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Chromosome 22 Central Inc.
is a registered Canadian Non-Profit Organization
and Registered Charity BN# 86009 3665 RR0001, and a Registered US
Corporation with Non-Profit Status
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What
is the 11;22 translocation and the Supernumerary der(22)Syndrome?
By Dr.
Beverly Emanuel,
The Children's Hospital of Philadelphia
In order to talk about the
Supernumerary der(22) Syndrome, first we need to step back and describe
some terminology. This is so that everyone reading this will begin on the
same footing. As you may know, a syndrome is really a collection of
findings that has been seen recurring over and over again in patients. For
example, one group of associated features actually includes: a heart
problem; malformed ears with pits or tags; small chin; and a high arched
or cleft palate. Syndromes are often named after the person or persons who
first described the collection of findings, although this has not happened
in this case. Once an underlying cause is identified, the name may be
changed to reflect the specific chemical abnormality, chromosome
difference, or gene change that caused the problem. Here, in the case of
the Supernumerary der(22)t(11;22), the name reflects the chromosomal
change.
Genes are made up of a
chemical called DNA and they are housed within larger structures called
chromosomes. Most people have 23 pairs of chromosomes (46 total), with one
of each pair coming from the mother and the other from the father.
Chromosomes are numbered 1 through 22; the 23rd pair are called sex
chromosomes because they determine a person's sex (male or female). The
chromosomes are found in every cell in the body. Cells are so small that
they, and the chromosomes they contain, can only be seen by observation
with a microscope.
Since genes are housed
inside the chromosomes, they themselves can't be seen at the microscope,
but they can be measured by using special "molecular" tests. A
good way to think about chromosomes and genes is to compare them to a
train. A train has a number of box cars just as a chromosome has a number
of stripes or bands. We can see the box cars when we look at a train, just
as we can see the chromosomes and their band patterns when we observe them
at the microscope. We cannot, however, see the packages inside the box car
without first opening the door. The same is true for a chromosome - the
genes are the packages inside.
When a baby is conceived
with either too much or too little chromosomal material, birth problems or
birth defects can occur. This may include a whole extra chromosome, as in
the Supernumerary der(22)t(11;22) syndrome (an extra
"derivative" 22 chromosome), a whole missing chromosome as in
Turner syndrome (a missing X), a piece of material missing or extra, or a
complex rearrangement of chromosomal material. When chromosomal material
is missing or extra, genes are generally missing or extra. Since genes are
the blueprint of the body, when they are deficient or duplicated, the
body's blueprint changes, frequently leading to birth problems and
learning differences.
So again you ask, what is
the 11;22 tranlsocation and the Supernumerary der(22) Syndrome?
In 1980, working at the
Children's Hospital of Philadelphia in the U.S.A., we (Dr. Elaine Zackai
and I) described the 11;22 translocation. At about the same time, the
t(11;22) was also described by a consortium of European scientists. People
who carry the 11;22 translocation have a very small piece of chromosome 22
(22q11 -> qter) transferred to chromosome 11 and a small piece of
chromosome 11 (11q23 -> qter) transferred to 22 (thus, it is called a
translocation). Chromosomes are divided into two parts, the top part being
called the "p"or short arm and the bottom part called the
"q" or long arm. Thus, the 22q11 -> qter and 11q23 -> qter
designation tells everyone who works in genetics that the area transferred
or translocated starts at a very specific spot on the "q" arm of
chromosomes 11 and 22 and goes to the end ("ter" or terminus) of
the "q" arm. It is very important to know the location of a
moved piece of chromosomal material in order to make some general
comparisons between individuals. This is because if two children have
different parts of the same chromosomes extra it would be like comparing
"apples to oranges" to compare them to one another. Most often
when there is a chromosomal rearrangement or translocation they are not
exactly alike.
However, with the t(11;22),
we suspect that the story is different. The 11;22 translocation is appears
to be the only translocation which seems to have recurred over and over
again, creating numerous carriers. The points of chromosome exchange
appear to be at the same spots on 11 and 22 in all instances. Several
hundred families with what appears to be the same rearrangement have been
described in the scientific literature. Carriers of the t(11;22) are
themselves normal, but come to the attention of the geneticist or
pediatrician subsequent to the birth of a child affected with the +der(22)
syndrome who has the derivative (22) or rearranged chromosome 22 as an
extra chromosome. Occasionally, translocation carriers are discovered upon
being studied for multiple miscarriages or infertility. Patients with the
+der(22) syndrome (or the extra chromosome) have distinctive features
which can include tags or pits in front of their ears, abnormally shaped
ears, a cleft or high arched palate, a small chin, a heart defect, mental
retardation and sometimes genital abnormalities in the male.
Geneticists have long been
interested in understanding the mechanisms and results of chromosomal
rearrangement. Chromosomal rearrangements or translocations are the result
of DNA rearrangements at the molecular level. Translocations are one of
the major categories of structural chromosomal alterations. The mechanisms
by which they are generated are largely unknown. Balanced translocations,
i.e. those in which there is no microscopically visible loss of genetic
material are amongst the most common of these rearrangements accounting
for roughly 0.2% of structural abnormalities. In general, the chromosomal
change is presumed to occur during the formation of either the egg or
sperm which created the first person with the rearrangement in a family.
Then, that person carries the change in every cell of his or her body and
is capable of passing the change to his/her children. It can be
transmitted either as a balanced rearrangement or as an extra chromosome
as in the Supernumerary der(22) Syndrome.
The cellular events which
end in chromosomal rearrangement or translocations, especially those like
the recurrent t(11;22), remain to be elucidated. Understanding the
molecular basis of this translocation may serve as a model for
understanding the mechanisms involved in creating other translocations.
Thus, efforts to map the elusive constitutional t(11;22) translocation
breakpoint are progressing. For example, we have already determined that a
major portion of the DNA which surrounds the region of the breakpoint on
chromosome 22 is duplicated several times on chromosome 22. This
duplication which is normally present on every chromosome 22 may make this
chromosome more prone to engage in rearrangements. The determination of
the exact size of the duplication, number of copies and their location is
currently under investigation. Further, the relationship between having a
translocation, especially an 11;22 translocation, and how chromosomes
separate during formation of egg and sperm, is not clear and has not been
well studied. These are some of the studies we are currently pursuing in
our laboratory research.
Further, our research team
includes several geneticists who specialize in identifying genes, how they
work, and why they cause problems when they are extra or changed. We hope
to provide the scientific community with new information about the genes
which reside in the duplicated pieces of chromosomes 11 and 22. We also
try to understand how genes influence each other. When there is a
supernumerary der(22), many genes are extra but probably not all of them
play a role in causing the symptoms associated with the duplication. Thus,
additional studies will be necessary to understand the role that each of
the genes plays in the cause of the complex and variable symptoms which
are seen in the children with the Supernumerary der(22) syndrome. Our
research studies will enable us to determine if these problems are caused
by the duplication of several genes, or by many duplicated genes. Further,
most individuals with the Supernumerary der(22) syndrome have a
duplication of the same exact pieces of chromosomal material but they do
not all have the same symptoms. Perhaps other factors play a role in who
develops which symptoms. Much more work needs to be done and this is our
job for the future. We welcome your participation in our research efforts
and thank you for all of your interest. TOGETHER, we will begin to
understand the t(11;22) and the Supernumerary der(22)t(11;22) syndrome.
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