Why study rare genetic conditions?

This week my research group published a paper in Nature Genetics, identifying a rare genetic cause of a rare childhood cancer. If both copies of the TRIP13 gene are mutated, so that TRIP13 function is lost, there is a high chance that a childhood kidney cancer, called Wilms tumor, will occur.


Studying rare genetic conditions – good for families

The most immediate value of this type of discovery is the improved information we can give patients and families. The TRIP13 discovery has enabled us to tell parents why their child got cancer. Equally importantly, we can provide information about the cancer risk to other children in the family. This can be a very pressing anxiety for parents and the wider family.


TRIP13 mutations cause a recessive genetic condition

TRIP13 mutations cause Wilms tumor through a recessive mechanism, similar to cystic fibrosis (which we described in a previous blog). This means that both copies of the TRIP13 gene were rendered useless by a mutation, in the children with Wilms tumor.

The parents had one useless TRIP13 gene (with the mutation) and one working TRIP13 gene (without the mutation). Having one TRIP13 mutation doesn’t have any health impacts because the working gene can cover for the useless one.

Other children in the families have a 1 in 4 (25%) chance of having two TRIP13 mutations and of being at high cancer risk. Now we know the cause of cancer in these families we can do a simple genetic test to see if other children have none, one, or two TRIP13 mutations. If a child has none, or one mutation, they are not at increased risk of Wilms tumor and do not require monitoring. If a child has two TRIP13 mutations they are at high risk of cancer and we keep a close eye on them. Fortunately, Wilms tumor is curable in the majority of children, whatever the underlying cause.


Not just cancer

TRIP13 mutations do not just cause cancer. In some of the children, they caused a vanishingly rare chromosome problem called ‘mosaic variegated aneuploidy’. This means that some of their cells have the wrong number of chromosomes (termed aneuploidy); either too many or too few. Normal cells have 23 pairs of chromosomes. The chromosomes carry our genes so it is vital our cells have the correct number of chromosomes, so they have the correct number of genes.


Cell division is a fundamental process in health and disease  

We all start as one cell and end up with 30 trillion cells! This happens through a process called cell division. One cell divides into two cells, then the two cells each divide into two more, and so on. Cell division is still important after we have stopped growing, because cells die, for various reasons, and need to be replenished.

When a parent cell divides it first duplicates its 23 pairs of chromosomes and then distributes the chromosomes so that each ‘daughter’ cell gets 23 pairs of chromosomes.  If this chromosome sorting goes wrong one of the daughter cells can get too many chromosomes, whilst the other can get too few. This is exactly the pattern we see in the children with TRIP13 mutations.


TRIP13 ensures chromosomes are sorted correctly when cells divide

TRIP13 is part of a sophisticated surveillance system that stops cell division starting until all the chromosomes are properly lined up ready to be correctly distributed into the daughter cells. If TRIP13 isn’t working, as in the children we reported, cell division may start before all the chromosomes are lined up, and the daughter cells end up with the wrong number of chromosomes.

So TRIP13 malfunction causing aneuploidy makes perfect sense. But why does it cause Wilms tumor? We don’t know. But it wasn’t a big surprise when TRIP13 popped up as the causative gene because we had previously shown that another key player in this surveillance mechanism, a gene called BUB1B, also causes Wilms tumor if mutations stop the gene working.


Aneuploidy – a hallmark of cancer

Cancer cells very, very often have the wrong number of chromosomes (i.e. are aneuploid). In fact, aneuploidy is said to be one of the hallmarks of cancer. We still don’t know whether aneuploidy is a cause or consequence of cancer; or maybe it can be either, or both, depending on the cancer and the context. There is so much we still need to understand.


Studying rare genetics conditions – good for science

Studying rare genetic conditions provides opportunities to have immediate clinical impact and to generate new scientific knowledge

The links between TRIP13, BUB1B, aneuploidy and Wilms tumor provide exciting, provocative new avenues for exploring these connections. For example, not all children with mosaic variegated aneuploidy are at high cancer risk, despite the problems with their chromosomes. Children with a malfunctioning cell division surveillance mechanism are at high risk of cancer. But we haven’t seen cancer in children with mosaic variegated aneuploidy due to other reasons.

The TRIP13 discovery is one small example of how studying rare genetic conditions can be important for science. There are hundreds of other examples. Indeed, many of our most important genes were first discovered through the study of rare genetic conditions, long before the human genome was sequenced.

The opportunities to have immediate clinical impact and to generate new scientific knowledge makes the study of rare genetic conditions hugely valuable and endlessly rewarding.