Table of Contents- Lesson 1) ( Next) (Glossary)


Abnormalities in chromosome structure follow a chromosome break and, during the repair process, the reunion of the wrong segments of the chromosome. If, following repair, there is a loss or gain of chromosomal material (an unbalanced rearrangement) there can be significant clinical consequences. If there is no loss or gain of chromosomal material (a balanced rearrangement), then the individual is mentally and physically normal. However, there is an increased risk of having chromosomally abnormal offspring because individuals who carry balanced chromosome rearrangements may produce chromosomally unbalanced gametes.


Of all the structural chromosome rearrangements, the most clinically significant is a translocation. Translocation involves two nonhomologous chromosomes (e.g., chromosome 2 and chromosome 6). Following a break in each of the chromosomes, and subsequent reunion, a segment of chromosome 2 becomes attached to chromosome 6 and vice versa.

Fig. 1.4. Translocation

In most cases, there is no loss or gain of chromosomal material during the exchange process. It is estimated that 1 in 500 individuals are normal translocation carriers.

On occasion, apparently balanced translocation carriers (on karyotype studies) are clinically abnormal. One explanation for this finding is that the break may have occurred in the middle of a gene which then results in the formation of an abnormally short, nonfunctional protein.

Individuals and families have been described with a translocation chromosome abnormality and a concurrent genetic condition; the genetic condition occurring because the chromosome breakpoint is in the midst of a gene. Research studies of these informative families have led to the localization of specific genes to specific chromosome segments (e.g., Duchenne muscular dystrophy on Xp21, neurofibromatosis on 17q, retinoblastoma on 13q14, etc.).

When an apparently balanced translocation is found on amniocentesis, chromosome studies are done on both parents. If the translocation is familial (one of the parents is a normal translocation carrier), then it is safe to assume that the fetus carrying a similar translocation is going to be normal. If the translocation is de novo (the parents are not translocation carriers), then the fetus has a 10% empiric risk of having a possible genetic abnormality. It may seem surprising that the risk is not much greater. This is because only 10% of the genome (genetic constitution of an individual) carries coding sequences for genes. The other 90% of the genome consists of noncoding sequences.

As previously noted, people who carry balanced translocations have a high risk of miscarriages and abnormal offspring because they are more likely to create unbalanced gametes. In meiosis, the normal chromosomes and the translocated chromosomes pair up by creating a cross figure (quadrivalent) (Figure 1.5). The chromosomes are distributed to the daughter cells by the centromeres which are attached to spindle fibers. The spindle fibers contract and draw the attached chromosome to each of the poles (segregation).

Fig. 1.5. Balanced reciprocal translocation. This figure shows the generation of a balanced reciprocal translocation between chromosomes 2 and 6, and formation of a quadrivalent in meiosis: t = translocated segment, c = centric segment, solid circle = chromosome 2 centromere, open circle = chromosome 6 centromere. Homologous centromeres are both solid or both open circles and nonhomologus centromeres are one solid and one open circle (see text).

There are three ways the chromosome pairs segregate. Adjacent 1 segregation occurs when adjacent chromosomes with nonhomologous centromeres move to daughter cells. Adjacent 2 segregation occurs when adjacent chromosomes with homologous centromeres move to daughter cells. Alternate segregation occurs when alternate chromosomes with nonhomologous centromeres move to daughter cells.

As shown by the six possible products in Figure 1.6, adjacent 1 and adjacent 2 segregation leads to unbalanced gametes, whereas alternate segregation leads to balanced gametes with a normal chromosome complement (in this illustration a normal 2 and a normal 6) or a balanced translocation complement (chromosome 2 with a piece of 6, and chromosome 6 with a piece of 2). Again from the illustration, two of the six possible gametes will lead to normal offspring, and four of the six gametes will result in chromosomally abnormal offspring. However, the actual risk for an abnormal offspring is highly variable, depending on the chromosomes involved and the size of the segments that are trisomic or monosomic.

Fig. 1.6. Six possible gametes following meiotic segregation of a reciprocal translocation

Noted above is the usual 2:2 segregation in meiosis where two chromosomes, of the original four chromosomes, are distributed to each of the two daughter cells. On occasion, a 3:1 segregation occurs in meiosis where three chromosomes go to one daughter cell and one chromosome goes to the other daughter cell; in effect an aneuploidy nondisjunction affecting translocation chromosomes.

The risk of abnormal offspring in translocation families depends to some extent on how the family was ascertained. If the family is being seen because they have a child with a chromosome abnormality, then obviously the unbalanced translocation karyotype is compatible with life. In such families empiric data suggests that the risk of recurrence is approximately 15%. If, on the other hand, the family comes to clinical attention because of multiple miscarriages, or as part of an infertility workup, then the unbalanced translocation karyotype is probably not compatible with life and the risk of abnormal offspring is probably low, around 1.5%.

A Robertsonian translocation is a particular type of translocation involving the reciprocal transfer of the long arms of two of the acrocentric chromosomes: 13, 14, 15, 21 or 22. On rare occasions, other non-acrocentric chromosomes undergo Robertsonian translocation, a reciprocal transfer of the whole long or short arms close to the centromere. A relatively common Robertsonian translocation is between chromosome 14 and chromosome 21. In meiosis, a trivalent is formed.

