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

Cost-effectiveness of genetic testing in patients with epilepsy: which test is the right test?

Which test is the right test? In clinical practice, determining an appropriate genetic testing strategy in the evaluation of a patient with unexplained epilepsy is often inconsistent and left to the treating provider, given the lack of evidence-based guidelines. Oftentimes external factors, such as insurance hurdles, dictate the genetic testing that can be ordered. A recent meta-analysis in Neurology attempts to answer the question about which genetic test is most cost-effective in patients with epilepsy, which may aid in the decision making when considering a genetic evaluation of a person with epilepsy. Continue reading

Constrained coding regions and genetic causes for epilepsy that we might have missed

Genetic architecture. Our reference dataset for genetic variation in humans has become so large that we can increasingly ask the question whether the distribution of genetic variants tells us something about genes and regions within genes without knowing anything about what these genes actually do. For example, it is well established that genes with fewer protein-truncating variants than expected are much more likely to be causative genes for epilepsy and neurodevelopmental disorders than genes that have an average number of these variants. A recent publication in Nature Genetics takes this approach one step further by looking at specific regions within genes rather than entire genes, a somewhat interesting approach that the authors introduce by discussing bullet damage to airplanes in World War II. Continue reading

The second ILAE GWAS or why 30% of genetic generalized epilepsy is explained

Genome-wide association. While most of the neurogenetics community was focused on exome sequencing and the discovery of novel monogenic forms of epilepsy in the last few years, something quite remarkable had happened in the background. Common variants and genome-wide association studies have made a remarkable comeback. The ILAE Consortium for Complex Epilepsy had slowly worked on increasing sample sizes over time, and the second analysis of common variants in common epilepsies was published in late 2018. Sample sizes have almost doubled since the first study in 2014, and as a result, the number of genome-wide significant loci has tripled. However, the most intriguing finding was something that completely caught me by surprise – more than 30% of the heritability of the genetic generalized epilepsies is explained through common variants, approaching the numbers we see in epileptic encephalopathies explained by monogenic causes. This is one more reason to discuss the recent ILAE GWAS in more detail. Continue reading

HCN1 enters the GEFS+ sphere

HCN1 update. Hyperpolarization-activated cation channels (HCN) are involved in neuronal pacemaker activity and regulate neuronal excitability through hyperpolarization-activated Icurrent. In 2014 de novo missense variants in HCN1 were identified in five unrelated individuals with a Dravet Syndrome-like developmental and epileptic encephalopathy (DEE). However, in the intervening four years relatively little additional evidence has emerged regarding the role of HCN1 in epilepsy. Now, a recent publication in Brain identifies additional individuals with HCN1-related epilepsies and significantly expands the clinical spectrum beyond Dravet-like DEE. Continue reading

AES 2018 Recap: The Epilepsy Community Invades the Big Easy

NOLA.The American Epilepsy Society (AES) has wrapped up its annual meeting, which was held this year in New Orleans. AES is the largest meeting of epilepsy professionals working in clinical practice, academia, industry, and advocacy. It is a meeting I always look forward to as an opportunity to connect with friends and colleagues from across the world. As we all pack away our beads and digest our beignets, I would like to reflect on some of the major messages I, as an epilepsy genetics clinician and researcher, took away from this year’s AES annual meeting. Continue reading

STXBP1-related disorders – one or two disease mechanisms?

Haploinsufficiency. STXBP1-related disorders are one of the most common neurodevelopmental disorders due to pathogenic variants in a single gene. Haploinsufficiency is the proposed disease mechanism and a significant number of individuals have deletions or protein-truncating variants. However, there are also recurrent missense variants in STXBP1, which is often seen in diseases that have a different disease mechanism. In a recent publication in Nature Communications, some of the recurrent variants in STXBP1 are suggested to have an additional disease mechanism, a dominant-negative effect. In this blog post, I want to discuss how we can reconcile both observations and whether STXBP1-related disorders are a single entity with a common disease mechanism. Continue reading

Big data, ontologies, and the phenotypic bottle neck in epilepsy research

Unconnected data. Within the field of biomedicine, large datasets are increasingly emerging. These datasets include the genomic, imaging, and EEG datasets that we are somewhat familiar with, but also many large unstructured datasets, including data from biomonitors, wearables, and the electronic medical records (EMR). It appears that the abundance of these datasets makes the promise of precision medicine tangible – achieving an individualized treatment that is based on data, synthesizing available information across various domains for medical decision-making. In a recent review in the New England Journal of Medicine, Haendel and collaborators discuss the need in the biomedical field to focus on the development of terminologies and ontologies such as the Human Phenotype Ontology (HPO) that help put data into context. This review is a perfect segue to introduce the increasing focus on computational phenotypes within our group in order to overcome the phenotypic bottleneck in epilepsy genetics. Continue reading

CACNA1E encephalopathy: a new calcium channel disease

The calcium connection. Pathogenic variants in genes encoding voltage-gated ion channels have long been known to cause neurological disorders in people. Dravet syndrome, caused by pathogenic variants in the neuronal sodium channel-encoding gene SCN1A, is one of the most common channelopathies. Although sodium and potassium channels play an established role in childhood-onset epilepsies, the role of voltage-gated calcium channels has been less clear. We have known for over a decade that disease-causing variants in CACNA1A cause a spectrum of neurological disorders, including developmental and epileptic encephalopathies. But evidence of a role for other neuronal calcium channels in epilepsy has been sparse until now. Our publication in the American Journal of Human Genetics now explores the phenotype and functional consequences of de novo variants in CACNA1E, representing a new and unexpectedly frequent disease entity.
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A critical step towards precision medicine – the ClinGen epilepsy gene curation

Clinical relevance. Pathogenic variants in more than 80 genes have been reported in childhood epilepsies over the last two decades. Developing precision therapies that target the underlying genetic changes is a major research focus and holds the promise to positively influence the lives of thousands of people with individually rare, but collectively common genetic epilepsies. However, in order to develop novel therapies, a formal, unbiased framework is needed to define whether the association between certain gene and disease is in fact valid and that a specific variant is truly pathogenic. This task has proven to be much more difficult than initially expected. Within the larger framework of the ClinGen Consortium, our epilepsy expert panel assesses the clinical validity of genes and variants for human epilepsies, starting with gene curation. In the recently published Human Mutation Special Issue on ClinGen/ClinVar, our panel reports our pilot data and reviews what it takes to connect two increasingly separate fields: the domain of traditional clinical epileptology and the rapidly evolving area of diagnostic genetic testing. Brace yourself: 50% of the alleged gene-disease associations evaluated in our pilot phase did not meet the criteria to be considered clinically valid. Continue reading