Pursuing Precision Medicine for Rare Diseases with Gemma Carvill, PhD

“It's by no means an isolated incident. We think that in the future, as more folks do genetic genome sequencing, we'll start to uncover more and more examples of this, where non-coding regions of the genome are implicated in health and disease.”  — Gemma Carvill, PhD 

• Assistant Professor in the Ken and Ruth Davee Department of Neurology, of Pharmacology and of Pediatrics 
• Member of Northwestern University Clinical and Translational Sciences Institute (NUCATS) 

• Carvill’s lab focuses on identifying the genetic causes of epilepsy and how these contribute to brain development and function. For more than a decade she has studied the CHD2 gene, which causes autism and epilepsy.  
• One day, Carvill received a “cold email” from Brian Broadbent, the father of a young patient, Emma Broadbent, who was struggling to get an accurate genetic diagnosis for Emma, who lives with severe neurodevelopmental delays and a host of other health issues. With help from the Undiagnosed Diseases Network, Brian had found that Emma has a pathogenic variant related to the CHD2 gene, but it seemed unlike CHD2 variants found in the genome of other children Carvill studied. That email led to a multi-institution collaboration and major discovery detailed in the The New England Journal of Medicine paper.  
• It was discovered that Emma has a deletion in a long non-coding RNA, CHASERR, upstream of the CHD2 gene. CHASERR acts as a “brake” to regulate CHD2 protein levels. Without it, Emma’s cells produced too much CHD2, causing developmental issues. 
• Emma’s cells were brought to Carvill’s lab and transformed into induced pluripotent stem cells, allowing her team to model the disorder in the lab and confirm elevated CHD2 levels as the cause of Emma’s condition. Through networking with colleagues around the world, Carvill was able to identify two other children with the same deletion in a long non-coding RNA as Emma.  
• This finding was only possible through an extraordinary collaboration between institutions and laboratories as well as patient advocates, contributing to the findings. Brian Broadbent’s work as an advocate led to him being named a co-author on the The New England Journal of Medicine paper.  
• Ninety-nine percent of the genome is non-coding, but its functions are still poorly understood. As more research takes place in these regions of the genome, Carvill says there is hope for better understanding of rare diseases and paving the way for gene-targeting therapies, focusing on treating the root cause of conditions like Emma’s rather than just the symptoms. 

Recorded on December 2, 2024. 

Additional Reading

• Watch a video about the New England Journal of Medicine publication.
• Learn more about Carvill's lab.
• Read about another study from Carvill's team in Brain.

Target Audience

Academic/Research, Multiple specialties

Learning Objectives

At the conclusion of this activity, participants will be able to:

1. Identify the research interests and initiatives of Feinberg faculty.
2. Discuss new updates in clinical and translational research.

Accreditation Statement

The Northwestern University Feinberg School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Credit Designation Statement

The Northwestern University Feinberg School of Medicine designates this Enduring Material for a maximum of 0.50 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

American Board of Surgery Continuous Certification Program

Successful completion of this CME activity enables the learner to earn credit toward the CME requirement(s) of the American Board of Surgery’s Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit.

Disclosure Statement

Gemma Carvill, PhD, has received grant or research support from Stoke Therapeutics and honoraria from Pfizer, Inc. Course director, Robert Rosa, MD, has nothing to disclose. Planning committee member, Erin Spain, has nothing to disclose. FSM’s CME Leadership, Review Committee, and Staff have no relevant financial relationships with ineligible companies to disclose.

All the relevant financial relationships for these individuals have been mitigated.

CME Credit Opportunity Coming Soon

[00:00:00] Erin Spain, MS: you are going to hear about the extraordinary collaboration between families, clinicians, and scientists around the world that led to the identification of a new rare genetic disorder, the first ever linked to a long non coding RNA gene. The discovery from Northwestern Medicine, the Broad Institute of MIT, and Harvard University scientists was recently detailed in the New England Journal of Medicine and highlights the need to examine non coding parts of the genome when diagnosing rare diseases. Northwestern Medicine Investigator, Dr. Gemma Carvill, is my guest. She is the corresponding author of the study and an assistant professor in the Ken and Ruth Davee Department of Neurology and of Pharmacology and of Pediatrics at Northwestern University Feinberg School of Medicine. Her lab's goal is to determine the genetic causes of epilepsy and how pathogenic variants in these genes affect how the brain develops and develops. She joins me today to talk about this important new discovery and how it came to be. Welcome to the show, Gemma. 

