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
Monthly Archives: July 2025
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.
Five principles for teaching epilepsy genetics
Transition. When our epilepsy genetics program was formally approved in 2019, my former division chief asked me what I was most excited about. I spontaneously replied that we finally got a fellowship and training program. This year marks the fifth anniversary of our epilepsy genetics fellowship, and I am stepping down in my role as the inaugural fellowship director. I wanted to mark this transition by pointing out five principles for teaching epilepsy genetics that have become relevant in the last few years. Spoiler alert: they are not what you think they are.
Predicting genetic epilepsies through EMR fingerprints
EMR. Clinical data on rare disease is not necessarily rare; it is our ability to unlock already existing data that is rare. Over the last decade, we have tried to understand the fingerprints that rare genetic epilepsies leave in the electronic medical record (EMR). In our flagship publication last year, we tried to push the boundary. Is EMR data, with all its strength and weaknesses, able to predict genetic diagnosis? Here is our journey through the hidden signals in large EMR datasets.