V is for valine – VARS mutations in epileptic encephalopathy

Transfer RNAs. A critical step in translating a cDNA into proteins involves transfer RNAs (tRNAs) that deliver a specific amino acid to the ribosome based on a specific codon in the messenger RNA. Thereby, tRNAs establish the physical link between the mRNA and the amino acid sequence of the growing protein, an essential cellular function. In order for tRNAs to be loaded with the appropriate amino acids, the organism has developed enzymes specific for the individual amino acids that are referred to as tRNA ligases or, more precisely, aminoacyl tRNA synthetases (aaRS). Despite the ubiquitous role of aaRS in the cell, pathogenic variants in genes coding for specific aaRS result primarily in neurological phenotypes, ranging from peripheral neuropathy to early-onset epileptic encephalopathies. In two recent back-to-back publications, bi-allelic pathogenic variants in VARS are described as a novel cause for epileptic encephalopathy, adding VARS to the list of aaRS genes linked to human disease and solving an almost decade-old mystery. 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

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

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

A polygenic trickle of common variants in neurodevelopmental disorders

Common variants. In addition to the gradual increase in gene discovery due to exome sequencing, there is a field of human genetics developing in parallel that we have not paid much attention to recently. The role of common genetic variants or Single Nucleotide Polymorphisms (SNP) was initially limited to genome-wide association studies, looking at single variants individually. However, more recently, common variants have been assessed jointly in various diseases, resulting in so-called polygenic scores. In a recent publication in Nature, the polygenic contribution to neurodevelopmental disorders is evaluated. Interestingly, there seems to be a very robust contribution of common variants in neurodevelopmental disorders, even in patients with known de novo variants. Here is a brief discussion on why common variants start getting interesting for the neurogenetics field again. Continue reading

The GABA link in Genetic Generalized Epilepsy

GGE. The Genetic Generalized Epilepsies (GGE) are common epilepsies in children and adults with a prominent genetic contribution. However, genetic risk factors for GGE have been more difficult than most researchers would have expected to pin down. Genome-wide association studies for common variants and association studies for ultra-rare variants have been able to identify several candidate genes, but much of the genetic risk for GGE remain unaccounted for. In a recent study in Lancet Neurology, we have tried a different approach to address the genetic contribution for GGE, looking at gene groups rather than single genes. Using this approach, we were able to detect a signal that would not have been found when looking at individual genes alone, a contribution of rare variants in genes for GABA-A receptors that reliably spans across three different cohorts. 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

Three things the beach told me about science in 2018

Baggersee. With an unprecedented heat wave hitting the northern hemisphere, I eventually found my annual vacation blog post. I wrote blog posts about our beach vacation in Marielyst, Denmark, or Rehoboth Beach, Delaware. However, this year, it took me the better part of two weeks to realize that I had this year’s beach right beneath my feet – the small artificial beach of the Rossenray Lake, a small lake in my home town in Germany where we spent our summer vacation. And here are the three things the beach (and the lake) told me about science in 2018. Continue reading