Reference. Today, the human pangenome was announced, the first reference of the human genome that systematically includes a cohort of genetically diverse individuals. The human genome, once thought to be a linear reference, is now a graph with nodes and edges. I came across the pangenome publications when I was thinking about a comment that I made earlier this week, when I was asked whether people on our team have their own flavor of variant interpretation. Let me share with you how both topics connect. Continue reading
Tag Archives: ClinGen
SCN1A gain-of-function, paralogs, and the Philadelphia variant
Between the ion channels. Rather than going “beyond the ion channel,” in this post, we aim to look between them. We want to dive into a study where examining the group of epilepsy-related sodium channels was initially more informative than the single gene itself—even when that gene was SCN1A, the most established epilepsy gene. A recurrent SCN1A variant turned out to be part of an emerging, previously underappreciated gain-of-function spectrum. Here, we discuss the unusual phenotype of SCN1A gain-of-function variants and how we are currently working on integrating information on paralogs into the official ACMG variant curation criteria.
Walking in Memphis – TARGETing Epilepsy at St. Jude
Memphis, TN. Prior to this year’s AES meeting, the epilepsy genetics community descended upon St. Jude Children’s Research Hospital in Memphis. I had previously largely associated St. Jude with pediatric cancer treatment, but within the last few years, a large-scale pediatric neuroscience program was launched, putting Memphis on the epilepsy genetics map. And with Heather Mefford’s new lab, the program at St. Jude includes one of the major epilepsy genetics groups. While blogging about scientific meetings is always tricky, one particular quote from the first day struck me as particularly relevant for the current state of therapeutic development: “quick, but not too quick”. Here is where the field of epilepsy genetics and precision medicine finds itself at the end of 2022. 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
A critical step towards precision medicine – the ClinGen epilepsy gene curation
Clinical relevance. Pathogenic variants in more than 80 genes have been reported in childhood epilepsies over the last two decades. Developing precision therapies that target the underlying genetic changes is a major research focus and holds the promise to positively influence the lives of thousands of people with individually rare, but collectively common genetic epilepsies. However, in order to develop novel therapies, a formal, unbiased framework is needed to define whether the association between certain gene and disease is in fact valid and that a specific variant is truly pathogenic. This task has proven to be much more difficult than initially expected. Within the larger framework of the ClinGen Consortium, our epilepsy expert panel assesses the clinical validity of genes and variants for human epilepsies, starting with gene curation. In the recently published Human Mutation Special Issue on ClinGen/ClinVar, our panel reports our pilot data and reviews what it takes to connect two increasingly separate fields: the domain of traditional clinical epileptology and the rapidly evolving area of diagnostic genetic testing. Brace yourself: 50% of the alleged gene-disease associations evaluated in our pilot phase did not meet the criteria to be considered clinically valid. Continue reading
Changing the debate on epilepsy genetics – the ILAE Epilepsiome Task Force
Epilepsiome. Within the new structure of the ILAE Genetics Commission, the Epilepsiome has become a Task Force for the current term. Our blog has accompanied the developments in the field of neurogenetics for the last seven years and has seen the rise of next-generation sequencing and formal gene and variant curation frameworks. This has left us with a basic question: what is left to say? Should the future Epilepsiome simply chronicle what is happening in the field or should we try to use our platform to develop novel and potentially provocative thoughts? Within the current Epilepsiome Task Force, we decided to try the latter. There has been much attention paid to, and understandably much excitement about, the prospect of targeted precision treatments based on specific gene mutations. But could this be a Potemkin village based on unrealistic treatment expectations? What else is happening in the field of epilepsy genetics, outside the spotlight? We agreed that the new Epilepsiome Task Force will strive to emphasize a richer, globally oriented, and multifaceted view of the genetic basis of human epilepsies and neurodevelopmental disorders. Here are the three things that our Task Force hopes to accomplish. Continue reading
Five elements to include in your manuscript to get full ClinGen points
ClinGen Epilepsy Gene Curation Expert Panel. For the past year I have been a member of the ClinGen Epilepsy Gene Curation Expert Panel, which has been a rewarding professional experience. I have gotten to know several colleagues within the epilepsy and ClinGen communities, I’ve become familiar with resources for gene curation including MONDO and HPO, and I’ve dived deeply into the existing literature linking genes with a broad spectrum of epilepsies. But working with ClinGen has had another unexpected benefit – it has influenced my approach to writing scientific manuscripts. I have been able to apply this knowledge recently when writing a manuscript about a new causative gene for developmental and epileptic encephalopathies. In this post I would like to share five insider tips about what to include in your genetics manuscript so that it can receive full consideration from the ClinGen Epilepsy Expert Panel.
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Guardians of the epilepsy genes
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.
The three challenges of epilepsy precision medicine
Half Moon Bay. I am on my way back from the Precision Medicine Workshop at Half Moon Bay, realizing again that blog posts from scientific meetings are often boring and difficult to write. However, let me try to put together a few thoughts about this meeting. Basically, there are three challenges for epilepsy genetics in the era of precision medicine. Continue reading
