Finding a Genetic Diagnosis

Frankie Macrae is a trainee clinical scientist in the Genetics Department at Addenbrooke's Hospital, Cambridge. Here she documents her experience of meeting up with Claire Wright, a mother whose child suffered from a genetic disease...

I start my day much like anyone else with an office job - with a strong coffee, a look through my e-mails and a recce of the cake table to see if anything takes my fancy. After that, I begin my day’s work: a spreadsheet full of numbers and letters, where each line represents a change in someone’s genome that could be causing a disease.

This is "Next-Generation Sequencing". I sometimes think of it as, rather than trying to find a needle in a haystack, trying to find a needle in a needle stack. If you compare the DNA of two random, unrelated humans, you find 3 to 4 million genetic differences between them. Some of these differences, or variants, will have no effect on that person’s health and are known as "polymorphisms". Others may be causing disease and are called "pathogenic variants" or mutations, although we’re trying to move away from using the word mutation because people associate it with horns, wings and hair where it shouldn’t be. Nevertheless, it can be very difficult to tell a mutation from a polymorphism.

My job is to trawl through pages of these variants, with (or sometimes without) a list of the patient’s symptoms, to see if anything fits. Much of this work has been done for me by computer programs, which filter out genes that we know are not related to the patient’s condition as well as any common polymorphisms. So, instead of looking at every single gene, we look at "gene panels". These are groups of genes that have a track record for causing specific disorders. That may sound simple, but some of these panels can contain over 100 genes. Other, fully-trained, scientists in the office can get through these cases much more rapidly. For me, as a trainee, it can take a day or more to just do one.

While I’m scrolling through my spreadsheet of variants, and my coffee’s gone cold and my slice of cake is becoming stale, it can sometimes be hard to keep my eye on the bigger picture - the patients with whose DNA I become so intimately familiar and yet never meet. So, I decided to pay a visit to Claire Wright, a family support co-ordinator at the Lily Foundation, a charity that supports patients and families with mitochondrial disease; she's also the mother of Jacob, who passed away from a mitochondrial disease in 2012 aged just 16 months.

Mitochondrial diseases are a family of genetic conditions that affect the workings of the mitochondria, which are a critical component of almost every cell in the human body. Mitochondria are like "batteries". They supply the energy that cells need to function. They also carry their own DNA sequences that code for key components that keep the mitochondria working properly. If this DNA message is damaged through mutation, the mitochondria don't work, robbing cells of energy and causing a range of diseases. But mitochondrial diseases can also be caused by mutations in the cell's nuclear DNA, which makes finding the cause of a patient's problem more tricky. At the moment, ten million people in the UK suffer from mitochondrial disease, and there is currently no cure.

On a cold, rainy day in Ely, Claire and I meet to talk about our own very different experiences of genetic disease (some of the wording of the conversation has been altered for clarity)...

Claire- Jacob was relatively healthy until he was 8 months old. He had a cataract in one eye and mild hearing loss, but the doctors thought that there was nothing more serious going on. I asked if the two could be related, and was told it was just an unfortunate coincidence. I felt that he wasn’t like other babies, as he was slower to reach his milestones. I was told not to worry, that he’d get there in his own time and I was a first time mum and bound to worry. But in my heart of hearts I knew something wasn’t right.

One of my clearest memories is of his first seizure. It was during an appointment with a paediatrician so we took him straight to A&E. I kept telling myself that it was a one -off and it wouldn’t happen again but it did, it happened another 5 or 6 times whilst we were waiting to be seen. So that started off our first 10-day stay in the hospital, which was traumatic. He was our little boy and we were worried. Quite quickly everything spiralled and it became clear that he had epilepsy that was hard to control and didn’t respond to medication. The doctors then thought there might be something more serious going on.

Frankie- At what point did they start to think it could be something genetic?

Claire- From when he had that first seizure. When we saw the consultant and he was going through Jacob’s history and I explained all the things that I was worried about, the milestones, the cataract and the hearing loss, that’s when they started to think it could be something genetic.

Frankie- And did they know then that it was mitochondrial disease?

Claire——不,直到后来才提到,当他们showed us the MRI scans of his brain. He’d had one when he was first admitted to the hospital and they did another one 6 months later. That’s another moment I remember really clearly, going in to get those results. We went to the usual appointment room, weirdly I can still see the picture hanging on the wall, and he showed us the images of Jacob’s brain scans, side-by-side. Now, I’m not a doctor but I could see the difference quite clearly; his first scan was normal, but the second had massive lesions, parts missing from his brain. At that point, we were told that Jacob had Leigh syndrome, and the chances were he wouldn’t see his second birthday. But there was no genetic diagnosis, which made it harder to process. And we still don’t have a genetic diagnosis.

