Inside Pathology: Clinical Genetics

by Nana Mensah | | 22 minute read


Inside Pathology

While working at Viapath, I was involved in creating a podcast series promoting the work of healthcare scientists. The clinical genetics episode changed the way I saw my profession and was a joy to record and edit. You can read the full transcript below or listen to the episode here (or wherever you get your podcasts).

Clinical Genetics Transcript

Nana: Welcome to Inside Pathology, a series where we bring you stories from the pathology services that support patient care. I’m Nana E. Mensah, one of the Viapath future leaders in innovation. In this episode, we’re entering the world of clinical genetics.

Aimee: Okay, well, Freddie’s eight and a half now, and the first idea that we ever had that anything would be different to a regular pregnancy was at my 20 week scan. We just went along and thought, oh, you know, they’ll just ask us if we want to know the sex of the baby, give us a rough due date, and then we’ll be on our way. That wasn’t our experience.

Nana: That’s Aimee Mann, a proud parent whose journey into motherhood led her to the doors of a clinical genetic service. Through my interview with Aimee, we’ll learn what a genetic test result means for patients and their families. We’ll also hear from the professionals who steer patients through the storms of uncertainty, and we’ll understand the role scientists play in this service today. So what exactly is clinical genetics? It’s a remarkable fact that nearly every cell in your body carries DNA, a molecule with the instructions to make you. You might know these instructions by another name, your genes. Nature isn’t perfect, and some rare instructions can cause life threatening health problems. Shortly after DNA was discovered in the 1950s, medical professions started to interrogate it in the hopes of treating these diseases, and the field of clinical genetics was born. Since then, it’s come leaps and bounds. In 2001, the sequence of the human genome was published, the first map of human DNA. From it, we learnt that our DNA is made up of 3 billion units and that just 0.1% makes each of us unique. We call these genetic variants. Today, clinical genetics has become genomic medicine. It’s transforming the way we help patients with genetic conditions, patients and their parents, like Aimee.

Aimee: And so what they could see by looking at the scan initially was that he had enlarged ventricles. We were then referred to a much bigger central hospital in the city, and that was really the beginning of, well, scans every week, quite scary. And actually, every time we went to have another scan, they would see something else. It would be another change, and another difference. They were checking out his kidneys and his liver, a hole in the heart, a corpus callosum, but it was really thin, and reduced sulci and gyration of his brain as well, and reduced white matter. All along this process, because there was no definitive answer and therefore no prognosis, no real idea what was going on, we were still being offered termination of that pregnancy.

Nana: As a prospective parent, nothing can prepare you for complications during pregnancy. Aimee was kind enough to share exactly how she felt.

Aimee: It’s just a blurred sea of nothingness. You really don’t know where you are. But that was our very first baby. We were the only ones as far as we could see in that situation, because we just felt so isolated and so alone. But no one could tell us, so we just had lots of hope, really. As it happened, Freddie was born spontaneously at 35 weeks.

Nana: Against the odds, Freddie was born. It’s hard to imagine anything other than relief at Aimee and her husband at this moment, but of course, questions remained.

Aimee: It’s so tricky because your emotions are so high. It’s really trying to accept that you feel the way that you do and that could be any manner of different levels. You could be delighted your baby came, which we were. We were just so relieved that he arrived and arrived safely. But equally, you’re confused, and you’re worried and you’re scared of the future and all of those things. Unless you work in that field, which you know, neither my husband nor I have ever worked in anything medical, you just have no idea. You have really no idea about what’s going on about what the tests are that are out there, what it really means. It just didn’t occur to us that it could be anything genetic anyway. When you’re in that state, it’s very - you’re looking for answers really. I spent a long time looking for another Freddie or someone that could tell me what was going to happen or what to do.

