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

DNM1 encephalopathy – interneurons, endocytosis, and study group

Dynamin 1. De novo mutations in DNM1 coding for Dynamin 1 are increasingly recognized as a cause for epileptic encephalopathies. However, given the role of Dynamin 1 in endocytosis in a large number of cells, the precise mechanisms how mutations may result in seizures are poorly understood. Now two recent publications in PLOS Genetics and Neurology Genetics explore the functional effects of epilepsy-related DNM1 mutations. The publication of both manuscripts is also a timely reminder to announce our international DNM1 study group that has the aim to better understand the phenotype of this disease. Continue reading

Cause or coincidence – recessive SCN1A variants in Dravet Syndrome

Recessive epilepsies. Dravet Syndrome is one of the most prominent genetic epilepsies and presents in the first year of life with prolonged fever-associated seizures. Haploinsufficiency of SCN1A, either through mutations or deletions, is the major cause of Dravet Syndrome. In a recent publication in the European Journal of Pediatric Neurology, two families with recessive Dravet Syndrome and biallelic SCN1A variants are reported. Let’s have a look at how to interpret these findings. Continue reading

These are the top 10 epilepsy genes of 2014

Top 10. 2014 has been a very productive year in epilepsy gene discovery and with our final blog post this year, we wanted to provide a brief overview of what has been pertinent this year. From the multitude of novel genes identified this year, here are the 10 most relevant findings – including some genes that you probably didn’t expect. Continue reading

Heat at the synapse – STX1B mutations in fever-associated epilepsies

Febrile Seizures. The discovery of the genes for fever-associated epilepsies was one of the most relevant milestones in epilepsy genetics. Discovery of the underlying genes including SCN1A, SCN1B and GABRG2 was tightly linked to the development of the Genetic/Generalized Epilepsy with Febrile Seizures Plus (GEFS+) concept, describing the spectrum of epilepsy phenotypes seen in families with these mutations. Gene discovery in GEFS+, however, has slowed down in recent years, and no further causative genes had been identified for more than a decade. Now, in a recent paper in Nature Genetics, mutations in STX1B are found as a novel cause for fever-associated epilepsies. Continue reading