The G Word

In this special episode, recorded live at the 2025 Genomics England Research Summit, host Adam Clatworthy is joined by parents, clinicians and researchers to explore the long, uncertain and often emotional journey to a genetic diagnosis. Together, they go behind the science to share what it means to live with uncertainty, how results like variants of uncertain significance (VUS) are experienced by families, and why communication and support matter just as much as genomic testing and research. The panel discuss the challenges families face when a diagnosis remains out of reach, the role of research in refining and revisiting results over time, and how collaboration between researchers, clinicians and participants could help shorten diagnostic journeys in the future. Joining Adam Clatworthy, Vice-Chair for the Participant Panel, on this episode are: Emma Baple – Clinical geneticist and Medical Director, South West Genomic Laboratory Hub  Jamie Ellingford – Lead genomic data scientist, Genomics England  Jo Wright – Member of the Participant Panel and Parent Representative for SWAN UK  Lisa Beaton - Member of the Participant Panel and Parent Representative for SWAN UK  Linked below are the episodes mentioned in the episode:  What is the diagnostic odyssey?  What is a Variant of Uncertain Significance?  Visit the Genomics England Research Summit website, to get your ticket to this years event. You can download the transcript, or read it below. Sharon: Hello, and welcome to Behind the Genes. My name is Sharon Jones and today we’re bringing you a special episode recorded live from our Research Summit held in June this year. The episode features a panel conversation hosted by Adam Clatworthy, Vice-Chair of the Participant Panel. Our guests explore navigating the diagnostic odyssey, the often-complex journey to reaching a genetic diagnosis. If you’d like to know more about what the diagnostic odyssey is, check our bitesize explainer episode, ‘What is the Diagnostic Odyssey?’ linked in the episode description. In today’s episode you may hear our guests refer to ‘VUS’ which stands for a variant of uncertain significance. This is when a genetic variant is identified, but its precise impact is not yet known. You can learn more about these in another one of our explainer episodes, “What is a Variant of Uncertain Significance?” And now over to Adam. -- Adam: Welcome, everyone, thanks for joining this session. I’m always really humbled by the lived experiences and the journeys behind the stories that we talk about at these conferences, so I’m really delighted to be hosting this panel session. It’s taking us behind the science, it’s really focusing on the people behind the data and the lived experiences of all the individuals and the families who are really navigating this system, trying to find answers and really aiming to get a diagnosis – that has to be the end goal. We know it’s not the silver bullet, but it has to be the goal so that everyone can get that diagnosis and get that clarity and what this means for their medical care moving forwards.    So, today we’re really going to aim to demystify what this diagnostic odyssey is, challenging the way researchers and clinicians often discuss long diagnostic journeys, and we’ll really talk about the vital importance of research in improving diagnoses, discussing the challenges that limit the impact of emerging research for families on this odyssey and the opportunities for progress. So, we’ve got an amazing panel here. Rather than me trying to introduce you, I think it’s great if you could just introduce yourselves, and Lisa, I’ll start with you. Lisa: Hi, I’m Lisa Beaton and I am the parent of a child with an unknown, thought to be neuromuscular, disease. I joined the patient Participant Panel 2 years ago now and I’m also a Parent Representative for SWAN UK, which stands of Syndromes Without A Name. I have 4 children who have all come with unique and wonderful bits and pieces, but it’s our daughter who’s the most complicated. Adam:  Thank you. Over to you, Jo. Jo:  Hi, I’m Jo Wright, I am the parent of a child with an undiagnosed genetic condition.  So I’ve got an 11-year-old daughter. 100,000 Genomes gave us a VUS, which we’re still trying to find the research for and sort of what I’ll talk about in a bit.  And I’ve also got a younger daughter. I joined the Participant Panel just back in December. I’m also a Parent Rep for SWAN UK, so Lisa and I have known each other for quite a while through that. Adam:  Thank you, Jo.  