Genomics. The use and importance of genomics in clinical research and practice has grown exponentially as the cost of acquiring human genomic sequences has continually decreased. Genetic variation can be inherited, acquired, or present at birth. Within the realm of inherited variants, the evolutionary history of humans can account for much of the genetic variation seen across different groups. Genomic research can help in identification of genomic loci or variants that are potentially associated with human diseases and, hence, also enable the development of precision medicine. However, accounting for the normal spectrum of human genetic variation is critical, and the currently available tools are significantly limited in their ability to do so for a diverse range of human populations.
GRIN2A. “Certainty” is a word that can only be used so often in epilepsy genetics—and GRIN2A has demonstrated a somewhat puzzling tension between “certainty” and “uncertainty”. For example, the association between GRIN2A and focal/multifocal epilepsy with/without centrotemporal spikes, as well as risk for ESES, is well understood at this time. Likewise, the relationship between speech disorders—a unique feature in neurodevelopmental disorders—and GRIN2A has been established. However, as our knowledge of GRIN2A has expanded, our understanding of phenotype as it relates to severity has continued to grow uncertain. Even within the same family, GRIN2A may have a wide phenotypic range. And so, one of the mysteries of GRIN2A reveals itself: how can a gene that has such specificity in some of its phenotypic aspects simultaneously have such wide variability?
Physics. When I tried to summarize the STXBP1 Summit in Colorado on my way back, I got stuck with the concept of momentum. Lots of things are happening in the world of STXBP1 disorders, but the most important thing is momentum, defined by Merriam-Webster as strength or force gained by motion or by a series of events. Buoyed by two natural history studies, STARR and ESCO, things are certainly in motion. Here are a few take-aways from the STXBP1 Summit.
Sparse data. Trying to match the growing body of genomic datasets with associated clinical data is difficult for a variety of reasons. Most importantly, while genomic data are standardized and can be generated at scale, clinical data are often unstructured and sparse, making it difficult to represent a phenotype fully through any type of abbreviated format. Quite frequently in our prior blog posts, we have discussed the Human Phenotype Ontology (HPO), a standardized dictionary where all phenotypic features can be mapped and linked. But these data also quickly become large and the question on how best to handle them remains. In a recent publication, we translated more than 53M patient notes using HPO and explored the utility of vector embedding, a method that currently forms the basis of many AI-based applications. Here is a brief summary on how these technologies can help us to better understand phenotypes. Continue reading
A big step forward. Disease natural history and clinical trial readiness are constantly discussed topics in the rare genetic epilepsy space. Additionally, these concepts have driven our work in the Helbig lab since the very beginning. So why then did last week’s launch of our group’s first prospective natural history study of STXBP1 and SYNGAP1 feel like such a monumental step forward? Last week, we evaluated our first participants in the prospective natural history study that is part of the newly established Center for Epilepsy and Neurodevelopmental Disorders (ENDD), and here are some reflections from our team.
Ketogenic diet. The ketogenic diet (KD) has been formally used to treat epilepsy for the past 100 years. Its history of use dates to Hippocrates who realized that while people with epilepsy fasted their seizures improved. The ketogenic diet mimics a long-term fasting state by having the body enter ketosis with a high fat low carbohydrate + protein diet.
Precision therapeutics. Ongoing research in precision therapies in neurological disorders, including 15q-related disorders, is occurring in three spaces: 1) gene therapy, 2) anti-sense oligonucleotides (ASOs), and 3) small molecules (repurposing existing drugs or generating new drugs), where the latter is primarily focused on addressing the symptoms of genetic disorders (i.e. seizures) rather than the cause (i.e gene dysfunction). Each of these forms of therapy has particular challenges, including, critically, the delivery method. The blood-brain barrier (doing its job well) restricts the access of large or hydrophilic medications to the central nervous system (CNS), therefore scientists building these drugs must not only consider efficacy and safety of the drug itself, but also efficacy and safety of the delivery method to the CNS. Below we explore ASOs and gene therapies and their application in 15q-related disorders in more depth. We will not discuss small molecule therapies here as the topic is too broad in scope for the purposes of this post, and we would like to focus primarily on genetically-based therapies.
NDD. Family-based (trio) exome sequencing has become the standardized method for identifying genetic etiologies that cause neurodevelopmental disorders. De novo variants have been responsible for the majority of pathogenic genetic findings, although the landscape of genetic disorders overall is highly heterogeneous. In a recently published study, the authors assessed variant classification to identify new molecular diagnoses and factors influencing the likelihood of receiving a diagnosis. The study reported a diagnostic yield of over 41%, highlighting 60 new genes associated with developmental disorders. The authors also emphasized the importance of structured and detailed phenotypic information for improving variant interpretation. This blog post provides a brief review of their publication in the context of improving diagnostic yield using a phenotypically driven approach in rare diseases.