Nana: Aimee was referred to her regional genetic service made up of doctors, technicians, scientists, counsellors and administrators working together to find the cause of Freddie’s disease. We call these rare diseases. They’re life-threatening genetic conditions. Individually, each disease affects only a small number of the population. Today, we know of over 5000 rare diseases and together they affect the lives of three and a half million people in the UK. When patients like Freddie visit a genetic service, doctors order tests from the lab looking for the instructions in Freddie’s DNA that may tell us the cause of his disabilities. In the last decade, the techniques we use in the lab to perform these tests have transformed. Dr. Dragana Josifova, a consultant in clinical genetics has seen this transformation with her own eyes.

Dragana: In the last 10 years there has been a huge move towards molecular diagnosis in patients with rare conditions. What we used to diagnose in the past on clinical grounds, we are now able to confirm those diagnosis by genetic tests. So the availability of genetic tests has enabled us to establish a specific causative ecological diagnosis in patients. That has had significant impacts on the families, and it has opened opportunities for couples to make informed choice for future pregnancies.

Nana: Genetics is one of the most recent disciplines in pathology, and genetic testing has transformed the practice. Technicians and scientists are the members of the workforce tasked with delivering these tests. It works like this. Patients and family members give a sample, often blood, which is sent to the lab for testing. DNA is extracted from the sample, and where once we were only able to look at chromosomes down a microscope, more modern technologies read the individual units of DNA. Whatever the technology, scientists come to a conclusion, and the findings are reported to the clinic. Rachel Mayhew is a scientist in a molecular pathology lab. Here’s how she describes her job.

Rachel: Essentially, in that role we’re performing tests, analysing the results of that test, interpreting it to find out what it means for the patient, then generating a report that can go back to the clinician.

Nana: What exactly ends up on the report?

Rachel: It kind of all depends on the question that’s being asked by the clinician. Sometimes it’s just a straightforward please can you test them and see if they have this condition. Sometimes we’re testing family members of a patient to see if they have genetic variants that could be important for them and their family. Then sometimes we’re testing to inform treatment.

Nana: The value of a diagnosis lies in its potential to change patients’ lives. Like all fields of pathology, the aim of genetics is to find answers to the questions raised by the genetic condition. Aimee and her husband had one of the most difficult questions of all.

Dragana: The question that any parent inevitably asks, what’s the cause of their child’s condition?

Aimee: From memory, I think he was about 14 months old, and we had been to the paediatrician. They had basically described a little bit about this DDD study and had asked us if we wanted to take part and it was completely voluntary, it was entirely up to us. But one of our biggest concerns at the time was really trying to find out if what was going on with Freddie was life limiting, because I’d come across a number of people that were having this sort of situation and losing their children very early. It’s just so frightening and you’re not really knowing how to plan for anything. We just wanted to know. We wanted to know if there was a possibility that that could be our situation. As awful as it would have been to hear those words, that your child is life limited, for us it made more sense for us to know what was happening.

Nana: Freddie was tested by his regional genetic service, but the results were negative. In genetics, we don’t always find an answer, but the negative report for modern technologies is actually filled with potential. It says, we didn’t find the cause of disease, but we have the patient’s data on record. In the future, when we better understand the genome, we may be able to search again and find an answer. Large scale research into rare diseases tries to find answers for patients. Freddie was recruited to one such project, the Deciphering Developmental Disorders study, and the wait began. In the meantime, Aimee wanted to know what would happen if she and her husband had another child.

Aimee: We wanted to get a little bit more information. I did call the genetics team and I explained the situation that we would like to expand the family, but we had reservations and we were concerned. We didn’t know if we could cope with having two children with those similar sorts of disabilities, because it’s really hard work. It’s emotionally exhausting, it costs more money, the time taken away from Bella as well. It’s very hard. There’s a lot of guilt involved in it. We just weren’t sure if we were really up for doing that again. We were hoping that they could give us answers a bit quicker. They did try their best and they would regularly sort of update and say, no, we still haven’t found anything.

Nana: This is the diagnostic odyssey. Despite the promise of genomic medicine, rare disease patients are often left in limbo. If a diagnosis comes at all, the typical wait lasts not days, not months, but years.

