Genes are instructions that control the way we grow and develop. We have around 20,000 different genes and, for the majority, these come in pairs. We get one copy from our mother and one copy from our father. In turn, we pass one copy onto each of our children.
Every time a cell divides all the genes are copied out. Not uncommonly, gene changes can occur in the copying process. Most of these have no significant impact but sometimes they can cause genes not function as they should. Sometimes these gene changes have been inherited from a parent and sometimes the changes happen for the first time in a child. These changes happen by chance.
What is mosaicism?
Mosaicism is the term used when someone has a mixture of cells – some of the cells have a gene change and some do not.
This is illustrated by these diagrams:
A cell with two standard copies of a gene
A cell with one standard copy of the gene and one with a gene change
Someone with completely standard genes will have this pattern of cells:
Someone with a genetic change in one copy of a gene in every cell in their body will have this pattern of cells:
Someone who is mosaic for a change in a gene will have this pattern of cells. You can see why it is called mosaicism as it looks like a mosaic tile pattern:
The proportions of cells will vary from person to person. Some people will have high numbers of cells with normal genes and some people will have high number of cells with altered genes. Everyone is different. The pattern of cells with normal genes and cells with altered genes can be different in different parts of the same person. This means that someone might have a lot of cells with normal genes and not many cells with an altered gene in one part of their body, but a lot of cells with an altered gene and not many cells with normal genes in another part of their body. Again, everyone is different.
The pattern of cells with standard genes and cells with gene changes can vary throughout the body. This means that someone might have a lot of cells with standard gene copies in one part of the body and very little in another. Where the gene changes are may influence how impacted that individual is by the condition caused by the gene.
How does mosaicism happen?
We all start as one cell, which is formed when an egg cell and a sperm cell fuse together at conception.
That cell divides into two cells, and each of those cells divide into two. This happens millions of times until a baby is fully grown and continues to happen in many cells throughout life. This is shown in this diagram:
If an egg or sperm has a genetic change this will be present at conception and will then be copied in every cell of the baby. Sometimes a gene change happens at the moment of conception and, again, that change will be present in every cell of a baby.
But sometimes a change in a gene happens after conception. It will then be present in every cell that comes from the cell where the change started but won’t be present in other cells. This is what causes mosaicism.
A change in a gene happens by chance and we all have many of them. The changes are not caused by anything that happens in a pregnancy and are no-one’s fault. Most of them do not have any effects at all
Generally, if a gene change happens soon after conception, the change will be in a lot of cells throughout the body. If the gene change happens later in development then it will be in fewer cells and may only be present in one part of the body.
Mosaicism happens often in nature and explains why different colour leaves can happen on the same plant and why some animals can have patterns on their coats, like a tabby cat.
Genetics of retinoblastoma
Everyone has two copies of the retinoblastoma gene (RB1). A retinoblastoma tumour develops when both copies of the RB1 gene in the same cell have a gene change and are not working as they should.
People who have the ‘genetic’ form of retinoblastoma have a gene change in one copy of RB1 in every cell. A retinoblastoma develops if a change develops in the other copy of the RB1 gene in any cell of the eye. If this second change happens only in one cell they will develop unilateral retinoblastoma. If this change happens in more than one cell, they will develop multifocal unilateral retinoblastoma, bilateral retinoblastoma or occasionally, trilateral retinoblastoma (this involves a tumour in the pineal gland).
People who have the’ non-genetic’ form of retinoblastoma are born with standard copies of the RB1 gene in all their cells. They develop changes in both copies of the RB1 gene in only one cell in one eye so will develop unilateral retinoblastoma.
Is mosaicism tested for when genetic tests are done for retinoblastoma?
Yes. The routine tests will detect most cases of mosaicism. But they may not detect it if the proportion of cells is quite unbalanced and more than 90% of cells are one type with fewer than 10% of the other type. This means that:
- No genetic change may be found in people with high numbers of cells with two standard copies of the RB1 gene:
- Only the genetic change may be found in people with high numbers of cells with an RB1 gene change:
Because we know that genetic testing might not detect all cases of mosaicism, we are quite careful in interpreting results. This is why we say to some families that the results are normal but any new babies in the family should still have eye checks.
Why is mosaicism relevant to retinoblastoma?
There are three things to think about with respect to mosaicism and retinoblastoma. These are:
- The chances of a child developing retinoblastoma
- The chances of passing a RB1 gene change to a child
- The chances of developing a second tumour
What are the chances of someone with mosaicism developing retinoblastoma?
It is impossible to give an accurate answer to this as the chances will be affected by the level RB1 gene change in the eye. We usually test genes in blood. We can occasionally test other tissues, but we cannot test the genes in an eye, unless the eye has been removed. The balance of standard genes and those with gene changes in the eye may not be the same as that in the blood.
Some people with mosaic changes in the RB1 gene will develop retinoblastoma but some will not. We cannot give precise chances for this, but the chances will be smaller than for someone who has a genetic change present in every cell.
Sometimes we find a mosaic gene change in someone who has retinoblastoma. In that situation, the gene change will be linked with the retinoblastoma.
Sometimes we find a mosaic gene change in the parent of a child with genetic retinoblastoma. In that case, we can be sure that the parent will not develop retinoblastoma, but there is a chance that they would pass the gene change on to a child.
What are the chances of someone with a mosaic RB1 gene change passing this to a child?
Again, it is impossible to give an accurate answer to this as the chances will be affected by the level of gene changes present in the ovaries or testes, where the eggs and sperm are made. We cannot test the genes in the ovaries and testes cannot be certain that the proportion would be the same as that in the blood.
This means that anyone who is found to have a mosaic gene change will have a chance of passing on the RB1 gene change to a child. Again, the chances will be smaller than for someone who has a gene change in every cell.
Accurate genetic testing will be possible for the children of anyone who has a mosaic change in the RB1 gene. The testing can be done after a baby is born, in pregnancy or using preimplantation genetic diagnosis, in exactly the same way as for anyone who has a gene change in every cell.
What are the chances of someone with a mosaic RB1 gene change developing a second tumour?
Again, it is impossible to give an accurate answer to this as the chances will be affected by the level of gene change present all over the body and we cannot test for this.
Most people with a change in the RB1 gene do not develop second tumours. The chance of someone with a mosaic gene change will be smaller than for someone who has a genetic change in every cell.
Summary
Mosaicism for changes in the RB1 gene is relatively rare and is only relevant for a few families.
It can cause some people to develop retinoblastoma.
It can mean that some families have a chance of having more than one child with retinoblastoma.
It is routinely tested for and if a mosaic change in the RB gene is found in a family, the results will be discussed with that family.
Written by Dr Ellie Hay, Consultant in Clinical Genetics and Genomic Medicine, Great Ormond Street Hospital for Children.