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.
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

The IQSEC2 mystery – exploring the phenotype of an X-linked disease in males and females

The X-factor. Interpreting variants in X chromosome genes in a clinical context is an ongoing diagnostic challenge, regardless of whether the variant is identified in a male or female patient. The majority of X-linked conditions affect hemizygous male individuals, with heterozygous carrier girls and women largely unaffected or much less severely affected. PCDH19-Epilepsy is, of course, a notable rule breaker in this regard. However, we are learning that other X-linked conditions don’t play by the traditional rules either, and affected heterozygous females are being described for some other X-linked conditions. In some cases, including SMC1A– and NEXMIF– (formerly called KIAA2022) related disorders, the phenotypes in males versus females are more or less distinct. However, in other X-linked conditions, including IQSEC2-encephalopathy, both affected males and females share a continuum of similar features. A recent publication in Genetics in Medicine explores and expands the spectrum of IQSEC2-encephalopathy and delves into what is similar – and what is distinct – in affected male and female patients. Continue reading

Returning genetic results to research participants: challenges and opportunities

A successful partnership. Making progress in understanding the genetics of the epilepsies requires a successful partnership involving many players. Researchers, clinicians, patients, and families must work together in order to advance scientific goals. Since the first genetic etiology was discovered in a large family with Autosomal Dominant Nocturnal Frontal Lobe Epilepsy nearly 20 years ago, we have made many strides scientifically, in terms of technologies, our clinical classifications, and our knowledge of genetics. Our views on how we approach research from an ethical perspective is also continuing to evolve. Genetic research hinges on the participation of patients and families, and returning results to participants is increasingly viewed as imperative. A recent paper has used the Epilepsy Phenome/Genome Project (EPGP) and Epi4K studies as a case example of the challenges and opportunities regarding returning genetic results to research participants. Continue reading

Exploring the dark matter of the human genome – de novo mutations in regulatory elements

Unsolved cases. We are in an era of dramatic progress in understanding the genetic causes of neurologic disorders. In spite of this progress, many cases remain unsolved even after whole exome sequencing. One hypothesis for this missing heritability is that “non-coding” mutations outside the exome may explain at least some of these unsolved cases. A recent study looked at de novonon-coding variants in patients with neurodevelopmental disorders. The study sheds new light on this question and reminds us that, despite all the recent progress, there is much still to learn about vast portions of the genome. 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

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!

Continue reading

Five elements to include in your manuscript to get full ClinGen points

ClinGen Epilepsy Gene Curation Expert Panel. For the past year I have been a member of the ClinGen Epilepsy Gene Curation Expert Panel, which has been a rewarding professional experience. I have gotten to know several colleagues within the epilepsy and ClinGen communities, I’ve become familiar with resources for gene curation including MONDO and HPO, and I’ve dived deeply into the existing literature linking genes with a broad spectrum of epilepsies. But working with ClinGen has had another unexpected benefit – it has influenced my approach to writing scientific manuscripts. I have been able to apply this knowledge recently when writing a manuscript about a new causative gene for developmental and epileptic encephalopathies. In this post I would like to share five insider tips about what to include in your genetics manuscript so that it can receive full consideration from the ClinGen Epilepsy Expert Panel.
Continue reading