Semantic similarity. The phenotype era in the epilepsies has now officially started. While it is possible for us to generate and analyze genetic data in the epilepsies at scale, phenotyping typically remains a manual, non-scalable task. This contrast has resulted in a significant imbalance where it is often easier to obtain genomic data than clinical data. However, it is often not the lack of clinical data that causes this problem, but our ability to handle it. Clinical data is often unstructured, incomplete and multi-dimensional, resulting in difficulties when trying to meaningfully analyze this information. Today, our publication on analyzing more than 31,000 phenotypic terms in 846 patient-parent trios with developmental and epileptic encephalopathies (DEE) appeared online. We developed a range of new concepts and techniques to analyze phenotypic information at scale, identified previously unknown patterns, and were bold enough to challenge the prevailing paradigms on how statistical evidence for disease causation is generated. Continue reading
Genome-wide association. While most of the neurogenetics community was focused on exome sequencing and the discovery of novel monogenic forms of epilepsy in the last few years, something quite remarkable had happened in the background. Common variants and genome-wide association studies have made a remarkable comeback. The ILAE Consortium for Complex Epilepsy had slowly worked on increasing sample sizes over time, and the second analysis of common variants in common epilepsies was published in late 2018. Sample sizes have almost doubled since the first study in 2014, and as a result, the number of genome-wide significant loci has tripled. However, the most intriguing finding was something that completely caught me by surprise – more than 30% of the heritability of the genetic generalized epilepsies is explained through common variants, approaching the numbers we see in epileptic encephalopathies explained by monogenic causes. This is one more reason to discuss the recent ILAE GWAS in more detail. Continue reading
Genetic literacy. Sometimes important milestones don’t feel like much when you eventually reach them. Last Thursday, I woke up sleep-deprived after working on a grant all night and found an NCBI update in my mailbox. Primer Part 2 of the genetic literacy series of ILAE Genetics Commission was now published in Epilepsia and available on PubMed. Finally, both the introductory primers of the genetic literacy series are out – Part 1 dealing with the building blocks including general concepts of epilepsy genetics and epidemiology and now Part 2 about the paradigm shifts that were introduced with the advent of massive parallel sequencing. Both publications were revised and re-written over and over again to fit the overall didactic mission of the literacy series, an effort that takes approximately 10x as long as writing a typical review. But finally, as of May 10, 2018, both Primers are now in their final shape, published and open access to the international epilepsy community. And here is just a quick overview of what this paradigm shift is really about. Continue reading
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?
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
Heterogeneity. The diversity of clinical presentations and responses to anti-epileptic drugs (AEDs) has posed a major obstacle in developing strategies to treat patients with SCN2A-related epilepsies. While the literature provides multiple examples of single case reports with favorable responses to various AEDs, the broad range of disease presentations and known or presumed effects on channel function has made it extremely difficult to extrapolate findings from one patient to another. In a recent publication in Brain, we reviewed the largest cohort of patients with SCN2A-related neurodevelopmental disorders so far, including a subset of patients with detailed phenotypic data over time. With this data, we were able to find support for the hypothesis that age of seizure onset correlates with the functional effect of the mutations and the response to common anti-epileptic medications, taking a first step towards understanding the SCN2A mystery. Continue reading
SCN2A. Last Thursday, I hopped on a plane to Chicago to join the first FamilieSCN2a Foundation Conference. SCN2A, one of the most common genes in genetic epilepsies, has emerged as a gene with a broad range of phenotypes, which makes understanding this gene relatively complicated. I am very happy that the SCN2A community is currently coming together to provide a platform for patient initiatives and connections to clinicians and researchers. Here is my list of five things I learned about the genetic shape-shifter in Chicago. Continue reading
Gene panels. Epilepsy gene panels have emerged as the first line genetic test for most suspected genetic epilepsies. Gene panels for childhood epilepsies are among the most common genetic tests ordered in a pediatric setting. While the role of gene panel testing is well established, the ideal design of gene panels remains an ongoing issue. A recent publication in the Journal of Medical Genetics provides additional evidence for the role of gene panel analysis in patients with genetic epilepsies. There are three aspects of this study that are particularly noteworthy. Continue reading
Issue 13/2015. Our pick for the publications of the week includes a recent publication on the felt stigma of epilepsy and genetic attribution. We also review a major publication on the broadening spectrum of SCN2A related epilepsies and one of the first reports of WDR45 mutations in male patients with epileptic encephalopathy.