What type of mutation is Down syndrome

This article explains what is known about the genetics of Down's syndrome.

Anna Kessling (UK) and Mary Sawtell (UK)

Introduction
Genes are present in every cell of the body. They are inherited from our parents and are responsible for our development from fertilized egg to fully grown adult. They provide the chemical information that is needed to maintain our body and keep it working well. People with Down's syndrome have the same genes as anyone else; they just have 1% extra. This is enough to change the finely-tuned balance of the body and produce the physical and intellectual characteristics found in people with Down's syndrome.

Cells
The human body is made up of cells. Each cell is like a tiny factory which makes the materials needed for growth and maintenance of the body. Different parts of the body have specialised cells with special tasks, for example muscle cells are different from nerve cells, heart cells are different from brain cells.

The production and output of each cell is controlled by genes. The genes are the same in every cell of the body. Not all the genes are active in any one cell at any one time, however. The active genes in a cell are only those appropriate to the cell type and its functions.

The body grows by making new cells. It does this by making an exact copy of the genes in a cell. The cell then divides in two with one copy of the genes in each new cell.

Genes
Genes contain the body's instructions for making its parts and for its day to day running. Genes therefore control or influence such things as:

• Our physical appearance
• The way babies and children grow and develop, even before they are born
• The timing of the milestones of growth and development
• The body's supply and use of building and maintenance materials
• The way the body ages
• A person's resistance to illness

Genes are passed from parents to children. Most people have two copies of every gene - in general one copy comes from the mother and the other from the father.

The genes are made of DNA (deoxyribonucleic acid). The arrangement of chemicals in the DNA is different for every gene. These chemical instructions tell the body what components to make, and how, when and in what quantity to make them, in order to ensure normal working of the body. There are also long stretches of DNA, the precise role of which is still a mystery.

Chromosomes
The genes are grouped together in long, thin, thread-like structures called chromosomes. Thus chromosomes carry our genetic information.

There are 46 chromosomes (in 23 pairs) in all body cells (except the sperm and egg cells). Each pair of chromosomes has different genes. One chromosome of each pair comes from the mother and one from the father. A person's characteristics are determined by the interaction of the copies of the genes from each parent.

The chromosome pairs are numbered 1-22 according to size. Chromosome 1 is the largest. Each chromosome has a long arm and a short arm.

The 23rd pair are the sex chromosomes which are called the X and Y chromosomes. Girls have two X chromosomes and boys have an X and a Y. The sex chromosomes are different from the others.

In chromosome tests, the chromosomes (usually from blood cells) are stained with dye. Each pair has a different staining pattern. When seen down a microscope the chromosomes lie in a haphazard manner, but when they are photographed, cut out and arranged in pairs, a picture of an individual's chromosomes known as a karyotype is obtained.

The genes, thousands on each chromosome, are spaced along the length of the DNA molecule, in a definite order. Apart from the X and Y chromosomes, the order of the genes on one chromosome exactly matches the order on the other chromosome of the same pair (and on chromosomes of the same number in everyone else). In general, there are only two copies of each gene and in all people they are always on the same chromosome pair.

The two copies of each gene may not be identical. Any changes may be small "misprints" or bigger alterations, with a corresponding effect of the "readability" of the instructions. When this happens, variation occurs between people - this variation is sometimes advantageous, sometimes neutral and sometimes unhelpful. Often a mistake in the one copy of a gene can be "cancelled out" when there is no mistake is the other copy of the same gene. Geneticists believe that everyone carries a number of defective genes which are partnered by a normal copy which "cancels" the defect. They also believe we all carry a number of genes with small variations which are not cancelled out, and which account for some of the differences in appearance or health among people in the general population.

Ordinary cell division
The body grows by making new cells. New cells are made by one existing cell dividing into two. In order to work, each new cell needs a set of 46 chromosomes. Before a cell divides an exact copy of each chromosome is made, creating a complete new set. The two sets of chromosomes move to opposite ends of the cell. The cell then divides across the middle producing two new cells, each with 46 chromosomes. This type of cell division is known as mitosis.

