Recognition. There are moments when a new disease gene is reported and immediately feels important. And then there are moments when the same gene appears in three independent papers in the same issue of Nature Genetics. That is what happened with RNU2-2. In three parallel studies, independent groups essentially came to the same conclusion: biallelic variants in RNU2-2 are an unusually frequent cause of neurodevelopmental disorders and typically present as developmental and epileptic encephalopathies (DEEs). Taken together, these papers expand the spliceosome story that began with RNU4-2 in 2024. Here is what I learned about the recently identified recessive RNU2-2 disorders.
Tag Archives: DEE
Beyond Sleep: BMAL1 links circadian time to neurodevelopment and epilepsy
The clock gene. Every cell in the human body keeps time. This intrinsic rhythm is roughly 24 hours long and driven by the molecular circadian clock: a transcriptional feedback loop that helps regulate sleep, metabolism, and hormone release. But what happens when these timekeepers stop working? In a recent study, we explored the role of BMAL1 (ARNTL), a core circadian regulator, in neurodevelopmental disorders. What we found surprised us: disruption of this central clock gene does not just affect sleep; it shapes the course of development itself.
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.
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?
Unlocking STXBP1 through Electronic Medical Records
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
KCNC2 – a novel epilepsy gene harbors an unusual phenotypic spectrum
Shaw. It has been a while since we have written about novel gene discoveries in the epilepsies, so I wanted to start this blog post with a general introduction to the genes that are still undiscovered, waiting to be identified. Currently, we assume that there are several hundred genetic etiologies for human epilepsies “out there” that we have not characterized yet. One of the most recent members to join the group of epilepsy genes is KCNC2 that we described in a recent publication. KCNC2, coding for a member of the Shaw-related voltage-gated potassium channels, presents with a phenotypic spectrum that is different from many other epilepsy genes. Continue reading
SCN2A – a neurodevelopmental disorder digitized through 10,860 phenotypic annotations
HPO. SCN2A-related disorders represent one of the most common causes of neurodevelopmental disorders and developmental and epileptic encephalopathies (DEE). However, while a genetic diagnosis is easily made through high-throughput genetic testing, SCN2A-related disorders have such a broad phenotypic range that understanding the full scale of the clinical features has been traditionally difficult. In our recent study, we used a harmonized framework for phenotypes based on the Human Phenotype Ontology (HPO) to systematically curate phenotypic annotations in all individuals reported in the literature and followed at our center, a total of 413 unrelated individuals. Mapping phenotypic data onto 10,860 terms with 562 unique concepts and applying some of the computational tools we have developed over the last three years, we were able to delineate the phenotypic range in unprecedented detail. SCN2A is now the first DEE with all available data systematically curated and harmonized in a computable format, allowing for entirely novel insights. Continue reading
OMIM to retire EIEE classification – an important step to overhaul terminology for genetic epilepsies
EIEE. Online Mendelian Inheritance in Man (OMIM) is the undisputed main resource for information regarding genes and disease. It is the resource that the majority of clinicians and researchers in the field turn to in order to get information about established or novel genetic etiologies in genetic epilepsies and neurodevelopmental disorders. However, historically, OMIM had decided to enumerate many of the genes for developmental and epileptic encephalopathies within a phenotypic series called Early Infantile Epileptic Encephalopathies (EIEE). The field has advanced, and we now understand that most genetic etiologies have a broad phenotypic range and can cause a wide range of epilepsy phenotypes. Accordingly, in collaboration and consultation with our ClinGen epilepsy clinical domain working group, OMIM will retire the EIEE classification and refer to them as developmental and epileptic encephalopathies (DEE). Dravet Syndrome, formerly EIEE6 will now become DEE6, which is the secondary annotation to the actual term “Dravet Syndrome”. For some, this might be a small change in semantics. However, as a clinician trying to make sure that the uniqueness and distinctiveness of childhood epilepsies in the era of large-scale data analysis is appreciated, this small step is likely to be highly influential in the future. Here is some background on how the EIEEs finally became DEEs. Continue reading