Fig. 1.7. Robertsonian translocation. This figure shows the formation of a Robertsonian translocation involving chromosomes 14 and 21, and the formation of a trivalent in meiosis. Alternate segregation results in gametes having either a normal (14 and 21) or balanced translocation (t(14;21)) chromosome complement. Adjacent segregation results in unbalanced gametes, either disomy (14 and t(14;21), or 21 and t(14;21)) or nullisomy (14 or 21).

With adjacent 1 and adjacent 2 segregation, the gametes produced result in trisomy 14, monosomy 14, trisomy 21 or monosomy 21 following fertilization. With alternate segregation, the resulting gametes have a balanced translocation 14;21 or the normal chromosome complement following fertilization. There are six possible gametes: one normal, one balanced translocation, and four unbalanced translocation complements.

Of the latter four, only trisomy 21 can come to term.

Theoretically, a person who carries a 14;21 translocation has a 1/3 chance of having a normal child, a 1/3 chance of having a child who carries a balanced translocation, and a 1/3 chance of having a child with Down syndrome. However, the actual risk for Down syndrome is much smaller because many of the trisomy 21 fetuses are spontaneously aborted. The empiric risk of having a child with Down syndrome is around 3 to 5% if the father is the carrier, and 10 to 15% if the mother is the carrier. The male translocation Down syndrome patient will have a karyotype of 46,XY,t(14;21) inferring that there are two normal chromosome 21s plus a third 21 that is attached to chromosome 14. The carrier mother of such a patient will have a karyotype of 45,XX,t(14;21) inferring a single chromosome 21, and a second 21 attached to chromosome 14.


Inversions involve only one chromosome in which two breaks occur and, in the process of repair, the intervening segment is rejoined in an inverted or opposite manner. Since there is no loss nor gain of chromosomal material, inversion carriers are normal. An inversion is paracentric if the inverted segment is on the long arm or the short arm and does not include the centromere. The inversion is pericentric if breaks occur on both the short arm and the long arm and the inverted segment contains the centromere. In meiosis, the normal chromosome and the inverted chromosome will form a loop to allow pairing of specific DNA sequences. Crossovers, or the exchange of chromatids (a normal event in meiosis between homologous chromosomes), that occur within the inversion loop result in gametes with both deletions and duplications that are often not compatible with life and result in a high incidence of miscarriages. Thus, inversion carriers have a relatively low risk of having abnormal offspring.

Fig. 1.8. Pericentric inversion


Deletion refers to the loss of a segment of a chromosome. This can be terminal (close to the end of the chromosome on the long arm or the short arm), or it can be interstitial (within the long arm or the short arm). Deletions have been described on all chromosomes. The deletions with an associated identifiable clinical phenotype (physical makeup of an individual) include Wolf-Hirschhorn syndrome (4p-), and cri-du-chat syndrome (5p-). They both involve the loss of the distal end of the short arm. Other deletions that are clinically recognizable are deletions of 18p, 18q, 22q, 21q, 15q, 11p, 17p and 4q. Deletions are expected to be more clinically severe than their counterpart, duplications.

Fig. 1.9. Deletions


Duplication refers to an extra chromosomal segment within the same homologous chromosome or an extra chromosomal segment on another nonhomologous chromosome. Again, the clinical findings are highly variable depending upon the chromosomal segments involved.

Fig. 1.10. Duplication


There are other rarer forms of structural chromosome abnormalities such as rings, insertions, isochromosomes and markers. In some cases these abnormalities lead to duplication of chromosome material. In other cases, such as ring chromosomes, a deletion occurs.

Fig. 1.11. Ring chromosome

Fig. 1.12. Isochromosome

The identification of a structural chromosomal abnormality in a child should trigger chromosome analysis of the parents to rule out the carrier state. In contradistinction, a numerical chromosome abnormality in a child is presumed to be due to a sporadic cell division error and parental chromosome studies are not indicated. There are, however, a few exceptions to this rule.


Abnormalities in chromosome structure occur when one or more chromosomes break and, during the repair process, the broken ends are rejoined incorrectly. Individuals who inherit a balanced chromosome rearrangement are physically and intellectually normal; however, they are more likely to produce chromosomally abnormal gametes. Individuals with balanced translocations often come to clinical attention following the birth of a child with a chromosome abnormality. They are also more likely to have miscarriages and may be identified if a chromosome study is done to determine the cause of the pregnancy losses.


Use a T or F to show whether each statement is true or false.

1. All parents of children with chromosome abnormalities should have a chromosome study.

  1. Individuals who carry a balanced chromosome rearrangement cannot have normal children.


1. False Chromosome studies on parents should be ordered if a child is found to have a structural chromosome abnormality (e.g., translocation, deletion, inversion, etc.) to rule out carrier status. However, aneuploidy such as trisomy 21 and monosomy X (Turner syndrome), is caused by nondisjunction. As nondisjunction occurs sporadically at the time the egg or sperm is formed, it is assumed that the parents of these children have a normal chromosome complement.

  1. False While it is true that individuals who carry a balanced chromosome rearrangement are more likely to have miscarriages and children with chromosome abnormalities, the vast majority can have chromosomally normal children. One exception to this rule is a person who carries a 21;21 translocation. He/she will either pass on the 21;21 translocation chromosome and have a child with Down syndrome, or he/she will fail to pass on the 21;21 translocation chromosome and the fetus, with monosomy 21, will be miscarried. Thus, a 21;21 translocation carrier has a 100% chance of having a child with Down syndrome.

Table of Contents- Lesson 1( Next) (Glossary)