Clinical neurogenetics. Characterization of the genetic landscape of the epilepsies continues at a rapid pace, and the effects of this vast gain of knowledge are beginning to show within routine clinical care of people with epilepsy. In our most recent review, we discuss an overview of epilepsy genetics in 2023, spanning topics of novel methods of gene identification, polygenic mechanisms, new presentations of established genes, and multifaceted efforts of phenotypic characterization. In addition, we discuss the increasingly critical roles of advocacy organizations. Here is a summary of our recent review.
Figure 1. The timeline of gene discovery in the epilepsies demonstrates the consistent, fast pace at which new genes are being characterized. Though, once these genes are identified, how do we fully understand the full clinical picture of each genetic condition? Efforts of phenotypic characterization are accelerating, and our knowledge of the clinical spectrum of each genetic condition will continue to accelerate at a pace at that is yet to be determined.
A new timeline. After lots of complaints that we had used our 2016 figure for too long, our updated timeline of gene discoveries in the epilepsies was just recently unveiled. As this visualization of gene discovery in the epilepsies demonstrates, the pace of gene discovery is not slowing. To generate the above figure, we manually curated the dates of discovery of 126 genes that we consider bona fide epilepsy genes. This timeline demonstrates that, after a steady crawl upwards for about seven years, the pace of gene discovery took off in 2013, and has continued at a rapid pace since. Gene by gene, epilepsy genomic science has been able to achieve up to a 30% rate of genetic diagnosis for children with developmental and epileptic encephalopathies (DEEs), a number that would have seemed unimaginable 10 years ago. What is even more encouraging is that gene discovery seems to show no signs of slowing, and one can imagine what this timeline might look like 10 years into the future. Beyond the excitement of more genes being identified over time that are explanatory for epilepsy, it is also fascinating to see that novel methods are being implemented to find new genes, such as phenotypic similarity analyses and computational phenotyping.
Standard of care. With the newest genetic testing guidelines recommending a genetic workup for all individuals with an unexplained epilepsy, we can officially state that genetic testing is standard of care for the majority people with epilepsy. This means that the spectrum of our known genetic etiologies is ever increasing, as more mildly affected individuals receive a genetic workup. In addition, genes that were discovered recently in people with milder epilepsies, are found much more commonly than would have been originally expected. The acceleration of clinical genetic testing will continue to progress efforts of gene discovery and characterization.
Phenotypic characterization. While the pace of genomic research has outpaced our understanding of phenotypes, new efforts of characterization through phenotypic reconstruction of large cohorts of affected individuals is beginning. As new etiologies are discovered, it often takes years of clinically diagnosing enough individuals until we can begin to develop a picture of each individual genetic condition. Over time, we expect our knowledge of the true range of presentation of the genetic epilepsies will continue to grow, perhaps enough so to match the pace of efforts of gene discoveries themselves.
Precision medicine. Not only are we identifying genetic diagnoses more frequently, the field has been able to consistently demonstrate that genetic diagnosis significantly influences the care and management of people with epilepsy. This way, the prior hopes for precision medicine slow become reality. However, the field still awaits to see the results of the first genetic therapy trials that have been administered to those with genetic epilepsy, including SCN1A and KCNT1.
Advocacy organizations. As more rare genetic epilepsies are identified and more individuals diagnosed, advocacy organizations have become critical in epilepsy genetics research. Disease concept model studies, which have largely been driven by advocacy organizations, have sought to redefine genetic disorders from the perspective of caregivers and affected individuals themselves. Studies such as these will ensure that, if and when precision medicine therapies become available, we are measuring outcomes that are relevant to the lived experience of reach condition.
What you need to know. In 2023, epilepsy genetics remains a space of fast-moving discovery. Gene discovery and phenotypic spectrum characterization in the epilepsies is not slowing. Now, there is even more impetus than ever to offer genetic testing to people with epilepsy, with the release of new clinical guidelines. Advocacy organizations are increasingly involved in genetic research efforts, ensuring that patient and caregiver perspectives are factored into each step of neurogenetic research. Each of these factors has measurably influenced the availability of precision medicine options and better medical care and counseling for people with epilepsy.
Sarah Ruggiero is a Genetic Counselor at the Epilepsy Neurogenetics Initiative and Helbig Lab, Children’s Hospital of Philadelphia.
