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

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