Aimee: It was about four, four years, I think it took. I really had resigned myself to the fact that we probably wouldn’t get an answer because it had been quite a long time. I had a call from a genetics team, and they said, we think we have an answer for you. I just couldn’t believe it. I thought, wow, I cannot actually believe that you now have an answer. Within a couple of weeks, it was quite quick for us actually, which we were grateful for, we were able to go in and meet with them and tell us about what they found, really.

Nana: Four years waiting and what did they find?

Aimee: There were a handful of cases. I think at the time, there were only about seven cases and Freddie. The children were aged between about two and nine on the caseload. They all had very similar markers within the development of their brain. Some of them were slightly different. Freddie does have a corpus callosum, but it’s thin, but some of them have no corpus callosum. There were little changes, but the thing that really connected them together is that Freddie and the other children that they came across have a neurological eyesight condition called hypoplastic optic disc. That in the end was the connecting factor, because she said there were so few genes that are actually connected to that area, that this is how they’ve come and made the decision. His diagnosis is so rare, he is less than one in a million currently, called TUBA1A.

Nana: Four years, one gene, and a genetic change that makes Freddie less than one in a million. TUBA1A, it’s an answer, but what exactly does it mean?

Dragana: TUBA1A is one of the families of genes known as tubulinopathies or tubulin genes. Tubulin genes are very important for brain development because they guide the neurons to reach their final destination in proper order. Changes in any of the tubulin genes are highly likely to be associated with what is known as cortical malformations, which may come in different types and different flavours. But the essential component of all of these is that children are highly likely to present with developmental delay, with small head circumference, and with susceptibility or overt seizures. The MRI scan, particularly in some forms of tubulin associated conditions, can be quite suggestive of a tubulin disorder. Often these MRI findings can be a guide for us to navigate the genetic investigations.

Nana: Every scan and every test Freddie took in the health service combined with the few similar patients guided researchers to one conclusion. A change in Freddie’s DNA that codes for the TUBA1A protein led to his disabilities. As a mother, Aimee went from knowing that her child had a neurological disorder to knowing the exact molecular cause. In that moment, what was the answer worth?

Aimee: I found the session quite enlightening. I was kind of relieved. There are just so many emotions that go with it. Really, what we still have to continue to do is really to treat him in a way that we did before we had a diagnosis, which was really to treat the symptoms. What it does do is it starts to give you a bit more understanding about why he’s got the difficulties that he has. Then the more you know, the more you learn, the more you can find other ways to help. Really, the reason for doing that, from our point of view, we are just trying to give him every single possibility that we can that’s within our power to have to him have the best possible experience of life going forward. With that information, it means that we can make some better choices, I guess. It is really worth it actually going through the process and getting an answer.

Nana: A clinical genetic test is unique because a diagnosis doesn’t guarantee a change in treatment or management, but it does open doors that were closed before. Layla Afkahmi is a clinical scientist working in a Viapath genetics rare disease testing lab, and she has insight into the impact these answers can have on patients’ lives.

Layla: Often as a lot of listeners are well aware of, not all genetic conditions have got treatments. Some do, but a cure is very rare, and even treatment a lot of the time isn’t fully effective. But just having an answer I think, gives patients a lot of clarity into what sort of diseases might run through their family. Also, that allows patients to get in touch with other patients or families who have also got that same condition. If it’s a rare disease, it may be a global network where there are only a handful of people in the world.

Nana: For Aimee, that’s exactly what happened.

Aimee: I know you know SWAN UK, which is ‘syndromes without a name’. It’s the only charitable organisation out there that supports children and adults who don’t have a diagnosis to explain their difficulties, and the families. That was a complete game changer for me because there were thousands of families out there. I think there are 6000 children born each and every year, who do not have a diagnosis to explain their disabilities and special needs. Suddenly, although all the children were totally different, I finally found my crew. Only last week in fact, I was contacted by a mum who lives probably only a couple of hours away from me who has twin daughters who both have TUBA1A. Her two daughters are about 16, but they present quite differently to Freddie. It’s still hard, but there is also a Facebook group which I found which was set up by a lady in the States. It’s TUBA1A Families, that’s what it’s called. Many of the children also have other things going on. There are a small, small handful, maybe about four, who present quite like Freddie where possibly they’ve just got TUBA1A. It has been really interesting.

