Stepping down. You may have noticed that the ILAE logo on the blog has disappeared. After having served on the ILAE Genetics Commission for roughly a decade, I decided to step down. It is somewhat of a bittersweet feeling. Being part of the international epilepsy genetics community has always been very important to me. However, over the last two years, I realized that I could no longer devote the effort to the ILAE that I wanted to. We were incredibly busy in two new areas: clinical trial readiness studies for STXBP1 and SYNGAP1 and our data-driven analyses of natural histories in genetic epilepsies. Here is a brief personal overview of the three things that made the ILAE Genetics Commission special during this time.
The history of epilepsy genetics. Over the last three decades, epilepsy genetics has moved from initial gene discovery, a period of stagnation, gene discoveries through next generation sequencing technologies, to the current post-genomic era where detailed description of phenotypic features and translation into therapeutic modalities current represent the main challenges (modified from Ruggiero et al., 2023). These various transitions would not have occurred without the ongoing involvement and guidance of the ILAE Genetics Commission.
Parity in genomic studies. The epilepsies have never received the same amount of interest and funding compared to neurodevelopmental disorders such as autism or neuropsychiatric conditions such as schizophrenia. This imbalance is somewhat dangerous as it may skew the perspective within the field. For example, the initial discovery a SCN2A as an “autism gene” is something that I still consider somewhat problematic as it continues to lead to an underappreciation of the severity of epilepsies in individuals with SCN2A loss-of-function variants. Over the last decade, ILAE-connected activities such as Epi25 and the ILAE GWAS consortium have made major efforts towards creating parity in the field. For example, the most recent ILAE GWAS study included data from almost 30,000 individuals with epilepsy. This is something worth highlighting.
Genetic literacy. One major topic that the ILAE Genetics Commission can be proud of is the Genetic Literacy Series that has now endured more than a decade. Some of the topics that we have covered are timeless and I still use the Open Access Primers 1 and 2 in my teaching lectures today as they cover some general aspects of epilepsy genetics, such as the difference between gene validity and variant pathogenicity or the idea of the “corridor” for epilepsy-associated genetic variants. Not to mention the cross-connection that the ILAE Genetics Commission had with other activities in the field, including our work with OMIM to retire the “EIEE” nomenclature. Going forward, such genetic literacy efforts will continue to be very important in the field, especially as we are moving towards precision medicine at a rapid pace.
A land bridge during continental drifts. During some of my talks, I use a figure of two big comments smashing into each other when trying to explain the difference between the concepts and language using in lab diagnostics and our clinical epilepsy knowledge. In brief, many clinicians do not understand the underlying mechanisms that result in a genetic variant appearing on a genetic testing report. Likewise, the lab-based variant interpretation, aimed at clear rules and scalability, struggles to integrate the complexity of epilepsy phenotypes. Over the last decade, we have tried to continuously build bridges and integrate our clinical epilepsy knowledge into variant interpretation. It takes several years to officially change the ACMG/AMP variant classification, an effort that is continued to be supported by the NIH/NINDS. Our variant classification rules for epilepsy-related sodium channel genes (SCN1A, SCN2A, SCN3A, SCN8A) is now in place, approved for official lab-based variant interpretation, and is expected to cut the rate of VUS by up to 30%. Making sure that variant classification rules are up-to-date is playing the long game, a trans-generational effort that will require the ongoing input of the ILAE Genetics Commission.
Thank you. I wanted to finish this post by thanking the current and past members of the ILAE Genetics Commission for putting up with me for the last decade. This time was a very transformative time for the epilepsy genetics community worldwide as it marked the transition from gene discovery to first approaches for precision medicines. Coordinating the international epilepsy genetics community will be a continued effort for the years to come. And the ILAE Genetics Commission is in the very strong position to help the community speak with a single voice.
