman syndrome are caused by a deletion in chromosome 5. If a child inherits the defective chromosome from the father, the result is Prader-Willi syndrome. If the child inherits the defective chromosome from the mother, the child will have Angelman syndrome. Prader-Willi syndrome is characterized by mental retardation, obesity, short stature, and small hands and feet. Angelmans syndrome is characterized by jerky movements and neurological symptoms. People with this syndrome also have an inability to control laughter and may laugh inappropriately at odd moments. Researchers believe that genes from the deleted region function differently in offspring depending on whether the genes come from the mother or father, but they are not sure about the exact nature of these differences.

The expression of fragile-X syndrome also depends on whether the defect is inherited from the mother or father. In fragile-X, an extra X chromosome hangs off the normal X by a thin thread of genetic material. The syndrome occurs in 1 out of 1, 000 male births and 1 out of 2, 000 female births. Males are affected more severely than females, and thus the syndrome is more pronounced if the child inherits the defect from its mother. To understand why this is so, remember that a male is XY and a female is XX. A male child receives a Y chromosome from the father and an X chromosome from the mother. A female child, however, can receive an X from either the mother or the father. Again, researchers believe this difference in fragile-X symptoms between boys and girls stems from a difference in gene function that depends on whether they come from the mother or father.

Genetic counseling

Currently, no cures exist for any of the syndromes caused by chromosomal abnormalities. For many of these conditions, the age of the mother carries an increased risk for giving birth to a child with a chromosomal abnormality. The risk for Down syndrome, for instance, jumps from 1 in 1, 000 when the mother is age 15-30 to 1 in 400 at age 35, increasing risk with increasing maternal age. One theory postulates that this is due to the buildup of toxins over time within the ovaries, damaging egg cells, which are present in females since early childhood. By the time they are ovulated after age 35, the chances of fertilizing a damaged egg are greater.

People at high risk for these abnormalities may opt to know whether the fetus they have conceived has one of these abnormalities. Amniocentesis is a procedure in which some of the amniotic fluid that surrounds and cushions the fetus in the uterus is sampled. The fluid contains some of the fetuss skin cells, which can be tested for chromosomally-based conditions. Another test, called chorionic villi sampling, takes a piece of tissue from a part of the placenta. If a chromosomal defect is found, the parents can be advised of its presence and the potential consequences for the fetus. Some parents opt to abort the pregnancy; others can prepare before birth for a child with special needs.

In addition to amniocentesis and chorionic villi sampling, researchers are working on devising easier tests to detect certain abnormalities. A test for Down syndrome, for instance, measures levels of certain hormones in the mothers blood. Abnormal levels of these hormones indicate an increased risk that the fetus has Down syndrome. These enzyme tests are safer and less expensive than the sampling tests and may be able to


Amniocentesis A method of detecting genetic abnormalities in a fetus; in this procedure, amniotic fluid is sampled through a needle placed in the uterus; fetal cells in the amniotic fluid are then analyzed for genetic defects.

Aneuploidy An abnormal number of chromosomes.

Angelman syndrome A syndrome caused by a deletion in chromosome 5 inherited from the mother.

Chorionic villi sampling A procedure in which hairlike projections from the chorion, a fetal structure present early in pregnancy, are suctioned off with a catheter inserted into the uterus. These fetal cells are studied for the presence of certain genetic defects.

Chromosomes The structures that carry genetic information in the form of DNA. Chromosomes are located within every cell and are responsible for directing the development and functioning of all the cells in the body.

Cri du chat syndrome A syndrome caused by a deletion in chromosome 5; characterized by a strange cry that sounds like the mewing of a cat.

Deletion Deletion of a segment of DNA from a chromosome.

Deoxyribonucleic acid (DNA) The genetic material in a cell.

Diploid Means double number;; describes the normal number of chromosomes for all cells of the human body, except for the sex cells.

Down syndrome A syndrome caused by trisomy 13; characterized by distinct facial characteristics, mental retardation, and several physical disorders, including heart defects.

Duplication A type of chromosomal defect in which a broken segment of a chromosome attaches to the chromosome pair.

Edwards syndrome A syndrome caused by trisomy 18; characterized by multisystem defects; is usually lethal by age 1.

Fragile-X syndrome A condition in which an extra X chromosome hangs from the X chromosome by a thread of genetic material.

Gene A discrete unit of inheritance, represented by a portion of DNA located on a chromosome. The gene is a code for the production of a specific kind of protein or RNA molecule, and therefore for a specific inherited characteristic.

Haploid Nucleus or cell containing one copy of each chromosome; the number of chromosomes in a sex cell.

Inversion A type of chromosomal defect in which a broken segment of a chromosome attaches to the same chromosome, but in reverse position.

Klinefelter syndrome A syndrome that occurs in XXY males; characterized by sterility, small testes, and female sex characteristics.

Meiosis Cell division that results in four haploid sex cells.

Metafemale An XXX female.

Mitosis Cell division that results in two diploid cells.

Monosomy A form of aneuploidy in which a person receives only one chromosome of a particular chromosome pair, not the normal two.

Patau syndrome A syndrome caused by trisomy 13; characterized by a hare lip, cleft palate, and many other physical defects; usually lethal by age 1.

Polyploidy A condition in which a cell receives more than two complete sets of chromosomes.

Prader-Willi syndrome A syndrome caused by a deletion in chromosome 5 inherited from the father.

Tetraploidy A form of polyploidy; four sets of chromosomes.

Translocation A genetic term referring to a situation during cell division in which a piece of one chromosome breaks off and sticks to another chromosome.

Triploidy A form of aneuploidy; three sets of chromosomes.

Trisomy A form of aneuploidy in which a person receives an extra chromosome of a particular chromosome pair, not the normal two.

Turner syndrome A syndrome that occurs in X0 females; characterized by sterility, short stature, and immature sex organs.

Zygote The cell resulting from the fusion of male sperm and the female egg. Normally the zygote has double the chromosome number of either gamete, and gives rise to a new embryo.

diagnose chromosomally-based conditions in more women. Most recently, scientists have devised a procedure called in situ hybridization, which uses molecular tags to locate defective portions of chromosomes collected from amniocentesis. The process uses fluorescent molecules that seek out and adhere to specific faulty portions of chromosomes. Chromosomes having these faulty regions then glow (or fluoresce) under special lighting in regions where the tags bind to, or hybridize with, the chromosome. The procedure makes identifying defects easier and more reliable.

See also Birth defects; Embryo and embryonic development; Genetic disorders.



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