Eggs and Sperm
Eggs and sperm are different from all other cells in that they contain only a single set of 23 chromosomes. This means that when the egg and sperm come together at fertilisation, the usual number of 46 is restored, ready for the baby's development.

There is a special type of cell division used only in the making of eggs and sperm.This special type of cell division is called meiosis. Meiosis involves two rounds of cell division. The first round is very specialised; it is called reduction division, because it reduces the number of chromosomes to 23. The second meiotic division is similar to ordinary cell division (mitosis).

Men make millions of fresh sperm, all the time, from puberty onwards. It is quite different in women. Long before birth, the female embryo has already started making the cells which will form her eggs when she is a mature woman. After puberty, a woman's ovaries release one egg (or occasionally more) per month until menopause.

All eggs made by the mother will contain one copy each (not a pair) of chromosomes 1-22, and an X chromosome. All sperm made by the father will contain one copy each (not a pair) of chromosomes 1-22 and either an X or a Y chromosome. If an X-carrying sperm fertilises the egg the baby will be a girl, whilst if a Y-carrying sperm fertilises the egg the baby will be a boy. When a 23-chromosome egg is fertilised by a 23-chromosome sperm, the first cell of a 46 chromosome embryo, fetus and baby is made. All that baby's cells will have the same 46 chromosomes which were in the original fertilised egg.

GENETICS OF DOWN'S SYNDROME

Overview
Down's syndrome occurs in babies born with extra chromosome 21 material in their cells. Down's syndrome is also known as trisomy 21. Trisomy 21 means there are 3 (tri) copies of chromosome (somy) 21.

There are three main types of Down's syndrome:

• Regular trisomy 21 - also known as standard or free trisomy 21 - in which all the cells have an extra chromosome 21. Around 94% of people with Down's syndrome have this type.
• Translocation - in which extra chromosome 21 material is attached to another chromosome. Around 4% of people with Down's syndrome have this type.
• Mosaic - in which only some of the cells have an extra chromosome 21. Around 2% of people with Down's syndrome have this type.

Chromosome 21 is thought to contain around 1% of the body's genes. Down's syndrome therefore arises from a change in gene quantity rather than gene quality.

We do no know exactly why Down's syndrome occurs. This makes it different from other genetic conditions, such as cystic fibrosis or sickle cell disease, whose inheritance can be traced through families. Down's syndrome can be traced through families in less than 1% of people with the condition. These people all have rare types of translocation.

It is very unusual for parents to have more than one child with Down's syndrome, or for relatives of these parents to have a child with the condition.

Regular Trisomy 21
Most people with Down's syndrome have this type.

Individuals with regular trisomy 21 have an extra chromosome 21 in every cell. They therefore have 47 chromosomes in each cell instead of the usual 46.

How does regular trisomy 21 occur?
Regular trisomy 21 occurs because of an unusual cell division which has produced either an egg or a sperm with 24 chromosomes instead of 23. When this egg or sperm fuses with an ordinary egg or sperm, the first cell of the developing baby has 47 chromosomes instead of 46, and all that baby's cells will have 47 chromosomes. No one knows why this happens. There is no way or predicting whether a person is more or less likely to make eggs or sperm with 24 chromosomes.

The extra chromosome can come from uneven division of the chromosomes (called non-disjunction) at either the first or the second meiotic division, in either parent.

Where does the extra chromosome come from?
The extra chromosome comes from either the mother or the father. It makes no difference to the person with Down's syndrome which parent the extra chromosome came from.

Why does regular trisomy 21 happen? Despite much research this question remains unanswered. There is no evidence that any nationality, ethnic group, diet, medicines, illnesses or upbringing have any influence on whether or not a parent can or will have a child with Down's syndrome. Also, because Down's syndrome is present from the time of conception, nothing a woman does in pregnancy will influence whether or not her baby has Down's syndrome. Nothing is known which could have stopped the parent giving an extra chromosome. There is nothing "different" about the parents of a child with the condition.

The parents' ages? Any couple can have a baby with Down's syndrome, but it is well known that older women are more likely to have a baby with the condition than younger women.

