Table of Contents- Lesson 1) ( Next)
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
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
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
OTHER STRUCTURAL ABNORMALITIES
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
PRACTICE ACTIVITY 3
Use a T or F to show whether each statement is true
1. All parents of children with chromosome abnormalities should
have a chromosome study.
PRACTICE ACTIVITY 3: ANSWERS
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
Table of Contents- Lesson 1( Next) (Glossary)