Synaptic transmission. Over the last several years, pathogenic variants in multiple genes involved in synaptic transmission have been identified in early-onset epilepsies. STXBP1 and STX1B both encode components of the SNARE complex, a complicated protein complex that mediates the fusion of the plasma membrane of the presynapse and the synaptic vesicle to allow for neurotransmitter release. DNM1, encoding the dynamin-1 protein, plays an essential role in recycling synaptic vesicles back into the presynapse after neurotransmitter release. A new study by Myers and collaborators has identified several patients with de novo variants in PPP3CA, which encodes another protein involved in synaptic vesicle recycling, further highlighting the importance of synaptic transmission in the etiology of severe neurodevelopmental disorders. In the interest of full disclosure, I am also a co-author on this study. Continue reading
Epilepsiome, meet ClinGen. For more than a year, I have meant to write about the extension of the Epilepsiome effort to our ClinGen epilepsy working group. The overall ClinGen framework is a NIH-funded resource dedicated to building a central resource that defines the clinical relevance of genes and variants for use in precision medicine and research. Within this framework, the ClinGen Epilepsy Working group is a group of curators to apply the formal framework to epilepsy genes. Given the explosion of genetic data, curating epilepsy genes is important as a basis for precision medicine and long overdue. Within our epilepsy working group, we build upon the ClinGen framework to make it applicable to epilepsy genes. Here is what you need to know about epilepsy gene curation.
Neuronal spectrinopathies. Spectrins are a major component of the neuronal cytoskeleton, the scaffold underneath the cell membrane that gives cells their characteristic shape and anchors transmembrane proteins such as voltage-gated ion channels. SPTAN1, the gene coding for the non-erythrocyte alpha-II spectrin, has been known as a rare cause of early-onset epileptic encephalopathies with hypomyelination and atrophy. However, the full phenotypic spectrum and the range of pathogenic variants was unknown. In a recent publication in Brain, 20 patients with pathogenic variants in SPTAN1 are reported, expanding the known range of phenotypes and suggesting a very unusual disease mechanism through in-frame deletions or duplications. Here is what links the neuronal cytoskeleton to epileptic encephalopathies. Continue reading
KCNB1 encephalopathy. Pathogenic variants in KCNB1 were first reported three years ago in three unrelated patients with an early-onset epileptic encephalopathy. Since the initial report, individual patients have been reported with de novo KCNB1 variants, but a comprehensive overview of the KCNB1 encephalopathy clinical picture has been lacking. A recent publication by de Kovel and colleagues provides a comprehensive overview of the clinical features and genetic variants in 26 individuals with KCNB1 encephalopathy, including 16 previously unreported patients, providing novel insights into the phenotype. In this post we will unpack this publication, including what new information about KCNB1 it tells us. Continue reading
Psychosocial implications of uncertainty. As navigators of genetic testing, genetic counselors have seen it all – smooth seas, choppy waters and even the rare tsunami. Genetic testing sounds, well, so promising. Huge gene panels for epilepsy, whole exome sequencing – guaranteed to find an answer, right? Wrong. And let’s not even talk about secondary (incidental) findings, variants of uncertain significance and (gulp) non-paternity. While our technology has changed, navigating the choppy waters of psychosocial issues in genetic testing has not. Previous EpiGC posts to this blog have highlighted the challenges inherent to interpreting variants of uncertain significance. Now let’s talk about the psychosocial implications of dealing with uncertainty.
Early-onset epilepsies. In recent years, we have discovered several causative genes for severe epilepsies beginning in the first year of life, including KCNQ2, SCN2A, and STXBP1. Several studies have reported a high yield of diagnostic genetic testing, including NGS panel approaches and whole exome sequencing, particularly in patients with seizure onset in the neonatal period where detection rates are often reported to be above 50%. Two recent studies add to the growing pile of evidence that genetic testing, and in particular NGS-based testing methods, are valuable in the diagnostic workup of children presenting with seizures early in life. Will these two studies help push us towards a new consensus regarding genetic testing in epilepsy?
SCN1A phenotypes. Readers of Beyond the Ion Channel will know that we often post about SCN1A, one of the first discovered and most common genetic causes of epileptic encephalopathy. We more or less assume that we understand the phenotypes associated with pathogenic variants in SCN1A: most commonly Dravet syndrome, which is associated with de novo variants, and less commonly genetic epilepsy with febrile seizures plus (GEFS+), associated with inherited missense variants. However, a recent publication by Sadleir and colleagues suggests that the phenotypic spectrum of SCN1A-related disorders may be broader than we have previously appreciated. Are there SCN1A-related epileptic encephalopathies in addition to Dravet syndrome? Continue reading
FamilieSCN2A. On July 14th and 15th, Ingo and I had the pleasure of speaking at the FamilieSCN2a Annual Family and Professional Conference, which was hosted at the DuPont Children’s Hospital in Wilmington, Delaware. This meeting brings together families of children and young adults with SCN2A-related disorders and medical professionals and scientists working in the field, with the purpose of sharing information, learning from one another, and moving the field forward. This post won’t be a comprehensive recap of all that was discussed, since we heard from a broad range of professionals including therapists, electrophysiologists, epidemiologists, neurologists, and geneticists and it would be nearly impossible to sufficiently summarize everything. But I did want to share some of my impressions and thoughts. Here my five things I learned at the FamilieSCN2a Conference. Continue reading
Genome to phenome. Meaningful patterns in human diseases are often only revealed when looking at larger groups of patients. Over the last decade, we have figured out how to make genetics scalable to fit this need. High-throughput genetics can now be performed on an industrial scale with the possibility of assessing almost every base pair in the human genome in thousands of people. Phenotyping, however, has remained a non-scalable task, requiring repeated review, extraction, and interpretation of phenotypic data. In addition, there is no agreed-upon format for phenotypic data that parallels the standards we have in genetics. To overcome this problem, projects such as the Epilepsy Phenome/Genome Project (EPGP) have collected systematic, standardized phenotypic data upfront on every patient. In a recent study in Neurology that analyzed familial clustering of phenotypes within this dataset, we get a first view of what working with the epilepsy phenome may look like. We were asked to provide an editorial for this study where we emphasized that systematic phenotyping in large datasets can reveal phenotypic patterns that are beyond our understanding of disease genetics. Basically, the phenome suggests patterns that are contradictory to what we think genes would do. Continue reading
Dynamin 1. Our recognition of DNM1 encephalopathy as a novel disease started out as a digital flicker. Deep inside some of the large-scale studies in epilepsy genetics, there were a few patients with de novo mutations in the gene coding for DNM1. However, amongst all the other likely and less likely candidates, it took a while for DNM1 to emerge as a true candidate. But even then, being a disease gene born out of large-scale studies with little information on clinical presentation and disease course, we had learned little about how patients with DNM1 encephalopathy actually present and how they develop over time. In our recent publication in Neurology, we describe the spectrum of DNM1 encephalopathy, including an unusual mutational landscape and the first genetic cause in a patient with FIRES. Continue reading