[00:01:05] Gemma Carvill, PhD: Thanks so much, Erin. I'm excited to be here. 

[00:01:06] Erin Spain, MS: very lucky to have you. And today we are talking about your involvement in this New England Journal of Medicine study that began after the family of a little girl named Emma Broadbent Broadbent reached out to you after struggling to get an accurate genetic diagnosis for Emma. lives with severe delays and brain development and a host of other health issues. So tell me a little bit about Emma, her condition and her family's outreach to you. 

[00:01:33] Gemma Carvill, PhD: Yeah, Emma is a fantastic little girl, a spirited little individual for sure. I first met Brian, her dad in person, actually only very recently. But on the interwebs a couple of years ago now. It all started back in 2013. So we first identified that pathogenic variance in a gene called CHD2.Could cause a neurodevelopmental disorder. But kids who had pathogenic variants in the CHD2 gene generally presented with very bad seizures. And some of them can have neurodevelopmental delays as well. But what Brian had found through collaboration with the UDN, which is the Undiagnosed Diseases Network he had been working with them for many years to try and find whether there was a genetic variant that caused Emma's condition.And so, what they found was a pathogenic variant that was a little bit different to the other kids with CHD2 variants. In that, this pathogenic variant wasn't actually in the CHD2 gene, it was just upstream. And so, he immediately appreciated two things, which is incredibly impressive for an individual who hasn't been classically trained in genetics.He immediately noticed, one, that the the symptoms that his daughter had were very different to the symptoms of the kids pathogenic variants in the CHD2 gene. So he immediately noticed the difference in kind of their clinical phenotype. The second thing he noticed was that those genetic variants weren't actually in the CHD2 gene.And so, he was very, he was somewhat suspicious that this might be the cause but really it's not. Essentially sent me a cold email out of nowhere to say, my daughter has this genetic variant, she looks a little bit different to the other kids, what are your thoughts in terms of this being the genetic cause for my daughter?And so that was really where this all started, was that cold email many years ago. But Brian was then really instrumental in bringing everybody in the team together, and like he was really the one that drove everybody, got everybody in the same room to try and answer this question of could this genetic variant be what is causing Emma's condition? 

[00:03:54] Erin Spain, MS: Because CHD2, this is one of your genes. This is something that you study in your work to establish the genetic cause of epilepsy. Tell CHD2 gene and why it's known as this Goldilocks gene. Well, 

[00:04:12] Gemma Carvill, PhD: these genetic variants in CHD2 and then linked them to this epilepsy phenotype. And since then, for the last It's more than 10 years now, I've been studying this gene and trying to figure out when you have a pathogenic variant in this gene, how does it end up causing those seizures.And so as a result we've also worked very closely with the family foundation. And so what tends to happen in these rare neurodevelopmental disorders is that when a family receives a diagnosis, so in other words a genetic diagnosis that that causes their disorder families tend to coalesce around that single gene and put family foundations together and essentially do a lot of work, finding other families who have mutations or pathogenic variants in that gene setting up NGOs, connecting with researchers, doing fundraising for research and so probably about five years ago now we connected with two moms whose daughters have a CHD2 variant and established what we call the Coalition to Cure CHD2. And so this is the family foundation who organizes a lot of the outreach CHD2 variants. So Brian connected with the family foundation through Emma's diagnosis and now helps guide kind of some research questions for both my lab, but other labs as well.But to answer your second part of the question is why is it this Goldilocks gene? So patients who have pathogenic variants in CHD2, what ends up happening is those variants essentially destroy the function of their protein. And so we call that loss of function. And so in individuals with this condition, they have about 50 percent of the levels of CHD2 compared to the general population. And so they have too little CHD2, and this is what causes the seizure disorders. In Emma's case, she doesn't have a pathogenic variant in CHD2, but we found that she has a deletion just upstream of CHD2. And her deletion encompasses the long non coding RNA called CHASERR. And the way in which we now think CHASERRworks is this long non coding RNA controls the amount of CHD2 that is made in the cell. And you can think of it almost as a break. So the long non coding RNA acts as a break and you take your foot off the brake or Put your foot down to control the amount of CHD two in the cell. In the case of Emma, with the deletion of that long coding, RNA, what ends up happening is there's no longer that break. And so now what happens in Emma's cells is that she has too much CHD two, and that's likely what underpins many of her challenges in terms of neurodevelopment, but also neurological function. And so it's a Goldilocks gene because both too little and too much is detrimental to brain development and function. 

