What the beach told me about science in 2022

Rehoboth. In 2013, I started a small segment on our blog that reflected on the summer and my time at the beach, weaving in small anecdotes that happened during my summer vacation. This was nine years ago and I have to admit that I didn’t keep up this annual tradition as well as I could have and I would like to start it up again. Here are my 2022 thoughts about the beach and science and what we learn about biomedical research during the times when we are not actually involved in it. While putting this post together, I realized that this year’s theme is about limitations. So how does a beach vacation relate to limitations and how does this all fit together? Please bear with me. Continue reading

The 2022 STXBP1 Summit – a personal reflection

STXBP1 in Philly. From August 18-20, the STXBP1 community met in the Bellevue Hotel in Philadelphia, the first in-person summit after our initial Philadelphia meeting in 2019. Much has changed since our initial meeting – an entire scientific community has woken up to study one of the most common (and enigmatic) neurodevelopmental disorders, the STXBP1 Foundation has grown significantly in activities and scope, and there are very promising developments in the main therapeutic areas, namely drug development, antisense oligonucleotides, and gene therapy. It is not an exaggeration to say that STXBP1 is on the map in 2022 and it is one of the genes with the fastest growing knowledge. Here are my personal reflections from the 2022 STXBP1 Summit – and I want to thank our entire ENGIN team for their fantastic work during our first Synapse Clinic the day before the Summit. Continue reading

A disease concept model for STXBP1-related disorders

STX. We typically don’t blog about preprints, but we are making an exception this time given the upcoming STXBP1 Summit in Philadelphia on August 19-20. This is a post about one of our projects on STXBP1 that tries to understand the clinical presentation holistically, trying to find a way to capture the lived experience of families with STXBP1. In our current manuscript that will be presented at the STXBP1 Summit, we introduce our disease concept model for STXBP1. Disease concept models are formal frameworks that are increasingly required by regulatory agencies such as the FDA. Here is a brief overview what we find when we conduct formal interviews with families how a disease concept model helps us define phenotypes. Continue reading

Claude Shannon and the U-shaped Information Content of developmental phenotypes

Spüre die Welt. This is the second post in our “phenotypic atomism series”, trying to explain how we can gauge the amount of information that phenotypes provide. However, let me start by going very far back. As a graduation gift, my high school teachers gave me a book that set me on the path of becoming a neuroscientist – the User Illusion by Tor Nørretranders, a book that has a more poetic title in its German translation (“Perceive the world”). This book examined the inner workings of human consciousness and explored how our human brains process information. Now, more than 20 years later, I am encountering the idea of measuring information again when trying to understand what phenotypic information is meaningful and how we can assess this. This is a blog post on how we can describe the value of phenotypic information, the importance of time, and how we slowly chip away at the mystery of developmental phenotypes. To put it differently: “Show me the longitudinal information content (IC) for absence seizures – it is going to be U-shaped and you have 60 min.” Continue reading

Outcomes and hidden subgroups in WDR45-related disorders

BPAN. WDR45-related disorders are one of the most common X-linked neurodevelopmental disorders. While initially conceptualized within the framework of rare conditions with neurodegeneration with brain iron accumulation, WDR45-related disorders challenge the traditional concept of neurodegenerative conditions. Most individuals are diagnosed in childhood with neurodevelopmental features. However, the full spectrum of the pediatric presentation of WDR45-disorders has not been fully delineated yet. In a recent publication, we delineate the pediatric presentation of WDR45-disorders. We find that typical outcome measures often fail to capture the full range of features in WDR45-related disorders and that there might be two distinct previously not appreciated subgroups. Continue reading

Phenotypic atomism – understanding outcomes by rethinking clinical information

Natural History. Over the last few years, there has been a renewed interest in outcomes and natural history studies in genetic epilepsies. If one of the main goals of epilepsy genetics is to improve the lives of individuals with epilepsy by identifying and targeting underlying genetic etiologies, it is critically important to have a clear idea of how we define and measure the symptoms and outcomes that characterize each disorder over a lifetime. However, our detection of underlying genomic alterations far outpaces what we know about clinical features in most conditions – outcomes such as seizure remission or presence of intellectual disability are not easily accessible for large groups of individuals with rare diseases. In this blog post, I try to address the phenotypic bottleneck from a slightly different angle, focusing on how we think about phenotypes in the first place. Continue reading

Rewriting the story of neurodevelopmental genes through CNVs in one million people

Copy numbers. When we think about genetic causes of neurodevelopmental disorders and the epilepsies, we typically discuss single genes and de novo variants. Over the last few years, exome and genome data of hundreds of thousands of people have been analyzed, creating large-scale resources to understand genetic variation in health and disease. However, there has been one resource that has always been larger by at least one order of a magnitude – information on copy number variation derived from SNP arrays and array CHG. Now, a recent publication pulls all the existing information together and performs a meta-analysis of rare copy-number variants in nearly one million people. Here is what this study tells us about neurodevelopmental genes and how we can use mismatches between CNV and exome data to answer old questions and find novel genes. Continue reading

Cosmic Spring, ATP1A3, and the dawn of the exome era

The exome decade. Last week, I accidentally looked back at our past blog posts. Exactly 10 years ago, we wrote about the discovery of ATP1A3 as the cause of Alternating Hemiplegia of Childhood (AHC). Quite a lot has happened since then in epilepsy genetics, including the discovery of at least twenty additional genes, initial clinical trials, and large-scale studies such as our Epi25 initiative. However, when seeing our 2012 blog posts, my immediate thoughts were not about achievement or progress – quite contrarily, I had the strange feeling that not much had changed in the last decade. I was reminded of a science fiction short story by Ken Liu – Cosmic Spring. Continue reading

Untying the Gordian knot – the return of Reelin

RELN. Amongst the various genes implicated in neurodevelopmental disorders, Reelin (RELN) has always been one of the more controversial genes. While bi-allelic variants have been implicated in lissencephaly with cerebellar hypoplasia, the role of autosomal dominant variants has been controversial and is currently considered disputed. Reelin is a relatively large gene – accordingly, missense variants are frequent. However, a recent study suggests that the picture might be more complicated and that both monoallelic and bi-allelic variant in Reelin may contribute to neurodevelopmental disorders. Here are my thoughts. Continue reading

A wrinkle in the polygenic risk story

PRS. While monogenic epilepsies are the main genetic etiologies diagnosed in clinical practice, the majority of the genetic epilepsies is not explained by single, strong genes. In contrast, on a population level, the main genetic risk for epilepsy is explained by common genetic variants. While these variants had been largely inaccessible in the past, recent studies have been successful in identifying these variants and understanding the joint risk for epilepsy that are conferred by multiple genetic factors. When assigned to individuals, this joint risk is typically measured as polygenic risk scores. In a recent study, we demonstrate that this finding extends to familial epilepsies, which are highly enriched for extreme polygenic scores. However, in the very moment that I was trying to type the first lines of this blog post, a similar study in schizophrenia appeared online, showing exactly the opposite. Here are some thoughts on why polygenic risk is not as straightforward as you would expect. Continue reading