Understanding patient advocacy – the Rare Epilepsy Landscape Analysis (RELA)

The Rares. The increasing number of genetic diagnoses in rare epilepsies has resulted in the formation of a large number of non-profit organizations and support groups over the last decade.  These support organizations for rare epilepsies (“Rares”) have already had an important impact on the epilepsy genetics field. However, the overall impact, direction, and needs of the Rares have never been assessed systematically.  In a recent editorial, Ilene Penn Miller summarized the findings of the Rare Epilepsy Landscape Analysis (RELA), which surveyed 44 advocacy and support organizations for rare epilepsies. Continue reading

The SCN1A rs6732655 enigma – a reply

rs6732655. I acknowledge that the title of this blog post looks like my keyboard is broken, but please bear with me. Last month, I blogged about a recent genome-wide association by the BioBank Japan (BBJ), discussing the evidence for a Single Nucleotide Polymorphism (SNP) in the vicinity of the SCN1A gene (rs6732655). In a prior study, the SNP in question was initially found to be associated with epilepsy and I discussed the fact that this SNP, albeit not significant by itself, was also seen at a higher frequency in cases than in controls in the epilepsy cohort of the BBJ study. I received some comments regarding this post and it was pointed out that my reasoning was incorrect given that rs6732655 was not nominally significant in the BBJ study. Therefore, this study was not a replication study in itself. Let me retrace my steps and revisit where my hunch came from to write the initial blog post. Continue reading

Entering the phenotype era – HPO-based similarity, big data, and the genetic epilepsies

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

Copy Number Variations in the epilepsies – a 2020 update

CNV. There are different forms of genetic variation and historically, our ability to query the entire exome or genome is a relatively recent development. However, the first type of genetic variation that could be assessed in the epilepsies in large cohorts were copy number variations (CNV), small gains or losses of chromosomal materials. In a recent study, the entire Epi25 cohort was analyzed for CNVs, giving a long-needed update on the role of the structural genomic variations in various forms of epilepsies and highlighting that the overall landscape of CNVs in the epilepsies is well understood and delineated. With up to 3% of individuals with epilepsies carrying some of the recurrent CNVs, this type of genomic variation remains a rare, but important source of genetic morbidity in the epilepsies. Continue reading

The natural history of genetic epilepsies as told by 3,200 years of electronic medical records

EMR. When we consider the natural history of rare diseases like the genetic epilepsies, we typically think about a lack of longitudinal data that contrasts with the abundant genetic information that is available nowadays – the so-called phenotyping gap. We typically suggest that we need to obtain this information in future prospective studies to better understand long-term outcome, response to medications, and potential early warning signs for an adverse disease course. However, a vast amount of clinical data is collected on an ongoing basis through electronic medical records (EMR) as a byproduct of regular patient care. In a recent study, our group built tools to mine the electronic medical records to assess the disease history of 658 individuals with known or presumed epilepsies using clinical information collected at more than 62,000 patients encounters across more than 3,200 patient years. Here is a brief summary of our first study on EMR genomics, an untapped resource that has the potential to improve our understanding of the genetic epilepsies. Continue reading

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