[00:07:16] Erin Spain, MS: a little bit about how you were able to determine this. You were able to bring Emma's cells here to your lab at Northwestern and grow them and study them. What were you looking for? And then again, what did you find? Yeah. Yeah. 

[00:07:31] Gemma Carvill, PhD: I spoke a lot about how too little and too much of CHD2 is bad, and so we knew from some studies in mice that if you deleted CHASERR, the long known coding RNA, in mice, what happened was their they There's an increase in the production of CHD2. So what we thought was maybe this is what is happening in Emma's cells as well.So our original hypothesis or idea was to test if in Emma's cells she had more CHD2 than the general population. And so the way in which we did this was Emma had a tiny little skin punch biopsy. It's essentially just a tiny little one centimeter skin punch biopsy. And so she underwent that procedure at Baylor. You can then take that teeny tiny little skin punch and you can put it essentially in a Petri dish. And what ends up happening is that these tiny skin cells essentially grow out of that tiny little piece of tissue. And you can establish what's called a fibroblast cell line. And so that cell line, you can grow for many different generations and you can keep that those cells alive. And they're incredibly useful for answering some certain types of questions, but what we really wanted to do was take Emma's fibroblasts cells and turn them into induced pluripotent stem cells. And so this is essentially taking a cell type and basically pushing it backwards into a type of cell that has the potential to be able to be differentiated to multiple cell types in the body. And so in other words, you can take that stem cell and you could turn it into cells that look like cells in the brain or cells that look like cells in the heart. And so it's a very nice model system where we can try and recapitulate some of the neuronal neurological features that we see in these kids using this IPSC stem cell model. So we did that with Emma's cells, turned them back into stem cells, and then we asked, we addressed our original question: what are the levels of CHD2 in MS cells? And what we found was that indeed, as with mice in humans who have a CHASER deletion, there's an increase in the amount of CHD2 protein relative to the general population. So we did that both with Emma's cells, but then also later there was, there's another patient from France and we did the same thing and showed that there's a, basically a 1. 8 fold increase in the amount of CHD2 in these individuals who have chaser deletions. 

[00:10:07] Erin Spain, MS: this discovery was made by looking into the non-coding regions of the genome, which has been understudied and mostly unknown to scientists. Why have these regions been so understudied and what challenges do they present for geneticists, people like you? Right. 

[00:10:26] Gemma Carvill, PhD: is basically job security because we basically have no idea what most of the genome does and so I'll probably be very old and we still won't know the answer to that question. All the answers to that question, rather to take a step back, what are non-coding regions?So, if we look at our genome, about 1 percent of the DNA in our genome makes proteins. And so what happens is there is a gene that codes for an RNA, and then RNA makes protein. And so, amazingly, everything that makes us human, or every single component of our cells, is essentially made from proteins. But it accounts for only 1 percent of the entire genome.The other 99 percent of our genome, we really don't know what it does. And so, we have, in some regions, we have a good understanding of how what the purpose of that DNA is, but by and large we don't. And so what chaser is a long, non coding RNA. And so chaser makes an RNA molecule, but then it doesn't make a protein molecule.And so rather what that RNA molecule does is it's the job of the RNA molecule to control the amount of CHD2 protein that is made. And so we think that's really its primary function in the cell is that you make this RNA and it's probably one job is to control how much of one protein is made. And so there are tens of thousands of long non coding RNAs in the genome. And I would say we know only a tiny percentage of the function of those long non coding RNAs. Some of it in the past, we haven't found cases like this because we haven't been looking. And so, traditionally, if an individual has a genetic test for breast cancer, for instance, what the genetic testing company will do is look at all of the coding regions, so the parts of the genome that make proteins, look at the coding regions for genes that are known to cause breast cancer.But that's it. And so, that is the sequencing that will be done. And some of that in the past has been a technological limitation, in that we could only sequence those pieces. But now, we have the technologies that are perfect. Pretty cost effective to be able to sequence the vast majority of the genome.So we can look at the 1% and we can look at the rest of the genome as well. And so now we were able very easily to sequence the genomes of individuals. But the real bottleneck and challenge now is that interpretation is if we find a genetic variant, or in this case a large deletion of a chunk of DNA, we have no idea what the downstream effect, if any, that may cause. And so this is an example of how you can have a deletion in a long non coning region that can have very profound impacts in terms of development and neurological function for these patients. It's by no means an isolated incident, and so we think that in the future, as more folks do genetic genome sequencing we'll start to uncover more and more examples of this, where non-coding regions of the genome are implicated in health and disease. 

