Presynaptic. Over the last decade, there has been significant interest in understanding the role of synaptic genes in neurodevelopmental disorders and epilepsy. While we have made significant progress on conditions such as STXBP1– and SYNGAP1-related disorders, many synaptic genes remain uncharacterized. In a recent publication, we delineated the phenotypic range of the newest member of this group of genes: BSN, encoding the presynaptic protein, Bassoon. Here is how we deciphered the landscape of BSN-related disorders, integrating real-world data and biorepositories.
The Spliceosome Connection – RNU4-2 in neurodevelopmental disorders
An RNA world. Last week, a simple bar graph caught my attention and prompted me to write my first blog post in over a year. I came across a figure comparing the frequency of de novo variants in RNU4-2 to other genes causing neurodevelopmental disorders. The data suggested that the recently identified ReNU syndrome may be one of the most common genetic neurodevelopmental disorders with a high frequency of seizures. This led me to take a closer look at a group of conditions that have emerged over the last few years: disorders of spliceosome function, providing some interesting insight into the dynamics of gene discovery in the post-genomic era.
Takeaways from the 2024 Dravet Syndrome Foundation Biennial Family and Professional Conference
DSF. This June, our team attended the Biennial Family and Professional Conference held by the Dravet Syndrome Foundation (DSF). Over three days in Minneapolis, research findings and therapeutic advances were discussed, and families shared their stories. As a first-time attendee, it was a humbling experience to be invited into this tight-knit, motivated, and inspiring community. Here, I would like to share some of the lessons I learned while in attendance.
Genetics of the GABA-A Receptor in Epilepsy
GABA. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system. The main function of GABA is to reduce the excitability of neurons, which is the opposite of the excitatory glutamate that we described more extensively on our blog when talking about GRIN– and GRIA-related disorders. Many variants in GABA receptors are linked to epilepsy. Here, we will dive specifically into the genetics of the GABAA receptor.
Epilepsy Genetics Spycraft, UGDH, and Mardi Gras
The gene on your hand. We should never apologize for telling people about genetic epilepsies, we should apologize for not telling people enough about it. At the 2024 Mardi Gras celebration of the Epilepsy Foundation of Eastern Pennsylvania, I had the honor of being given the Charley and Peggy Roach Founders’ & Eric Burton Osberg Award, also known as “Philadelphia Epilepsy Medical Professional of the Year”. I am quite sure that there must have been a data entry error or that the selection committee slipped in the line when they made this decision. Many of our epilepsy nurses, nurse practitioners, EEG techs, researchers, and physicians caring for people with epilepsy in Eastern PA would have been much more eligible for this honor than myself. However, given this unlikely opportunity, I used my moment on the stage to highlight our team and dedicate this award to Connor Maule, one of my patients who passed away from a rare genetic epilepsy in 2021. To honor Connor and epilepsy patients alike, I asked the audience to take a gene home with them – signing their hands with a gene name using a sharpie.
Disparity in Genomic Databases
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 – this is what you need to know in 2023
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?
Five reflections from the FamilieSCN2A Annual Family and Professional Conference
FamilieSCN2A. On July 21-23, the FamilieSCN2A Foundation had their Family & Professional Conference in Boston. Having gone to the conference for the past several years, it is truly remarkable to see the changes over time. Here are five key changes I’ve noticed at this year’s event.
STARR, ESCO, and building the STXBP1 momentum
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.
Narrowing the phenotype gap through vector embedding
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