STXBP1. Today is the first day of the 1st European STXBP1 Summit and Research Roundtable, held from May 16-18th in Milan, Italy. This meeting is bringing together voices from academia, industry, organizations, and family foundations to discuss the current state of research – spanning from preclinical efforts investigating mechanisms of disease to moving towards the clinic and the future therapeutic landscape. In 2023, it feels like an understatement to say that STXBP1 is on the map. In spirit of the ongoing momentum in the field, we wanted to refresh the gene page and outline three emerging frameworks to think about STXBP1.
Phases. Today is Rare Disease Day. I would like to use this opportunity to explain some of the phenotype science that is critical for rare diseases. In contrast to common disorders, rare diseases face an unusual challenge. Once identified, the overall rareness of these condition poses the question of where phenotypes begin and where they end. For rare genetic disorders, is the phenotype of the first individual identified with a rare disease characteristic, or is there a larger spectrum that we should be aware of? Enter the various approaches to phenotype science that aim to decipher the full depth of clinical features associated with rare diseases. In order to understand the various approaches to rare diseases phenotypes, I would like to suggest a somewhat unusual analogy: phenotypes are like water.
Understanding the EMR. Several weeks ago, I gave a presentation at the STXBP1 Summit conference, the third annual meeting since the first in 2019 – a time when I had just entered the field of neurogenetics. It has been fascinating to follow one of the neurodevelopmental genes with the “fastest growing knowledge,” with the expanded scope of clinical studies and emergence of novel avenues for targeted gene therapies on the horizon. However, one of the many projects our STXBP1 team is currently working on takes a somewhat atypical approach – we aimed to map the natural disease history of STXBP1-related disorders based entirely on reconstructed Electronic Medical Records (EMR). Here are some of the challenges we have had to confront and what we learned searching for meaning in the depth of the EMR. Continue reading
STX. Neurodevelopmental disorders due to disease-causing variants in STXBP1 are amongst the most common genetic epilepsies with an estimated incidence of 1:30,000. However, despite representing a well-known cause of developmental and epileptic encephalopathies in the first year of life, relatively little has been known about the overall genetic landscape and no genotype-phenotype correlations have been established. In our recent publication including almost 20,000 phenotypic annotations in 534 individuals with STXBP1-related disorders, we dive deep into the clinical spectrum, examine longitudinal phenotypes, and make first attempts at assessing medication efficacy based on objective information deposited in the Electronic Medical Records (EMR), including information from the almost 100 “STXers” seen at our center in the last four years. Continue reading
Semantic similarity. The phenotype era in the epilepsies has now officially started. While it is possible for us to generate and analyze genetic data in the epilepsies at scale, phenotyping typically remains a manual, non-scalable task. This contrast has resulted in a significant imbalance where it is often easier to obtain genomic data than clinical data. However, it is often not the lack of clinical data that causes this problem, but our ability to handle it. Clinical data is often unstructured, incomplete and multi-dimensional, resulting in difficulties when trying to meaningfully analyze this information. Today, our publication on analyzing more than 31,000 phenotypic terms in 846 patient-parent trios with developmental and epileptic encephalopathies (DEE) appeared online. We developed a range of new concepts and techniques to analyze phenotypic information at scale, identified previously unknown patterns, and were bold enough to challenge the prevailing paradigms on how statistical evidence for disease causation is generated. Continue reading
EMR. When we consider the natural history of rare diseases like the genetic epilepsies, we typically think about a lack of longitudinal data that contrasts with the abundant genetic information that is available nowadays – the so-called phenotyping gap. We typically suggest that we need to obtain this information in future prospective studies to better understand long-term outcome, response to medications, and potential early warning signs for an adverse disease course. However, a vast amount of clinical data is collected on an ongoing basis through electronic medical records (EMR) as a byproduct of regular patient care. In a recent study, our group built tools to mine the electronic medical records to assess the disease history of 658 individuals with known or presumed epilepsies using clinical information collected at more than 62,000 patients encounters across more than 3,200 patient years. Here is a brief summary of our first study on EMR genomics, an untapped resource that has the potential to improve our understanding of the genetic epilepsies. Continue reading
WGS. Whole-genome sequencing is increasingly used to understand the cause of rare diseases in a research and diagnostic context. However, while the usefulness of this technology has been shown in smaller studies, it remains unclear whether strategies to understand the cause of rare disorders through whole genome sequencing can be performed on a national level. A recent study in Nature reported the first results from a national sequencing campaign for rare disorders in the UK, including the analysis of more than 13,000 genomes. In this blog post, I would like to focus on the neurogenetics component of this enormous study, which identified disease-causing variants in GNAO1 as the most common cause within the study’s subgroup of neurological and developmental disorders. Continue reading
Haploinsufficiency. STXBP1-related disorders are one of the most common neurodevelopmental disorders due to pathogenic variants in a single gene. Haploinsufficiency is the proposed disease mechanism and a significant number of individuals have deletions or protein-truncating variants. However, there are also recurrent missense variants in STXBP1, which is often seen in diseases that have a different disease mechanism. In a recent publication in Nature Communications, some of the recurrent variants in STXBP1 are suggested to have an additional disease mechanism, a dominant-negative effect. In this blog post, I want to discuss how we can reconcile both observations and whether STXBP1-related disorders are a single entity with a common disease mechanism. Continue reading
Controversy. Our recent post that featured our Neurology publication on STXBP1 generated much interest, discussion, and debate. In particular, we received feedback from the online STXBP1 parent community that our assessment of STXBP1 encephalopathy as a static rather than a degenerative disease may be incomplete. Let me try to reconcile the results of our study with the experiences that families have shared with us in the last two weeks, trying to understand how STXBP1 can be a disease with many faces and what the common features are. Continue reading
Synaptic. This is STXBP1 week and things are currently happening in rapid succession. We are getting ready for the first STXBP1 Charity Ball and our publication in Neurology reviewing the phenotypic features of 147 patients recently came online. STXBP1 is one of the five most common genes for epileptic encephalopathies and related neurodevelopmental disorders. However, in contrast to SCN1A, SCN2A, CDKL5, or SCN8A, it has received relatively little attention in the past from the epilepsy community. Let’s revisit a common epilepsy gene that holds more secrets than most people would imagine. Continue reading