And, Jamie, you’re going to be covering both the research and the clinician side and you kind of wear 2 hats, so, yeah, over to you. Jamie:  Hi, everyone, so I’m Jamie Ellingford and, as Adam alluded to, I’m fortunate and I get to wear 2 hats. So, one of those hats is that I’m Lead Genomic Data Scientist for Rare Disease at Genomics England and so work as part of a really talented team of scientists and engineers to help develop our bioinformatic pipelines, so computational processes. I work as part of a team of scientists and software engineers to develop the computation pipelines that we apply at Genomics England as part of the National Health Service, so the Genomic Medicine Service that families get referred to and recruited to, and we try to develop and improve those. So that’s one of my hats. And the second of those is I am a researcher, I’m an academic at the University of Manchester, and there I work really closely with some of the clinical teams in the North West to try and understand a little bit more about the functional impact of genomic variants on kind of how things happen in a cell. So, we can explore a little bit more about that but essentially, it’s to provide a little bit more colour as to the impact that that genomic variant is having. Adam: Great, thank you, Jamie. Over to you, Emma. Emma: My name’s Emma Baple, I’m an academic clinical geneticist in Exeter but I’m also the Medical Director of the South West genomic laboratory hub, so that’s the Exeter and Bristol Genomics Laboratory. And I wear several other hats, including helping NHS England as the National Specialty Advisor for Genomics. Adam: Thank you all for being here. I think it’s really important before we get into the questions just to ground ourselves in like those lived experiences that yourself and Jo and going through. So, Lisa, I’m going to start with you. The term ‘diagnostic odyssey’ gets bandied around a lot, we hear about it so many times, but how does that reflect your experience that you’ve been through and what would you like researchers and clinicians to understand about this journey that you’re on, essentially? Lisa: So I think ours is less an odyssey and more of a roller-coaster, and I say that because we sort of first started on a genetic journey, as it were, when my daughter was 9 weeks of age and she’s now 16½ – the half’s very important – and we still have no answers. And we’ve sort of come a bit backwards to this because when she was 6 months old Great Ormond Street Hospital felt very strongly that they knew exactly what was wrong with her and it was just a case of kind of confirmation by genetics. And then they sent off for a lot of different myasthenia panel genes, all of which came back negative, and so having been told, “Yes, it’s definitely a myasthenia, we just need to know which one it is,” at 4 years of age that was removed and it was all of a sudden like, “Yeah, thanks, sorry.” And that was really hard actually because we felt we’d had somewhere to hang our hat and a cohort of people with very similar issues with their children, and then all of a sudden we were told, “No, no, that’s not where you belong” and that was a really isolating experience. I can remember sort of saying to the neuromuscular team, “Well is it still neuromuscular in that case?” and there was a lot of shrugging of shoulders, and it just…  We felt like not only had we only just got on board the life raft, then we’d been chucked out, and we didn’t even have a floaty. And in many ways I think I have made peace with the fact that we don’t have a genetic diagnosis for our daughter but it doesn’t get easier in that she has her own questions and my older children – one getting married in August who’s already sort of said to me, you know, “Does this have implications for when we have children?”  And those are all questions I can’t answer so that’s really hard. Adam:  Thank you, Lisa. Yourself, Jo, how would you describe the odyssey that you’re currently experiencing? Jo: So my daughter was about one when I started really noticing that she was having regressions. They were kind of there beforehand but, I really noticed them when she was one, and that’s when I went to the GP and then got referred to the paediatrician. So initially we had genetic tests for things like Rett syndrome and Angelman syndrome, which they were all negative, and then we got referred on to the tertiary hospital and then went into 100,000 Genomes. So we enrolled in 100,000 Genomes at the beginning of 2017, and we got our results in April of 2020, so obviously that was quite a fraught time. Getting our results was probably not as you would want to do it because it was kind of over the phone and then a random letter. So, what I was told in that letter was that a variant of uncertain significance had been identified and they wanted to do further research to see if it might be more significant. So we were to be enrolled into another research project called Splicing and Disease, which wasn’t active at the time because everything had been put on hold for COVID, but eventually we went into t