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.
Monthly Archives: May 2026
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.