[00:13:44] Erin Spain, MS: I think there's about 30 million people with rare diseases in the U. S. About half of those are children, and be of genetic origins. So you do think that these long coding RNAs and non coding regions could play a role in these other disorders? 

[00:13:59] Gemma Carvill, PhD: Almost certainly. Yep. Not all of them, but I think a very large percentage of the unsolved rare disease cases be due to non coding genetic variants as well. 

[00:14:12] Erin Spain, MS: What kind of message does this send, this discovery, to your colleagues and other folks who study these types of diseases and are looking for answers for families? 

[00:14:21] Gemma Carvill, PhD: I think one of the main takeaways from this is that we shouldn't ignore the non-coding regions of the genome and that we really need concerted efforts to come up with a roadmap of what does the rest of the genome do. And this is not something that we've completely ignored as scientists. Scientists have been working for many years in trying to figure out what the non coding regions do but I think we need even more research as essentially the answer to try and figure out what these non coding regions do which ones are important in health and disease, and just in general development as well. 

[00:14:58] Erin Spain, MS: Now, you mentioned this story didn't end with identifying the genetic cause of Emma's disorder. There were two other children, you mentioned one in France, with this exact condition. So tell me how this came to be that you were able to connect and diagnose these other children. 

[00:15:14] Gemma Carvill, PhD: So about probably two or three years ago we had done the confirmation experiments that showed that Emma had increased CHD2 levels relative to the general population. And so we had Emma's answer, we were pretty confident we had Emma's answer, probably about three years ago. The big sticking point was if you have one patient, it's very hard to say conclusively that this is the cause of their disease. And so really we spent the last two or three years reaching out to collaborators across the globe giving presentations in multiple different forums, so in human genetics conferences, at rare disease conferences, and essentially asking the world collaborative of rare neurological conditions to go and look at their data and see if they could find this deletion. And that was really how this discovery came about at the end of the day. It was via a conference where one of our colleagues was giving a poster, and they happened to see it and go and look in their data, and then found the second and then third individual who have, who has a CHASERR deletion. Interesting, both of the other two patients are both from France. And so, again, this just speaks to that we don't think that these are the only three individuals in the whole world who have CHASERRdeletions. It more speaks to nobody's looking in the right place. But as soon as people start to look, that we find these deletions. And I think that's true for CHASERR but I think it's true for many other conditions as well, is that we really just need to start looking in a concerted way. 

[00:16:50] Erin Spain, MS: mean, you just mentioned there's so many different people around the world with different areas of expertise who contributed to this discovery. How important is this type of collaborative team science to study such complex genetic problems? 

[00:17:04] Gemma Carvill, PhD: So, it's one of my favourite parts of my job, and one of the most underrated and sometimes difficult parts of my job. It can sometimes be very difficult to get researchers in the same room, playing on the same team. And I will say that probably Brian was really our cheerleader who put us all together and got us all in the same room across often two or three different continents on different time zones and worked with everybody to bring everybody in the same room. But I think it's really is a nice testament to how team science done right, can really advance our knowledge of the genome and the types of genetic variants that can cause rare diseases. And so we've been working on this. Like I said, for three, five years to put this, the story together. And everybody had their own part to play. Broad and Baylor were very instrumental in the beginning in finding theCHASERR deletion and then my lab came in later to look at what happens when we delete CHASERR to the levels of CHD2 and looking more in Emma's cells. 

And now moving forward, we are still collaborating. And so, we're moving forward with trying to think of ways in which we can use CHASERR to control the amount of CHD2 as a potential therapeutic, as well as looking in MS cells and the other French patient cells, can we reduce the amount of CHD2 as well? 

So we call these gene targeting or precision therapies, where we're now trying to develop therapies for this very, very rare condition. And so we're doing that really in collaboration with Brian and his family and the other families, but also the Broad as well. And so it's a kind of an ongoing and I think a nice case study of how these team science approaches can really work. 

[00:18:55] Erin Spain, MS: looking into these possible therapies, how could such treatments hypothetically work? 

[00:19:01] Gemma Carvill, PhD: Yeah, so we know thatCHASERR controls the amount of CHD2. And we know that in individuals with that seizure disorder, they have too little CHD2, right? And so, in theory, if you could target CHASERR, reducing the amount of CHASERR, that might be a way to boost the amount of production of CHD two in those individuals that have too little. 

And so the way in which we are doing that is we manipulate the amount of RNA of the CHASERR long non-coding RNA. We manipulate how much RNA is made from that transcript. And so it's taking advantage of a natural process to tinker with protein levels. 