Nana: Having a name for the challenge that you and your family face is invaluable, because not only does it reduce uncertainty about the condition, it opens doors that connect you with others on the same journey. Perhaps unlike any other test, it also holds hope for future patients. As more rare diseases are discovered, studies lead us to understand them in more detail. Aimee was approached to join a TUBA1A study three years after Freddie’s diagnosis.

Aimee: I said yes straight away. Because if we can give our information over and anybody else, so that the next generation of families and mothers and fathers that are in my situation, you have a child and they don’t know and they get a diagnosis of TUBA1A, they’ve got somewhere to go. They haven’t got to be in the limbo that we were in. Hopefully in the near future, there will be a study put together about TUBA1A, which I think would be hugely beneficial to many, many people.

Nana: The fact that a diagnosis can change the lives of people now and in the future has led to ever larger research studies. In 2013, the UK government launched the 100,000 Genomes Project, and the aim was to sequence 100,000 genomes from patients with undiagnosed rare diseases and cancers within the NHS. The project was ambitious in its scale and technology, because it used whole genome sequencing and newer technology that was able to interrogate the genetic code in more detail than ever before. In December 2018, the project reached a milestone, the 100,000th genome was sequenced. From our seat in the crowd at the celebration event, we heard Sir Mark Caulfield, then CEO of Genomics England, telling us how the project has transformed lives.

Mark: Okay, to illustrate how the diagnostic odyssey is painful, this child at four months developed epilepsy and development delay, had been in various different projects, not got an answer, and came to our attention at the age of four. We found that she had a sugar transporter change that affected the sugar transfer from the bloodstream into her brain. When her brain sugar dropped down, she would get seizures. These seizures were unresponsive to any medicines. This change was just in her and not in the rest of her family. Her mum and dad can now consider having other children. The important thing is that this paved the way, and this won’t happen for all of our participants but for some it will, paved the way for the application of a treatment, a high fat diet, which reduced seizures and it also improved some of her developmental delay. This child had 6.4 million variants, of which 2826 changed the protein, of which 67 were different from her mum and dad, and of one was the clear cause. If that’s the process that we do between 10 and 35 hours on the 3.3 billion letters that make you the person you are, it can also sadly carry susceptibility to disease.

Nana: From the beginning this wasn’t just a research project. It was a pilot to figure out what whole genome sequencing could do for patients in the NHS, patients and families just like Aimee’s. On the project, one in five rare disease patients are receiving diagnoses and around half the cancer patients are being exposed to clinical trials to therapies. From the back of this, the NHS has launched the world’s first national genomic medicine service, upgrading 25% of the 300,000 genetic tests to newer technologies. The future is bright, but so much more needs to be done, not just in diagnostics, but in developing therapies for rare disease patients. At the celebration event, one speaker quoted Winston Churchill, he said, “Now, this is not the end. This isn’t even the beginning of the end. But it is perhaps the end of the beginning.”

Mark: But the future needs a global coalition of intellects to solve these diseases. Our goal must be, and it is your mission for these coming five years, to help me and the team at Genomics England to make the UK, with the NHS in England, the leader in transformation for world health care for genomic medicine. Thank you very much.

Nana: There are many professionals working to deliver this mission. First and foremost, there are doctors. On Freddie’s journey to date, he’s been supported directly by his geneticist, neurologist, paediatrician and physiotherapist. Behind the scenes, scientists are also mission critical. We ask the question, what’s it like to be a genomic scientist? First, let’s hear from Rachel and Lisa.

Lisa: I’m Lisa. I’m a genetic technologist, and I’m going to be asking Rachel some questions about our job today. How would you describe your role to a patient, Rachel?

