ZARD. Last year I became acquainted with a neurodevelopmental disorder that I knew relatively little about before, ZC4H2-Associated Rare Disorder, or ZARD. First of all, this was a good reality check for me that the field of genetic neurodevelopmental disorders is broad and includes many conditions where more than a hundred individuals have been reported in the literature and twice as many families are represented by advocacy organizations. And yet, these some of these conditions remain rare enough that our program largely misses them, even after having evaluated more than 7,000 individuals with epilepsy and neurodevelopmental disorders. However, this gap in knowledge gave me the opportunity to rapidly acquaint myself with a condition based on available information. And this is when I stumbled upon an unusual feature of ZC4H2-related disorders that made me pause: the surprisingly high frequency of congenital contractures for a neurodevelopmental disorder. Here is what I learned.
After the Genome Comes Time: Kids First and the Next Wave of Phenotype Science
Wave. Earlier today, I was invited to speak at the Kids First Spring Public Webinar, part of the Gabriella Miller Kids First Pediatric Research Program. The theme was “Ride the Wave of Discovery,” fitting for a program built around shared pediatric data and collaboration. In my talk, I focused on epilepsy genetics and on a question that now sits in front of pediatric genomics: what can we learn when many children already have genomes? My answer was that we need to move from genomes to phenomes to time.
The Spliceosome Strikes Again: Biallelic RNU2-2 Variants and the Phenotypic Code
Recognition. There are moments when a new disease gene is reported and immediately feels important. And then there are moments when the same gene appears in three independent papers in the same issue of Nature Genetics. That is what happened with RNU2-2. In three parallel studies, independent groups essentially came to the same conclusion: biallelic variants in RNU2-2 are an unusually frequent cause of neurodevelopmental disorders and typically present as developmental and epileptic encephalopathies (DEEs). Taken together, these papers expand the spliceosome story that began with RNU4-2 in 2024. Here is what I learned about the recently identified recessive RNU2-2 disorders.
Love for Liam — Sustaining the Improbable
Birdie. Last year at the Love for Liam golf outing, I accidentally scored a birdie. I say accidentally because my golfing abilities remain mostly hypothetical, and my usual contribution to the team is better measured in persistence than athletic excellence. A birdie, at least in my case, is an anomaly that is rare enough to remember – and our ENGIN team keeps reminding me of this. However, over the last few months, I have found myself describing our epilepsy genetics program in similar terms. Not as an accident, but as a historical anomaly. A program like ours, with sixteen attendings, two nurse practitioners, seven genetic counselors, three genetic counseling assistants, a dedicated administrative structure, and multiple connected research labs is not something that naturally happens. We have now seen more than 7,000 patients and made more than 1,000 genetic diagnoses. The question I have been thinking about recently is not how a program like this was built, but how it can continue. I know that this blog post has two separate threads that only come together later, but please hang in there. Continue reading
The Hidden Genome of Treatment: Lessons for Epilepsy Pharmacogenomics from GLP-1 Agonists
Signal. I admit that the title of this blog post is somewhat misleading, but please bear with me. Yes, GLP-1 receptor agonists have very little to do with epilepsy, but there is a larger story behind this. In a recent study, nearly 28,000 people taking GLP-1 receptor agonists answered a seemingly simple question: how much weight did you lose, and how bad were the side effects? This simple survey, coupled with genetic data, produced one of the cleanest pharmacogenomic signals seen in recent years. But it also emphasized that the genetics of treatment are often not the genetics of disease, and that matters far beyond obesity and weight loss. Here is why this should make us rethink pharmacogenomics in epilepsy.
STRIPE – When RNA Speaks Louder Than DNA
RNA. More than a decade ago, I remember reading an article arguing that we actually live in an RNA world. At the time, this felt a bit academic and not really relevant. Genetics was about sequencing and interpreting DNA. However, over the last few years, our ability to think in terms of RNA transcripts rather than DNA sequence has become increasingly relevant. When I teach trainees, I sometimes tell them: we do not care about genes. And then I pause, usually long enough to make people uncomfortable. Then I correct myself: we care about transcripts. In a recent publication, we assessed how a novel targeted long-read RNA sequencing approach can help with rare disease diagnosis. Here is what we found.
What Cerebral Palsy Research Tells Us About STXBP1 and SYNGAP1
Scales. Decades of cerebral palsy research suddenly become meaningful for STXBP1 and SYNGAP1. The CP field has built a mature framework of classification systems such as the Gross Motor Function Classification System (GMFCS), along with related tools for manual ability and communication. These systems were not developed for synaptic disorders, which were largely unknown when these scales were first conceptualized. However, as we move toward trial readiness, they offer exactly what we need: structured ways to describe function. The question is whether they translate and can be used. Here is what we found.
The Fluency Illusion
Circuit. Last week, I had the opportunity to give the keynote speech at our local Friends conference in Philadelphia. Friends is the National Association of Young People Who Stutter, and I gave an update on the science of stuttering, including our genetic studies. However, rather than starting with the zebra finches or images of the unusual representation of speech in my own brain, I started my talk by showing the book cover of The User Illusion. This book made me interested in neuroscience in the first place, and I thought that the underlying theme is a great introduction to the mysteries of human fluency. Here are my thoughts.
Moving AI in Epilepsy Beyond the Buzzwords
Signals. Two weeks ago, I participated in this year’s AI in Epilepsy Conference. The meeting brought together a field that is moving quickly, but not always at the same pace. I presented our computational approaches for real world data and natural history studies. However, in many areas of epilepsy, AI is already more advanced than what we currently use in genetics and rare disease research. Therefore, I was mainly there to learn. Here are three aspects of AI in medicine that I have thought about more since returning from the conference.
Familial Epilepsy Is Not as Simple as We Think
Families. We tend to think that we understand familial epilepsy. The mental image is almost fixed: large pedigrees, clean inheritance, recognizable syndromes, and genes that segregate exactly as expected. But in a recent study from our epilepsy genetics program, we looked at something different. Not discovery cohorts and carefully selected multiplex families, but real-world genetic testing in 484 consecutive families. All families were evaluated in routine clinical care through ENGIN, our Epilepsy Neurogenetics Initiative, which has now evaluated more than 7,000 individuals with epilepsy and related disorders. The result was a picture of familial epilepsy that is both reassuring and unexpectedly complicated. Here is what we found. Continue reading