[00:19:45] Erin Spain, MS: I mean, and it's unknown if a hypothetical treatment like this would be able to help Emma in her lifetime, yet her father still plays such a critical role in moving this along. He's actually an author on this New 

[00:19:57] Gemma Carvill, PhD: Yep. 

[00:19:57] Erin Spain, MS: of Medicine article. How essential are the Bryans of the world in pushing science like this forward? 

[00:20:04] Gemma Carvill, PhD: Yeah, I would say it's been remarkable how this has changed over my career. And, my career's not that long, in that I started in this field 12, 13 years ago. And we didn't even know what the genetic causes were for these conditions. And now one, we know that the majority of rare disease is caused by genetic variants.But also, it's no longer just a scientist sitting in isolation studying a gene for 20 years. Now it's very much a collaborative effort with people like Brian, with foundations like CCC. I would say that all of us that work in rare genetic diseases, I would say that we spend a significant proportion of our time working with family foundations and people like Ryan. 

And I think that's a great lesson for young trainees as well, to understand that their science matters, it matters for the people behind the condition as well. And I also think it informs our science. We know what is important to families. We know what their struggles are and we can tailor our science so that it best fits addressing their needs. 

And so I think that has really changed a lot over the last couple of years. And I think it's good for science. It's good for moving towards gene targeting therapies and getting answers for patients. 

[00:21:33] Erin Spain, MS: lab's focus is to determine the genetic causes of epilepsy. This could lead to gene targeting therapies to correct the root cause of this disorder. How does this new knowledge in Emma's case get the field closer to designing such therapies for 

[00:21:48] Gemma Carvill, PhD: so 

epilepsy is the third most common neurological disorder, And in addition, 30 percent of individuals who have epilepsy are resistant to current medications. 

And so as a result, they have ongoing seizures that we do not have the tools to treat and to rectify. One of the ways that we're trying to rethink how to treat epilepsy is instead of treating seizures, which is really just the manifestation of this condition, is instead to treat the root cause. And so, in so doing, our goal is to, one, identify what is the genetic variant, or sometimes variants, that cause an individual's epilepsy and treating that root cause, as opposed to treating the symptoms of epilepsy, which is the seizures. 

And so Emma is an excellent example of this in that if we can manipulate the levels of CHD2, we're not really treating the symptoms of the condition, but we're treating the root cause. And so by correcting this, the goal is to eventually have very precise therapies to treat rare genetic conditions. 

And so it applies to Emma, but it's really the goal broadly of the field of rare neurogenetic conditions. 

[00:23:04] Erin Spain, MS: the environment at Northwestern that really allowed you to pursue this. This was a one off case in a lot of ways. Tell me about the support that you had in order to make this science happen. 

[00:23:16] Gemma Carvill, PhD: So while this is a very rare cause of a neurological condition, I think it speaks to a broader effort across neurology and across Northwestern to do more precision medicine type approaches in treatment of health and disease. And so traditionally, like in epilepsy, we treat the seizures, so the symptoms of the condition, rather than the root cause of the condition. I think we in my lab, I was starting to think about precision therapies and gene targeting therapies, but we are not operating within a vacuum. And so, one of the really encouraging things and exciting things about being at Northwestern is that there is a very big movement towards this line of thinking. 

where we're committed to identifying the cause of an individual's neurological or other condition and treating patients based on their genetic makeup, as opposed to treating the symptoms of a variety of different conditions across the university system as well. 

[00:24:17] Erin Spain, MS: Is there anything else that you would like folks to know who are hearing this story for the first time and they're excited about this new approach that there could possibly be precision medicine for people with diseases that this has never been an opportunity for them before? 

Any parting words as we leave today? 

[00:24:35] Gemma Carvill, PhD: I think it's a nice example of the power of genetics and how having a genetic diagnosis can move you towards precision therapy.So I think this is one of the most encouraging things is that genetic testing is becoming more and more available across, So across the US and worldwide. And I think I would love to encourage people to think a little bit more about genetics in terms of your health and disease and the potential options that are out there in terms of a genetic diagnosis. 

[00:25:03] Erin Spain, MS: Carville, thank you so much for sharing this really extraordinary story and the work going on in your lab, and we will continue following along as more discoveries are made. 

[00:25:14] Gemma Carvill, PhD: And thanks so much for your time and getting the story out there. It's a very exciting collaborative story and I'm really glad that the world is getting to hear about it.