Exome sequencing in the rolandic epilepsies

Beyond GRIN2A. The childhood epilepsies traditionally referred to as Benign Rolandic Epilepsy (BRE) or benign epilepsy with centro-temporal spikes (BECTS) have had various names in the past, which reflects somewhat the difficulties of fully putting this group of seizure disorders into clear categories. While most presentations are relatively mild and self-limited childhood epilepsies, a sizeable fraction of these non-lesional focal epilepsies have an atypical course. The genetics of the rolandic epilepsies and the related epilepsy-aphasia spectrum are tightly linked to GRIN2A, the most prominent gene in this group of conditions. However, are there other genes? A recent publication examined the genetic basis of self-limited focal epilepsies of childhood and found interesting new candidate genes in atypical presentations. Continue reading

The genetics of Doose Syndrome or Myoclonic Astatic Epilepsy

MAE. There are many distinct childhood epilepsy syndromes that we have become critically aware of in the genomic era as they are linked to prominent genetic causes, including Dravet Syndrome (SCN1A) and Epilepsy of Infancy with Migrating Focal Seizures (KCNT1). However, there are many other epilepsy syndromes where a genetic cause has long been suspected, but has remained elusive. One of the epilepsy syndromes that has largely remained unexplored is Doose Syndrome, also referred to as Myoclonic Astatic Epilepsy (MAE) or Epilepsy with Myoclonic-Atonic Seizures. In a recent study in Epilepsia, we explored the genetic architecture of Doose Syndrome and identified monogenic causes in 14% of individuals, including SYNGAP1, NEXMIF (KIAA2022), and SLC6A1. Our study suggests that Doose Syndrome is genetically heterogeneous, possibly with a distinct genetic landscape. Continue reading

SCN3A – a sodium channel in epilepsy and brain malformations

The missing ion channel. A little more than two years ago, we wrote about our discovery of SCN3A as a novel disease gene in epileptic encephalopathies. At the time, SCN3A was the missing ion channel, the only brain-expressed voltage gated sodium channel that did not have a clear gene-disease relationship. However, since the initial discovery of SCN3A as a disease gene, both the phenotypic spectrum and variant landscape have expanded considerably. In a recent publication, we updated our knowledge based on information of 22 individuals with SCN3A-related disorders, which showed brain malformations in more than 75% of individuals and an unusual clustering of pathogenic variants in parts of the Nav1.3 channel. Continue reading

Ten steps ahead while six feet apart – telemedicine in child neurology

Telehealth. Yes, looking at my last post, this blog has been silent for a while. With the COVID-19 pandemic ongoing, it has been difficult to find a good launching point to write about genetic epilepsies again without somehow feeling that I’m missing the point with regards to the major challenges that the epilepsy genetic community is facing in 2020. But was has actually happened in epilepsy genetics in the United States during the pandemic? In parallel to the dramatic medical issues at the frontline, something very interesting has happened in the background – the shift from in-person medicine to telemedicine, including the vast majority of outpatient visits in child neurology. Telemedicine, remote healthcare services that include audio and video equipment, has long been technically feasible, but has led a niche existence due to licensing restrictions and lack of reimbursement. However, this all changed quickly during the COVID-19 pandemic. But did this transition work? Is telemedicine really as effective as suggested and were we able to provide care along the entire spectrum of disorders in child neurology, including the genetic epilepsies? In a new publication in Neurology, we analyzed more than 2,500 telehealth visits in child neurology, facilitated by a new healthcare analytics pipeline that we built in response to the challenges of the telemedicine transition. Continue reading

Epi25 – redefining epilepsy genetics through exomes of 17,000 individuals

The Epi25 study. On August 1, the Epi25 study was published in the American Journal of Human Genetics. Epi25 is the major, international effort to understand the genetics of common and rare epilepsies through exome sequencing, and our current study now presents the first results on what we can see if we look at the genetics of the epilepsies in thousands of individuals, including more than 9,000 persons with epilepsy and 8,000 controls. The Epi25 study finds that individuals with epilepsy carry more ultra-rare, deleterious variants than controls, especially in known or presumed candidate genes. This is a significant finding that tells us about the inner genetic architecture of the epilepsies beyond the role of monogenic causes. However, as with many previous studies at this scale, the first publication merely scratches the surface and provides an enormous amount of data for further studies. Here is a brief summary of the Epi25 study and some of the most prominent genes in the epilepsies that were completely unknown previously. Continue reading

