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
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
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
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.
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.
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