KCNQ2. I have to admit we have not written about KCNQ2 for a while, which does not do justice to the role of KCNQ2 in human epilepsies. KCNQ2-related epilepsies represent some of the most common genetic epilepsies and almost exclusively present with neonatal seizures. Historically, KCNQ2 was identified in families with self-limiting neonatal seizures. Subsequently, disease-causing variants were also identified in neonatal developmental and epileptic encephalopathies (DEEs). While self-limiting epilepsies were attributed to protein-truncating variants, KCNQ2-related DEEs are attributed to dominant-negative variants. However, as in many other DEEs, this conceptual black-and-white distinction is somewhat oversimplified, and the genotype-phenotype correlation in KCNQ2-related disorders is more complex. In a recent study, we assessed a total of 81 KCNQ2 variants’ functional effects in parallel, leading to some unexpected results about the function of disease-related KCNQ2 variants. Here is what this first large-scale electrophysiological analysis of an epilepsy-related ion channel told us. Continue reading
What is the most common monogenic cause of epilepsy? This is a question we often ask students and trainees who rotate with us in our Epilepsy Neurogenetics Clinic. This is not meant to be a trick question, and the answer we previously sought was based largely on published studies, estimates of population frequency of individual genetic epilepsies, and our own clinical experience. And we are sometimes surprised by how skewed such a view can be. Now, a new study by Symonds and colleagues answers the question of population-incidence of common genetic epilepsy syndromes through a prospective population-based cohort study in Scotland. This study provides important data on risk factors that are more likely to predict a genetic diagnosis in infants and young children with seizures and answers the question of which genetic epilepsy is most common. I was initially surprised, but really not surprised at all, by the answer. 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?
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
KCNQ2. The next ion channel gene to be reviewed in the Epilepsiome blog posts is KCNQ2, encoding a subunit of a voltage-gated potassium channel. Known for years as a gene for a familial and self-limiting neonatal epilepsy syndrome, mutations are now also shown to be a frequent cause of neonatal epileptic encephalopathy. Here is what you need to know about KCNQ2 in 2015. Continue reading
Issue 8/2015. This week’s review of the relevant publications in the field is about a novel risk factor for focal epilepsies, a gene involved in mRNA transport from the cell nucleus, and a small, confirmatory study on exome sequencing in Infantile Spasms.
Comments. After posting our 2015 update on what you should know about SCN1A, we received a number of comments on our blog and by email. We usually have the policy to respond to every comment individually. However, after we had realized that we had fallen behind with a few replies for several weeks, we felt that it might be worthwhile rephrasing some of the questions as general topics to write about, especially since many of your questions raised interesting points. Here are the questions that you asked regarding SCN1A and Dravet Syndrome. Continue reading
Interpretation. There is huge promise in discovering the genetic basis of neurodevelopmental disorders using exome sequencing, but it is often not clear how ambiguous results are communicated to families. In a recent publication in Clinical Genetics, the authors try to understand what happens to exome results as they land on the clinician’s desk – and leave us with the conclusion that diagnostic exome sequencing when reviewed in a clinical setting may have a false positive rate of up to 20% with 5% of false negatives. Continue reading
Nav1.6. For some reason, SCN8A always met some resistance. In contrast to other epilepsy genes, it took a while for the community to embrace this gene as a genuine cause of epileptic encephalopathies. A recent publication in Neurology now investigates the phenotypic spectrum of SCN8A encephalopathy – and points out important features that distinguish this condition from Dravet Syndrome. Continue reading
Where do all the ion channels come from? I would like to start off with a brief commentary about the current state of gene discovery in human epilepsy. Some of our readers rightfully took offense to my previous statement that gene discovery in epilepsy it over – quite the contrary is true, and I apologize for any confusion that I may have caused. Gene discovery in epilepsy is one of the few areas of human genetics with an ongoing, rapid sequence of gene discovery with a tremendous translational potential. But we also need to reconsider the name of this blog – we are far from being beyond the ion channel. The ion channel concept has made a remarkable return in human epilepsy genetics. Let’s find out why. Continue reading