How common is rare? A population-based study into genetic childhood epilepsies

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

Deciphering the phenotypic code – AP2M1 in epileptic encephalopathies

Synaptic. Identifying the genetic changes underlying severe childhood epilepsies is one of the key steps for predicting outcomes and developing better treatments. However, while our ability to analyze genetic data at scale allows us to simultaneously query tens of thousands of exomes or genomes, our understanding of large phenotypic data has been limited. This limitation, the “phenotypic bottleneck”, is often frustrating, especially as many developmental and epileptic encephalopathies present with unusual and very complex phenotypic features that we would like to better understand for our clinical decision making. The lack of concepts and methods to handle large amounts of phenotypic data has been one of the main contributing factors to this shortcoming. In a new publication in the American Journal of Human Genetics, we aim to overcome this problem by identifying a measurement for phenotypic similarity, using a computational approach to determine how similar patients are to each other based on Human Phenotype Ontology terms. When combined with exome sequencing data, we identified AP2M1, a gene that caused such a similar phenotype that it stood out from the remainder of the cohort. It is the first epilepsy-associated gene identified not from a genetic association, but from phenotypic similarity. Continue reading

ICK, Juvenile Myoclonic Epilepsy, and the burden of proof

Pathogenic or benign. In 2018, ICK, coding for Intestinal-Cell Kinase, was reported as a novel causative gene in Juvenile Myoclonic Epilepsy (JME) in the New England Journal of Medicine. JME is one of the most common epilepsy syndromes, and the authors suggested that up to 7% of JME in their study may be explained by pathogenic variants in this gene, suggesting that, if applicable to all individuals with JME, it may provide a genetic diagnosis for an expected 500,000 individuals worldwide. In a reply to the initial study, the investigators of the EuroEPINOMICS-CoGIE, EpiPGX, Epi4K, and EPGP Consortia attempted to replicate these initial findings, but could not find any evidence in for a role of ICK in JME and indicated that the initial results may have arisen by chance and due to methodological issues. Given the potential implications for future research and therapy development in a relatively common epilepsy, the controversial ICK story is a good example to highlight why it is important to revisit the current consensus on when we consider a candidate a true disease gene and why a category mistake confusing variant pathogenicity for gene validity may result in false positive findings. Continue reading

The Epilepsy Genetics Initiative – novel diagnoses through exome re-analysis

The negative exome. Despite writing a lot about the power of next generation sequencing technologies to provide a genetic diagnosis in individuals with severe epilepsies, it is important to remember that most exome tests performed in a diagnostic setting are negative. Even the most optimistic studies do not find a diagnostic yield that exceeds 40%. However, what can be done about the 60-70% of patients who had undergone exome sequencing, the current gold-standard diagnostic testing, but have received a negative test result? A systematic re-analysis after 12-24 months is currently considered one possibility to make sense of existing exome data. In a current publication, the Epilepsy Genetics Initiative (EGI) reports their results of a systematic research-based re-analysis in 166 individuals with epilepsy. In eight individuals, a novel diagnosis could be achieved, including novel genes not known at the time of the initial report and novel mechanisms such as alternative exons. With a diagnostic rate of 6%, this study provides a unique benchmark of what can be expected when exomes initially come back as negative. Continue reading

V is for valine – VARS mutations in epileptic encephalopathy

Transfer RNAs. A critical step in translating a cDNA into proteins involves transfer RNAs (tRNAs) that deliver a specific amino acid to the ribosome based on a specific codon in the messenger RNA. Thereby, tRNAs establish the physical link between the mRNA and the amino acid sequence of the growing protein, an essential cellular function. In order for tRNAs to be loaded with the appropriate amino acids, the organism has developed enzymes specific for the individual amino acids that are referred to as tRNA ligases or, more precisely, aminoacyl tRNA synthetases (aaRS). Despite the ubiquitous role of aaRS in the cell, pathogenic variants in genes coding for specific aaRS result primarily in neurological phenotypes, ranging from peripheral neuropathy to early-onset epileptic encephalopathies. In two recent back-to-back publications, bi-allelic pathogenic variants in VARS are described as a novel cause for epileptic encephalopathy, adding VARS to the list of aaRS genes linked to human disease and solving an almost decade-old mystery. Continue reading