Leigh syndrome is a name for a severe and sometimes life-limiting mitochondrial disease, which can have many different genetic causes. It can be caused by mutations in mitochondrial DNA, but around 80% of cases are caused by mutations in the DNA in the nucleus. When we talk about a clinical diagnosis, we mean the diagnosis based on symptoms - in this case, Leigh Syndrome. A genetic diagnosis is finding the single variant that is causing Leigh Syndrome in that patient, which could be in any of the >75 genes associated with the disease.

Frankie- Before you went through the process of trying to find a genetic diagnosis, what were you expecting? Did you think that the first test would give you an answer, or did you know there was some uncertainty?

Claire- I do have a background in biology, I knew what mitochondria were, which was a start! So I understood that there was a chance we wouldn’t find anything, but I hoped that we would. I do think there is a level of misunderstanding - some people think that you guys in the lab are like gods and just know everything which, unfortunately, is not true - and I think that’s what sometimes causes disappointment.

Frankie- One of the things we’re told when we’re training is that a genetic diagnosis is the most important thing for patients and their families, from your experience, how important is it?

Claire- I think that having genetic diagnosis might have made it easier to accept that Jacob had mitochondrial disease, but it wouldn’t have made a difference to him. I think some people believe that having a genetic diagnosis might change the outcome, but it doesn’t if there’s no cure. The main reason you want to know is if you want to have more children. I still think it’s incredibly important as it might help with research in years to come, but at the moment a genetic diagnosis will not change what happens to your child.

对我们来说,我们所做的have that clinical diagnosis, we knew it was mitochondrial disease and that meant we could contact the Lily Foundation. We were still dealing with something that was horrific, but we were part of a community that understood it - some families don’t even get that.

If a family has a known genetic diagnosis, there are many reproductive options out there for them. They can have a prenatal diagnosis, where we test the amniotic fluid for the mutation, and this can be offered on the NHS. But without knowing what we’re looking for, we can’t do those tests.

Claire——所以没有选项的产前诊断,but we did still want another child. I mean, Jacob was never able to give me a cuddle, or give me a kiss, or say ‘mummy’. I wanted the chance of a child who could do those things, which is true for most parents. We spoke to a genetic counsellor at Great Ormond Street and were told there was probably a 1 in 4 chance of having another affected child. So we decided it was worth a try, we ‘rolled the dice’, and we had a healthy daughter, Charlotte in March 2017.

The Lily Foundation is a mitochondrial disease charity. They support families by holding annual meet-up events, helping pay for specialist care equipment and funding short leisure breaks. They also raise awareness about mitochondrial disease and raise money to fund research into new tests and treatments.

Frankie- Some scientists in my department are working on an exciting project called Next Generation Children, where they do rapid whole genome sequencing of babies in intensive care in as little as 4 weeks. This means that parents might know sooner whether the disease can be cured or not. How do you think something like that would have affected you and your family?

Claire- I think it would have made a huge difference. When I look back, I feel that we did what was right for us and our baby at the time, but perhaps if there was less going on, fewer tests and procedures, I might have enjoyed my time with him more. He had two eye operations, that in the end he didn’t need, and maybe we would have moved over to hospice care a lot sooner. We could have had more time to just cuddle him, and when you only have 501 days with your child, a couple more days of just cuddling would have been lovely.

Frankie- So finally, what advice would you give someone like me who works in the lab, never sees patients, who are normally just a tube or a number on a screen to me - how can we keep the patient in our mind?

Claire——我认为,如果可以的话,做一些像volunteering with children and families affected by genetic disease would make a massive difference. And I think it would be amazing for people like you to have the opportunity to go and volunteer somewhere or talk to someone like me to get an idea of what we go through. It’s also a really good way of raising awareness - which is why charities like the Lily Foundation are so important. Without awareness there’s no funding, without funding there’s no research and without research there’ll be no cure. And it might give you a better understanding how important the work you do is - and what a responsibility you have. In a way you’re holding peoples’ hopes and dreams in your hands - and we’re all really grateful that you’ve chosen to do that.

What my experience talking to Claire¹showed me is that, as geneticists, we need to descend from our ivory tower, go out there and meet the people whose lives our work can change so dramatically. I think this is true for all scientists, including researchers, as we can spread the word about the amazing work we are doing whilst learning more about its real-life effects. As for me, when I’m feeling bogged-down by a data overload, unable to see the wood for the genes, I'll think of Claire and Jacob and of their journey through the genetic wilderness. Knowing that each line in my spreadsheet could give this patient or family the answer they are looking for is worth all the stale cake in the world.