James Ware - Tackling Titin

Kat - And now it's time for a look at one of the genetics stories that hit the news this month, about a condition known as dilated cardiomyopathy, where the heart muscles become enlarged and don't work properly. It affects around one in every 250 people in the UK, and is a major cause of sudden death in apparently fit and healthy individuals, as well as being the leading reason for needing a heart transplant.

In 2012, researchers discovered that one in four cases of dilated cardiomyopathy are due to faults in a huge gene called Titin. But it turns out that many people carry faults in Titin, but don't seem to have the disease. So are they at risk? I spoke to James Ware from Imperial College London, who's been looking at the Titin gene in thousands of people, to find out.

James - Titin produces the largest protein in the human body. It's a massive gene which was essentially previously too big really to study in large numbers of people. So, that really changed the landscape of the genetics of this condition.

Kat - How did you then set about seeing how faults in the gene were related to this particular heart problem?

James - It was exciting to find one in 4 cases might be explained. We were less excited to find that about one in 50 people in the general population also have a similar variant. So really, the biggest question in our mind was, why do many healthy people have these variants and how are they different from the variants that are causing disease.

Kat - So, people like you, me, regular people could be walking around with a fault in this gene that in some cases, causes a heart problem but in most cases, just doesn't.

James - It's a change in the gene that looks like it should cause a fault in a gene, if you like. What we don't know is, is it actually causing a fault in the gene but that just doesn't harm you. Is it that, it could harm you but it hasn't yet? There are lots of possibilities and that was the first thing we really wanted to disentangle.

Kat - I guess that's quite an important question because if someone's walking around with a gene fault, that means they could just drop dead at any minute, you would want to know about it.

James - Exactly. It's a huge question. Particularly, as your listeners may have heard press about things like Hundred Thousand Genomes project, even the prime minister saying he's going to sequence the genomes of 100,000 people. Well, a thousand of them will have a variant of this sort in Titin. Do we need to get them all into cardiology clinics urgently? Do we need to tell them all that their families are at risk? More and more people having genome sequencing for other reasons when they're healthy to start with. So, we really need to understand that.

Kat - So, how did you go about then trying to unpick what the faults in Titin might mean for someone who carries one of these mistakes?

James - We looked at more than 5,000 people from a whole of backgrounds. So, we sequenced some people who have dilated cardiomyopathy who were severely ill and were waiting for transplant. We sequenced people who just came to our clinic for a heart scan with dilated cardiomyopathy, and then we sequenced many thousands of people who had just been selected from the community. They were apparently healthy. And so, in all of those people, we sequenced this gene and we catalogued all the variation that we saw. We also had some heart tissue samples from people who'd consented to give us a sample at the time of transplantation. And so, we were able to look in detail how the Titin molecule had changed in people with and without abnormalities in the protein.

Kat - So, what's the bottom line? What did you find?

James - The bottom line is, firstly, that we were able to find features that discriminated between the variants that cause disease and those that don't. So, we can categorise certain types of variants. We can now reassure people that is not a variant that causes a problem. If we find it incidentally, we can reassure them we won't drag them into a cardiology clinic and that's fantastic news for them. Secondly, there are other variants that we now can be very confident they are causing trouble. The most relevant use of this is, when we find an individual who has dilated cardiomyopathy, we want to find out whether their family members are also at risk. 

We can do that by examining them in the clinic and doing a scan of their heart. But very often, that would be normal. We don't know if it's simply that they haven't got the condition yet and we need to keep an eye on them. And so, what happens at the moment is people, a brother, a sister, a father, a child of someone with dilated cardiomyopathy will probably be followed in a cardiology clinic for the rest of their life. What we can now do is test their gene, test their Titin gene in the person who has the condition in the family. If we can pinpoint the exact genetic cause, we can then test the family for that and anyone who doesn't have it can be reassured, they can be discharged from the clinic. They don't have to have that long term follow up. That's a big burden for them and also for the NHS. So, I think that's the biggest of win from this study.

Kat - As we start sequencing more and more genomes from more and more people, it's becoming clear that there are these bad variations popping up all the time in people who don't appear to be ill. Do you think the work that you've done might be almost a flagship research project for this kind of investigation for other conditions? Are there any other diseases you know about where this kind of thing might be relevant?

James - Definitely. I think that one of the things we need to do at the moment is to better understand the variation in normal people and how we can distinguish between variants that are going to cause trouble in the future and variants that aren't. I think we need two things for that. One is we need more knowledge of the genetic variation present in a population. The second part is really knowing the precise phenotype, the clinical situation of the people who have those variants. That is more challenging because although we can sequence people from the general population, we can't get everyone back to do heart scans or brain scans, or whatever test is appropriate for the particular condition. So, that is the next phase I think. And projects like the Hundred Thousand Genomes project in the UK are really going to help to catalogue the clinical situation of the people whose sequences we are starting to look at.

Kat - That was James Ware, from Imperial College London. That work was published in the journal Science Translational Medicine, and we'll be taking a closer look at the Hundred Thousand Genomes project he mentioned in next month's podcast.