There is controversy about the influence of the father's age. Most researchers consider that the father's age does not appear to affect the chance of having a child with Down's syndrome.

At the present time about one baby with Down's syndrome is born for every 1,000 total births. More babies with Down's syndrome are conceived than are born, because the chance of miscarriage is higher if the foetus has Down's syndrome.

The reason why older women are more likely to have children with Down's syndrome is unknown. There are two main current theories. One theory suggests that all women have some eggs with an extra chromosome, and that these eggs are more likely to be used last, towards the end of a woman's reproductive life. The other theory suggests that the rate of trisomic conceptions is the same at all maternal ages, but that affected pregnancies are more likely to continue (less likely to end in miscarriage) in older women. The assumption is that the body recognises that this is a late pregnancy, perhaps the last or only one, and thus tries harder to make sure the pregnancy comes to term.

What is the chance of having another baby with the condition?
Parents with one baby with regular trisomy 21 are usually told that the chance of having another baby with Down's syndrome is 1 in 100. Very few families are known who have more than one child with Down's syndrome, so the real chance is probably less than this.

There are differences of opinion as to how the much-quoted figure of 1 in 100 should be interpreted for older mothers who already have one child with Down's syndrome. Some feel that this 1 in 100 chance should be added to a woman's chance for her age, so that for a woman of 43 years for example, her (age-related) chance would be 1 in 49 (approximately 2%), added to 1 in 100 (1%), giving an overall chance of 1 in 33 (approximately 3%). Others feel that, when the age-related chance is more than 1 in 100, this alone gives the more realistic estimate (so for a woman of 43, the chance remains 1 in 49).

Translocation and partial trisomy
Some 4% of people with Down's syndrome do not have an extra whole, separate chromosome 21 (see regular trisomy 21 above), but have an additional part of chromosome 21 attached to another chromosome. This usually arises when the small arms of chromosome 21 and another chromosome break, and the two remaining long arms join together at their exposed ends. This process of chromosomes breaking and rejoining to other chromosomes is known as translocation (because the chromosome material has transferred its location).

People with Down's syndrome which has arisen in this way still have an extra copy of a large part of chromosome 21. Their features of Down's syndrome are no different from those in a child with regular trisomy 21.

The chromosomes that can be involved are numbers 13, 14, 15, 21, 22.

How does translocation occur? In two-thirds of people with Down's syndrome due to a translocation, the translocation was an isolated event during the formation of the individual egg or sperm involved in their conception. As with regular trisomy 21, there is no known reason why this occurs. It cannot be predicted and it is not a result of anything the parents or other family members have done.

Because it is a new event, this is sometimes called a de novo translocation.

The egg or sperm contains the usual number of chromosomes (i.e. 23) but these include the translocated one. Thus there is one free, whole chromosome 21 and most of a second chromosome 21 attached to another chromosome. If this egg or sperm containing 23 chromosomes (+ translocated part) fuses with an ordinary sperm or egg, the fertilised egg, fetus and baby will have 46 single chromosomes, but one of the chromosomes will have an extra copy of most of the chromosome 21 material attached to it. The translocated chromosome acts like a single chromosome in cell division, and hence all the cells produced from this first cell will contain the extra chromosome 21 portion. This baby will therefore have Down's syndrome.

In the other one third of people with the translocation type of Down's syndrome, the translocation is inherited from one of the parents. This parent has two whole number 21 chromosomes in each cell but one of them is attached to another chromosome. As there is no loss or gain of any genetic material this is known as a balanced translocation and the parent is a carrier of the translocation. It is important to realise that because such parents have the usual amount of genetic material, they have no traces of the syndrome themselves and never will have. They cannot be expected to know they are carriers, as the only way of knowing is to study their chromosomes.

When people who carry a translocation produce an egg or sperm, it is possible for them to pass on both the translocated chromosome and the free chromosome 21 in the egg or sperm. This will result in a fertilised egg with two free 21 chromosomes and a translocated chromosome. The baby will therefore have Down's syndrome.

