The novel gene dilemma

N-of-1. The use of whole exome sequencing has led to many of the recent genes discovered in the epilepsy field. However, in contrast to established genes or emerging genes that are found in several patients, there is a significant proportion of patients who carry de novo mutations in novel genes. In many cases, these novel genes look very suspicious. One aspect of a recent publication in Genetics in Medicine was to assess how these suspicious candidates convert to established genes over time. 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

How to get started in epilepsy genetics – The Channelopathist’s third birthday

Happy birthday. The Channelopathist turned three last week, i.e. exactly three years ago we started writing regular blog posts on epilepsy and genes, starting with a post on how SCN2A was rediscovered in neurodevelopmental disorders. Since we had many new subscribers last year, I thought that I could use this opportunity to write a brief post on how you can get started on Beyond The Ion Channel and how you can navigate our blog. 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

SETBP1, ZMYND11, and the power of joint exome and CNV analysis

Parallel worlds. There are two fields of genetics for neurodevelopmental disorders that currently produce large amounts of data – the field of copy number variation analysis and the field of exome sequencing. When assigning pathogenicity, information from both genetic technologies are rarely considered jointly. A recent study in Nature Genetics now performs a combined analysis of a large CNV and exome datasets in intellectual disability and autism. Interestingly, this method produces robust results, highlighting novel causative genes. Continue reading

Dynamin 1, the synapse, and why epilepsy gene discovery is now officially over

E2 consortium. Infantile Spasms and Lennox-Gastaut Syndrome are two epilepsy syndromes with a strong genetic component. De novo mutations play an important role in genetic epilepsies. However, given the overall mutational noise in the human genome, telling causative genes from innocent bystanders is difficult. In the largest and most comprehensive analysis so far, our E2 consortium just published a joint analysis of 356 patient-parent trios, which were analyzed by exome sequencing. In addition to implicating DNM1, GABBR2, FASN, and RYR3, this publication sends a clear message: the age of gene discovery in epilepsy is over – from now on, genes will find themselves. Let me tell you what I mean by this. Continue reading