STXBP1-related disorders: deciphering the phenotypic code

STX. Neurodevelopmental disorders due to disease-causing variants in STXBP1 are amongst the most common genetic epilepsies with an estimated incidence of 1:30,000. However, despite representing a well-known cause of developmental and epileptic encephalopathies in the first year of life, relatively little has been known about the overall genetic landscape and no genotype-phenotype correlations have been established. In our recent publication including almost 20,000 phenotypic annotations in 534 individuals with STXBP1-related disorders, we dive deep into the clinical spectrum, examine longitudinal phenotypes, and make first attempts at assessing medication efficacy based on objective information deposited in the Electronic Medical Records (EMR), including information from the almost 100 “STXers” seen at our center in the last four years. Continue reading

Introducing the revised Human Phenotype Ontology (HPO) – a new language for Big Data in the epilepsies

Classification. Our classification of the epilepsies periodically undergoes revision to align the way we think about the epilepsies with scientific progress in the field. While it is intuitive that relatively novel frameworks such as the 2017 International League Against Epilepsy (ILAE) Operational Classification of Seizure Types capture the current spirit of the field more accurately than prior classifications, one relatively simple question is not easily answered: how much more accurate? How we get to such an answer requires us to take a step back and think about how the value of clinical information can be measured and compared. In our recent publication, we describe the revision of the Human Phenotype Ontology (HPO) according to the most recent ILAE classifications and other respected definitions in current use. This gives the answer to the prior question: 40% (which is a lot). 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

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

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

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

Heat at the synapse revisited: an STX1B update

Heat at the synapse revisited. STX1B encodes syntaxin 1B, one of three proteins – along with SNAP25 and synaptobrevin – that form the SNARE complex. The SNARE complex is part of the protein machinery responsible for Ca2+-dependent fusion of the presynaptic neuronal cell membrane with the synaptic vesicle to enable neurotransmitter exocytosis. STXBP1 also plays an important role in this process, as the syntaxin binding protein encoded by STXBP1 interacts with the SNARE complex via binding to syntaxin. While pathogenic variants in STXBP1 are a well-established cause of early-onset epilepsies and related neurodevelopmental disorders, after the initial description of STX1B-related epilepsies in 2014, very little more was heard regarding STX1B in the intervening four years. Now, we contributed patients to a publication in Neurology, which provides an update regarding the clinical and genetic landscape of STX1B-related epilepsies. Continue reading

The 2018 neurological phenotyping course for systems genetics – an invitation to Luxembourg

Computational phenotypes. Clinical epilepsy research requires the capturing of complex information in a way that then can be subjected to statistical analysis. For the analysis on the phenotype level, new standards are emerging that are heavily informed by genetic studies. In fact, in addition to the known domain-specific classifications such as the ILAE classification for epilepsy, interdisciplinary action is often required to improve the classification of neurological syndromes for a larger analysis. During the upcoming EMBO Practical phenotyping course in Luxembourg, we will introduce trainees in the field to concepts like the Human Phenotype Ontology (HPO), a controlled vocabulary to characterize syndromes and one of pillars of research in complex syndromes such as epilepsy and how to address aspects not covered in HPO. The course will be held in Luxembourg from Oct 4 to Oct 10, 2018. There has already been a strong interest in this course, but we have a few spots left if you would like to register!

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Somatic mosaicism of SLC35A2 in focal epilepsy: an emerging common genetic mechanism

Somatic mosaicism in focal epilepsy. Recent findings highlighted the role of somatic parental mosaicism in epileptic encephalopathies. However, somatic mosaicism has also emerged over the last few years as a prominent mechanism in the pathogenesis of lesional focal epilepsies, including focal cortical dysplasia (FCD) type 2 and hemimegalencephaly. Previous studies have identified the role of mosaicism of genes such as MTOR, TSC1/TSC2, and genes encoding components of the PI3K/AKT pathway in patients with epilepsy secondary to brain malformations. A recent study in Annals of Neurology has identified a new unrelated genetic cause of refractory non-lesional focal epilepsy, which leads us to wonder what role mosaicism may be playing in focal epilepsies without obvious findings on MRI.
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The genetic architecture of the epilepsies, as told by 8,500 gene panels

Epilepsy gene panel. Testing for genetic causes in human epilepsy is typically performed using gene panels. In contrast to our research-based exome studies in an academic setting, much of the gene panel testing is performed through commercial laboratories and much of the existing data is usually inaccessible to the scientific community. In a recent publication in Epilepsia, a large US-based diagnostic laboratory reports on some of their existing data on epilepsy gene panels by reporting the results of more than 8500 epilepsy gene panels – a cohort size that is more than five times larger than any prior exome or gene panel study in the epilepsy field. I was asked to write an editorial on this publication, and I also wanted summarize on our blog three key messages that you can take away from this study. Continue reading