As 4% of people with Down's syndrome have the translocation type, and one third of this group have inherited it, only about 1% of people with Down's syndrome have inherited the condition.

Is age a factor in translocation Down's syndrome? No. unlike regular trisomy 21, translocation occurs equally frequently whatever the age of the parents.

What is the chance of having another child with the condition?
When neither of the parents is a carrier, the translocation was an isolated event with only a small chance of its happening again (geneticists quote less than 1%). Translocation carriers can have children who are carriers, children whose chromosomes show no rearrangement at all, or children with Down's syndrome.

For translocations involving chromosomes 21 and any other chromosome, the chance of another child with Down's syndrome being born is about one in six if the mother is the carrier and about one in twenty if the father is the carrier. A few people are carriers for a translocation between two chromosomes 21; in these people, who are quite ordinary themselves, the only possible outcome is a child with Down's syndrome.

How can we know which type of Down's syndrome a baby has?
There are no differences in the features or ability levels of people with regular trisomy 21 and translocation Down's syndrome. The only way of knowing what type of Down's syndrome a person has, is by taking a blood sample and looking at the chromosomes.

A very few children with translocation have partial trisomy 21 - where only a part of chromosome 21 is present in 3 copies. These children may have fewer characteristics of Down's syndrome. Like the more usual type of translocation described above, this type may arise de novo, or a parent may carry it.

As one third of people with translocation Down's syndrome have inherited the condition, their parents have a high chance of having another affected child and may wish to know whether this is so. To identify these parents, chromosome tests are done on all new babies with Down's syndrome. Blood samples can then be taken from parents of babies with translocations, to find out whether one of the parents carries the translocation.

Genetic counselling should always be available to families with a child with Down's syndrome.

Translocation carriers and other members of the family? Even if parents do not intend to have more children, knowing that one of them is a carrier can be important for all their children or other relatives. Relatives of a person who carries a translocation have an increased chance of being translocation carriers.

Mosaicism
People with mosaic Down's syndrome have an extra chromosome 21 in only some of their cells. They therefore have a mixture of trisomic cells and ordinary cells. The mixture can vary from very few to nearly 100% trisomic cells. Depending on the proportion of trisomic cells, and which parts of the body contain these cells, individuals may be less affected both in their physical features and in their ability level than those with regular trisomy or translocation. As for all types of Down's syndrome, it is not possible to say at birth how affected a person will be, only time will tell as the child develops.

How does mosaic Down's syndrome happen?
Mosaicism arises after the egg and sperm have fused at conception. As the cells divide and multiply by ordinary cell division, a chromosome goes astray and a single cell with an extra chromosome 21 is formed. This cell continues to divide by ordinary cell division together with the non-trisomic cells and a mixture is produced.

As with the other two types of Down's syndrome (apart from when a parent is a carrier) there is no known reason why mosaic Down's syndrome occurs. It happens equally often in parents of all ages.

What are the chances of having another child with mosaic Down's syndrome?
Mosaic Down's syndrome is very rare, therefore there are no accurate figures on this. It is believed that the chance is lower than it would be if the child had regular trisomy 21.

Some questions we have been asked
Can a test-tube baby have the condition?
Yes - full chromosome tests are not carried out before the embryo is implanted.

Is trisomy 21 the only kind of trisomy?
No. some babies are born with trisomy 13 or trisomy 18. Chromosomes 13 and 18 are larger than chromosome 21 and so the genetic imbalance is greater and the effects on the baby are generally more severe than in trisomy 21. Trisomy for the X chromosome or an extra copy of the Y can occur, with relatively few effects for the child. Trisomies of every other chromosome can occur, but usually those pregnancies end in miscarriage. Parents who have had a baby with one kind of trisomy are not thought to be more likely to have a baby with any other kind of trisomy.

Is trisomy much more frequent in miscarriages?
Much more. In about half of all miscarriages occuring in the first 3 months of pregnancy, the developing baby has an altered number of chromosomes.