Rachel: I work in a molecular pathology lab that specialises in haematology, bone marrow transplant, or whether their sibling is an appropriate donor, things like that. I would say it’s very varied. No two patients are the same, so no two cases are the same. Because it’s very varied, you do get exposure to a lot of different things. We use lots of different tests. There are lots of different methodologies that are being used.

Lisa: Could you tell us a bit more about your career route?

Rachel: I started off training as a biomedical scientist, similar but different to clinical science. I did that as part of my degree. Then after that, I decided to do a master’s. I just wanted to learn a bit more about genetics and genomics, that’s something I was really interested in. Then after that, I took a job as a bioinformatician, got some really good experience and worked for about a year. A pre-registration clinical scientist job opportunity came up in the same lab, and so I applied for that and was successful.

Lisa: Are there any alternative routes to become a clinical scientist?

Rachel: Yes, I’d say the main route is the Scientist Training Programs, the STP, which is like a three year course with intercalated master’s, and you apply for a particular specialism and compete the training program over three years, and then you get to rotate round as well to get quite a lot of breadth as well. Then there’s the route that I’m doing, which kind of, I guess, more in house training. You’re based in one lab, and they provide all of your training. Then there’s an equivalent route, I think, for people that have a lot of experience and training, probably equivalent to that of a clinical scientist but just haven’t got registration as a clinical scientist. Ultimately, with all of those three routes, you create a portfolio of evidence to say that you’re competent. Then once you submit that portfolio, they assess it and then determine whether you pass or fail, I guess.

Lisa: That sounds great.

Rachel: Sounds lovely.

Lisa: What advice would you give to someone who would like to become a clinical scientist?

Rachel: I would say if you’re just starting out, getting any experience in a lab setting is really useful beyond just your research lab setting at uni. Understanding how things work, why testing is performed, is really, really useful, because I think a lot of jobs now want people with experience, people that are really competent and then can just get stuck in because it’s a very, very busy specialty.

Lisa: Thank you very much.

Rachel: Thanks, Lisa.

Nana: Clinical genetics is a rewarding field that spans many specialist services focusing on a wide range of genetic conditions. The scientists all share certain number of skills. Here’s Layla once again.

Layla: Investigative skills are critical to be able to do this job. You have to take different bits of evidence from different parts of the patient pathway and incorporate these together to be able to come up with a diagnosis for the patient. I went into this career because I love a challenge. If there’s a puzzle that I need to solve, I’m straight on it, so that’s kind of how my job feels every day. Giving an answer to patients can be very rewarding. Also, just working at the forefront of science, genetics is a really hot area at the moment, and I can see that continuing in the future. So yeah, it’s a really exciting area to work in.

Nana: As a trainee scientist myself, I can echo what Rachel and Layla have shared. It’s been extremely rewarding to work in a field that helps patients from behind the scenes. To end, I asked Aimee if she had any advice for budding young scientists interested in clinical genetics.

Aimee: Go for it, because I think it’s still under studied to a degree and we need more bright, brilliant young people who are dedicated to finding out what happens to the human body, to humans, to children, to adults, because all of those things, all of the information that you can gather and put together through genomics means that we’re just better educated. We can help treat people better, we can perhaps look at preventing illnesses from happening, and the actual fact the more that we understand. I think it is such a fascinating topic and one that can be so incredibly helpful to families like mine, but many, many other people with lots of other challenges going on. I would just say go for it, because we need as many good people in this country as we possibly can. So yeah, do it.

Nana: This episode of Inside Pathology was brought to you by Viapath and the Viapath future leaders in innovation. We’d also like to thank our guests Aimee Mann, Dragana Josifova, Lisa Rauter, Rachel Mayhew, and Layla Afkhami. Special thank you to Aimee Mann for sharing her story with us. Aimee runs her own podcast for parents like herself called CEO of Your Special Needs Family. You can find out more at her website, Links to this and other information in our show notes. Thank you for listening.