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

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

Changing the debate on epilepsy genetics – the ILAE Epilepsiome Task Force

Epilepsiome. Within the new structure of the ILAE Genetics Commission, the Epilepsiome has become a Task Force for the current term. Our blog has accompanied the developments in the field of neurogenetics for the last seven years and has seen the rise of next-generation sequencing and formal gene and variant curation frameworks. This has left us with a basic question: what is left to say? Should the future Epilepsiome simply chronicle what is happening in the field or should we try to use our platform to develop novel and potentially provocative thoughts? Within the current Epilepsiome Task Force, we decided to try the latter. There has been much attention paid to, and understandably much excitement about, the prospect of targeted precision treatments based on specific gene mutations. But could this be a Potemkin village based on unrealistic treatment expectations? What else is happening in the field of epilepsy genetics, outside the spotlight? We agreed that the new Epilepsiome Task Force will strive to emphasize a richer, globally oriented, and multifaceted view of the genetic basis of human epilepsies and neurodevelopmental disorders. Here are the three things that our Task Force hopes to accomplish. Continue reading

ARX – a 2017 Update

Aristaless. When you look at the genes for neurodevelopmental disorders identified in modern-day exome studies, one gene is notably absent: ARX. The X-chromosomal aristaless related homeobox gene was one of the first genes for epilepsies and brain malformations to be discovered. Pathogenic variants in ARX can be identified in male patients with a variety of neurodevelopmental disorders including idiopathic West Syndrome – accordingly, ARX is on the differential list for patients with intractable infantile spasms without a known cause. One of the reasons why we hear so little about ARX is the fact that this gene is poorly covered in exomes. Furthermore, one of the major disease-causing variants is a repeat expansion that cannot be assessed through exome studies at all. Here is a brief summary of what we know about ARX in 2017. Continue reading

MECP2 – Rett Syndrome in the era of exome-first studies

Rett. We have written very little about MECP2 on Beyond the Ion Channel. MECP2 is the gene for Rett Syndrome, a neurodegenerative disorder almost exclusively affecting females. Classical Rett Syndrome is characterized by developmental regression in the first two years of life and the development of distinctive hand movements, which historically led to Rett Syndrome being considered a recognizable entity. This blog post is the introduction to our MECP2 Epilepsiome page. However, in 2016, a time when many genes are re-defined by exome studies, I was wondering whether Rett Syndrome is still the classical syndrome that I initially learned about.

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SCN1A – what’s new in 2016?

The story of SCN1A. Variants in SCN1A were first reported in association with epilepsy in 2000, when familial heterozygous SCN1A missense variants were identified in two large families with GEFS+. The phenotype was characterized by incomplete penetrance and significant variable expressivity between family members, making it clear from the beginning that the SCN1A story would not be simple. Within the next few years, we learned that SCN1A variants could cause a wide spectrum of epilepsy phenotypes, including GEFS+, Dravet syndrome, intractable childhood epilepsy with generalized tonic-clonic seizures, and, less frequently, infantile spasms and simple febrile seizures. As it became clear that SCN1A variants played an important role in genetic epilepsies, focus turned towards understanding the mechanism underlying seizure genesis, as well as identifying management and therapy options. Even after 15 years of study, our understanding of SCN1A-related epilepsy is still evolving. Keep reading to learn more about the most recent discoveries related to SCN1A. Continue reading

TBC1D24 – what’s new in 2016?

The story of TBC1D24. As with many epilepsy genes, the TBC1D24 story increases in complexity over time. Initially described to be associated with autosomal recessive familial infantile myoclonic epilepsy by Falace and colleagues and with autosomal recessive focal epilepsy by Corbett and colleagues in 2010, pathogenic variants in TBC1D24 have since been identified as a major cause of DOORS syndrome and have also been identified in individuals with familial malignant migrating partial seizures of infancy, progressive myoclonus epilepsy, early-onset epileptic encephalopathy, and autosomal dominant and autosomal recessive non-syndromic hearing loss. However, little is known about a potential genotype-phenotype correlation of TBC1D24-related disorders, as well as the underlying mechanism. Keep reading to learn more about recent discoveries related to TBC1D24. Continue reading

Closing the knowledge gap – this is SYNGAP1

Mind the Gap. Ever since its discovery in 2009, SYNGAP1 has been a prominent gene connected to autism and intellectual disability. However, even though probably more than half of all patients with pathogenic SYNGAP1 variants have seizures, it was never a gene that was particularly prominent in the epilepsy field. In a recent publication, we were able to delineate the epilepsy phenotype of patients with pathogenic SYNGAP1 variants, identifying a peculiar combination of generalized seizures types. Here is a blog post about a gene that I admittedly knew very little about before we started working on it. Continue reading

PCDH19 – what’s new in 2016?

The story of PCDH19. The clinical features and unique inheritance pattern of PCDH19-related epilepsy were first described in 1971, and the clinical entity was coined Epilepsy in Females with Mental Retardation (EFMR), due to the presence of epilepsy and cognitive disability that seemed to be limited to females. Pathogenic PCDH19 variants were identified in females in 2008, and it soon became clear that PCDH19 is a major player in the genetic basis of epilepsy, with more than 100 patients with PCDH19 variants described to date. The inheritance pattern is one of the most striking features of this condition. Heterozygous females are affected, while hemizygous transmitting males are spared. At the cellular level, the disease mechanism seems to be loss of function. However, at the tissue level, the current hypothesis for the underlying mechanism is gain of function, resulting from the co-existence of two different PCDH19-expressing neuronal populations in females and mosaic males. Keep reading to learn more about recent discoveries related to PCDH19. Continue reading

What’s new with SCN8A – a 2016 update

An unexpected twist in the SCN8A story. SCN8A mutations were first implicated in epilepsy in 2012, when a de novo missense variant was identified in a patient with early infantile epileptic encephalopathy (EIEE) via genome sequencing. Since then, a number of patients with de novo heterozygous SCN8A variants and epilepsy have been reported, firmly establishing the role of SCN8A in EIEE, and we have learned a lot about the associated phenotype, mutation spectrum and disease mechanism within the last four years. Recently, a heterozygous familial SCN8A missense variant was identified in several families with a significantly milder epilepsy phenotype than reported in previous patients. Read further to learn more about the expanded SCN8A-associated epilepsy phenotype. Continue reading