A paradox in the hippocampus. Immature dentate granule cells are often described as the “plasticity reserve” of the hippocampus. They provide a pool of neurons that integrate into existing circuits, supporting learning, memory, and repair. In neurological disease, these cells have been suggested to buffer against injury or degeneration. In a recent publication, researchers showed that the hippocampus continues to generate new neurons throughout life, but that the molecular instructions for doing so vary dramatically across species. The surprising finding is this: the processes of neurogenesis are conserved, while the genes underlying these processes are often completely different. This is an important reminder that biology often converges at the level of function, even when the building blocks are not the same.
The placental mirror – methylation and neurodevelopment in congenital heart disease
Neurodevelopment. Congenital heart disease (CHD) refers to a broad group of structural abnormalities of the heart that are present at birth and affect approximately 1% of all live births. Over the past two decades, advances in neonatal surgery and perioperative care have dramatically increased survival rates. Yet this success has revealed an important challenge, and focus has gradually shifted from the heart alone to the brain. A growing body of evidence has shown that children with CHD are at increased risk for neurodevelopmental disorders, including delayed language acquisition, executive dysfunction, and visuospatial processing difficulties. In a recent publication, we took advantage of a unique biorepository to explore how early differences can be identified on the molecular level that may inform later neurodevelopmental features. Here is what we found.
Three things the beach told me about science in 2025
Rehoboth. It has been a while since I posted my annual post-beach-vacation thoughts about how my experiences at the shore made me think about science. I initially started these posts after a vacation in Marielyst, Denmark when I realized that my sandcastle building skills were not appreciated as much as I thought. This reminded me that similar things happen with our scientific achievements. Here is what the beach told me about science in 2025, twelve years after I started to compare academic endeavors with alluvial relaxation. Continue reading
Chasing the Demosthenes gene – the complex genetics of stuttering
Fluency. When we think of stuttering, we might first think of speech therapy, of pauses and repetitions, and of the courage it takes to speak when words get stuck. But what if we could step back and see its genetic architecture laid out across the globe? A recent study looked at the genetics of stuttering at an unprecedented scale: over 1.1 million individuals, including almost 100,000 people who self-reported a history of stuttering. Stuttering shows a significant overlap with other neurodevelopmental disorders and enrichment of genes expressed in the brain. Here is a brief summary of one of the most important studies in stuttering research in the last few decades.
Beyond Sleep: BMAL1 links circadian time to neurodevelopment and epilepsy
The clock gene. Every cell in the human body keeps time. This intrinsic rhythm is roughly 24 hours long and driven by the molecular circadian clock: a transcriptional feedback loop that helps regulate sleep, metabolism, and hormone release. But what happens when these timekeepers stop working? In a recent study, we explored the role of BMAL1 (ARNTL), a core circadian regulator, in neurodevelopmental disorders. What we found surprised us: disruption of this central clock gene does not just affect sleep; it shapes the course of development itself.
Tenure into the Unknown
Monastic. I am now roughly one month into the first real job of my life. I celebrated this transition by spending a week with my family in Kamp-Lintfort, Germany, a small town at the Western edge of the Ruhr area known for its coal mining heritage and Cistercian abbey. After two decades of training roles and academic positions that were either time-limited or contingent, I was tenured at the University of Pennsylvania in July 2025. But tenure is a strange thing these days. Here are my thoughts about modern academia, monastic life in the 12th century, and the possibilities of being able to venture into the unknown.
The power of paralogs in epilepsy genetics
Paralogs. Every week in our variant review meetings, we encounter a familiar issue: understanding a missense variant of uncertain significance. Unless it matches a known disease-associated variant or is found to be de novo, our confidence often stalls. But what happens if we stopped looking at genes in isolation? In a recent publication, we had the opportunity to explore this idea by looking at paralogs and variants at identical sites across gene families, and we found evidence that was strong enough to be included in the official ACMG/AMP variant curation criteria. Continue reading
The rare disease with fastest growing knowledge – the 2025 STXBP1 Summit+
Westminster. The Westin in Westminster, Colorado has an inbuilt alarm clock. As the hotel is a relatively isolated tall building, you get the most intense sunrise over the big Colorado sky that gently wakes you up as it intensifies – a consolation prize if your hotel room doesn’t have the majestic mountain view, as was my case this year. The Westin the venue for this year’s STXBP1 Summit+ Family Meeting. Here are three takeaways from the summit, from my perspective as a clinician researcher.
AP2M1 and the mystery of missing haploinsufficient genes
AP2M1. The genetic landscape of neurodevelopmental disorders is shaped as much by what we see as by what we don’t. In 2019, we discovered dominant-negative mutations in AP2M1 as a novel cause of neurodevelopmental disorders with epilepsy, but it also left a lingering question. Judging from large population databases, AP2M1 has all the features of a haploinsufficient gene rather than a dominant-negative disease mechanism. However, protein-truncating variants or deletions in AP2M1 have never been described. In a recent study, we demonstrate that a small deletion on chromosome 3 offers a compelling insight into this mystery. By narrowing down the candidate region of the 3q27.1 deletion syndrome to a 430 kb region, AP2M1 remerges as the most likely candidate. But it also reopens a broader question: Where are the missing haploinsufficient genes?
RBFOX3 and the hunt for epilepsy genes in 100,000 genomes
Large scale. Novel epilepsy genes are typically discovered through collaborative studies that combine information across various centers and research groups. However, there are also large-scale sequencing initiatives on a national level that include individuals with epilepsy. In a recent study published in Nature, a wide range of clinical phenotypes were assessed in an initial cohort of 34,000 individuals in the UK 100,000 Genomes Project. Let me dive into the associations related to epilepsy in this publication.