Will gene therapy make a difference?
As we understand more about how the genes on chromosome 21 interact to cause Down's syndrome, we can imagine a situation in which it might eventually become possible to switch off some of the genes (or maybe even the whole extra chromosome) responsible for Down's syndrome. A great deal more understanding of the basic mechanisms of Down's syndrome and a great deal more development in gene therapy is needed before we can contemplate such treatment, but it remains a long-term possibility.

Are there any differences in the genes or chromosomes of grandparents of children with Down's syndrome?
Unless the grandparent is a carrier of a balanced translocation (a very rare event) there are no known differences in the genes or chromosomes of grandparents of children with Down's syndrome from those of anyone else's grandparents. There is nothing known that the grandparents might have done which would explain their grandchild being born with Down's syndrome.

Can adults with Down's syndrome have children; and if so, what is the chance of their children having the condition?
Yes. A woman with Down's syndrome can have children. If her partner does not have Down's syndrome, the theoretical chance of the child having Down's syndrome is 50%. There have been only a few reports of men with Down's syndrome fathering children. Again, if a man's partner did not have Down's syndrome, the chance that the baby would have the condition is 50%. If both partners have Down's syndrome there is a high chance of their children having the condition. As these events are still rare it is difficult to obtain accurate figures.

My grandmother's sister had Down's syndrome. She died 40 years ago when she was 30. Does this mean that I could have an increased chance of having a baby with the condition?
It is unlikely. There is a small chance that she would have had the inherited form of translocation Down's syndrome, in which case you could be a carrier. Chromosome testing was not introduced until 1959 so the family may not know what kind of Down's syndrome she had. If your grandmother had a lot of children and grandchildren and none of them was affected, it is very unlikely that she was a carrier. If you want to be completely sure that you are not a carrier, chromosome test would need to be carried out on your blood.

People with Down's syndrome are all very different from each other, in looks and personality and ability. Why is this, when they all have extra material from chromosome 21?
People with Down's syndrome get the extra chromosome material along with the full set of chromosomes from their parents. All the genes they inherit are ordinary ones, which explains why they resemble their families in the same way as ordinary children. The differences in genes that children with Down's syndrome inherit from their parents, together with differences in their environment, explain the differences between one child with Down's syndrome and another.

Can the tests ever be wrong?
If an experienced health professional has seen features of Down's syndrome in your child, and the blood test result shows regular trisomy 21 or a translocation type, there should be no doubt. In mosaic Down's syndrome, because all the cells in the body do not show trisomy, it is possible for a blood sample not to include any trisomic cells, or to contain only trisomic cells, which may lead to difficulties in arriving at the correct diagnosis. In this situation, while further tests may help, it is not actually possible to disprove mosaicism.

Blood tests are done by humans. Mistakes can, of course, be made at one of the many stages that a blood sample passes through before a result is given to the patient. This, however, is very rare.

Summary

• Down's syndrome is always caused by the presence of extra chromosome 21 material in a person's cells.
• There are 3 types of Down's syndrome. Most people with the condition have regular trisomy 21. Much smaller numbers have translocation, or mosaic Down's syndrome.
• The only way of finding out what type of Down's syndrome people have is to do a blood test and examine their chromosomes under a microscope.
• 4% of people with Down's syndrome have the translocation type. About 1 in 3 of these (about 1% of people with Down's syndrome) have inherited the conditions. One of their parents will be a carrier of the translocation. These parents have an increased chance of having a second child with the condition.
• There is no known reason why Down's syndrome occurs (except on the rare occasions when it has been inherited).
• Parents who have one child with regular trisomy 21 are thought to have a slightly increased chance of having another child with the condition.

REFERENCES

H. S. Cuckle, N. J. Wald and S. G. Thompson (1987) British Journal of Obstetrics and Gynaecology, vol. 94, pp. 387-402. E. Alberman et al. (1995) British Journal of Obstetrics and Gynaecology, vol 102, pp. 445-447. C. Cunningham (1988) Down's Syndrome: An Introduction for Parents. Souvenir Press.

M. Selikowitz (1990) Down Syndrome: The Facts. Oxford University Press.