GNAO1 and 13K genomes – rare disease sequencing on a national level

WGS. Whole-genome sequencing is increasingly used to understand the cause of rare diseases in a research and diagnostic context. However, while the usefulness of this technology has been shown in smaller studies, it remains unclear whether strategies to understand the cause of rare disorders through whole genome sequencing can be performed on a national level. A recent study in Nature reported the first results from a national sequencing campaign for rare disorders in the UK, including the analysis of more than 13,000 genomes. In this blog post, I would like to focus on the neurogenetics component of this enormous study, which identified disease-causing variants in GNAO1 as the most common cause within the study’s subgroup of neurological and developmental disorders. Continue reading

Common genetic risk factors for epilepsy in the Japanese population

GWAS. While our blog mainly deals with monogenic epilepsies, assessing common genetic risk factors through genome-wide association studies has been an established way of understanding potential genetic contributors to both common and rare disorders. More recently, polygenic risk scores have entered the stage, composite measures of many common variants which explain a significant proportion of the overall population risk for epilepsy. However, a major limitation of many genome-wide association studies has been the focus on populations of European ancestry. So far, very few studies have examined common genetic risk factors in the epilepsies in non-European populations. In a recent publication examining results from the BioBank Japan Project, 42 disorders were examined in more than 200,000 individuals, including the epilepsies. While no single epilepsy variant stood out, the study provides an interesting confirmation of a previously known common risk factors for the epilepsies. Continue reading

Understanding the genetics of FIRES

FIRES. Without a clear trigger, some children suddenly develop super-refractory status epilepticus, ongoing seizure activity that is difficult to control despite maximal therapy in the intensive care unit. In cases when the onset of seizures is preceded by a febrile illness, these rare conditions are referred to as FIRES (Febrile Infection-Related Epilepsy Syndrome). Understanding why children develop FIRES has been an ongoing quest, and the underlying mechanisms are poorly understood. FIRES shares many features with some of the known genetic developmental and epileptic encephalopathies. In a recent study, we tried to understand the genetic basis of FIRES using exome sequencing and HLA sequencing. We were unable to identify genetic causes for FIRES, but we found interesting candidate genes and demonstrated that the genetic architecture of FIRES is substantially different from what we see in other genetic epilepsies. Continue reading

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

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